Epinephrine Hydrochloride is a white crystalline powder. Its appearance can be judged by observing its color, shape and size. The appearance of DL-ADRENALINE HYDROCHLORIDE is the result of factors such as purity, method of preparation and storage. Soluble in water, can form a clear solution. It is also soluble in some organic solvents such as methanol and chloroform. Its solubility is related to temperature and pH value. The refractive index is 1.57. The index of refraction is the degree to which light is deflected when it travels from air to a material. The measurement of the refractive index can be used to determine the purity and structure of substances. is an important compound used in biological, medical and chemical research. The drug of this end product is widely used in the treatment of diseases of the cardiovascular system, asthma treatment, local anesthesia and other treatment methods. However, it should be noted that this product is a primary chemical product and is only used for scientific research purposes.
This article will discuss several synthetic methods of DL-epinephrine hydrochloride:
1. Noradrenaline to Adrenaline to DL-epinephrine hydrochloride synthesis method:
This synthesis method needs to start from Noradrenaline, and through an intermediate compound (4-Methoxyphenylacetone), under the catalysis of food additives, two reactions convert Noradrenaline into Adrenaline. Adrenaline is then subjected to alkylation and N-Boc deprotection with protection of the OH group to give DL-adrenaline hydrochloride.
1.1. Synthesis of Noradrenaline to Adrenaline:
Noradrenaline is an important neurotransmitter, and its synthetic pathway in the human body is mainly through the action of dopamine β-hydroxylase to catalyze the conversion of dopamine. Copper ions in dopamine β-hydroxylase play an important catalytic role in this reaction. During this reaction, dopamine is oxidized to dopaic acid under the catalysis of carboxylase, and then converted into Noradrenaline under the catalysis of dopamine β-hydroxylase.
The structure of Noradrenaline is very similar to that of Adrenaline, except that there is an extra hydroxyl group in the molecular structure. Therefore, on the basis of Noradrenaline, Adrenaline can be obtained only by oxidizing hydrogen atoms to hydroxyl groups through enzymatic reactions.
1.2. Synthesis of Adrenaline to DL-epinephrine hydrochloride
Adrenaline is a compound with important pharmacological activities, so it has been widely used in the field of modern medicine. However, both chiral centers in Adrenaline are asymmetric, so it has two isomers, namely left-handed and right-handed. In addition, the pharmacological activities of these two isomers are quite different. Therefore, special attention should be paid to controlling the chiral selectivity when preparing Adrenaline.
The synthetic steps of DL-epinephrine hydrochloride are as follows:
(1) Oxidation of Adrenaline to DL-epinephrine by N-hydroxysuccinimide as an oxidizing agent:
During this process, DL-epinephrine was first added to N-hydroxysuccinimide dissolved in acetone, stirred slowly and heated to 62-64°C during the addition, and the reaction conditions were maintained for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the produced amino acid was filtered off, and the produced DL-epinephrine hydrochloride was separated from the reaction solution by concentrated HCl.
(2) Purification of DL-epinephrine hydrochloride:
By adding a mixed solution of anhydrous hydrochloric acid and ethanol to the reaction product, the DL-adrenaline hydrochloride is purified to obtain crystals of the DL-adrenaline hydrochloride.
In summary, the synthesis of Epinephrine Hydrochloride is basically divided into two steps, the first is to oxidize Noradrenaline to Adrenaline, and then oxidize Adrenaline to DL-epinephrine hydrochloride. In order to obtain high-purity DL-epinephrine hydrochloride, multiple steps of separation and purification are required.
2. Pyrocatechol is the synthetic method of raw material:
The Carandiz synthesis is a common method for the preparation of DL-epinephrine hydrochloride using Pyrocatechol as a starting material. The steps of the method are: hydrolyzing Pyrocatechol with FeCl3 to Hydroquinone, and then carrying out condensation reaction of Hydroquinone and Glyoxylic acid to generate DL-adrenaline ketal. The ketal is reduced to DL-epinephrine, and then acidified with HCl to synthesize DL-epinephrine hydrochloride.
Part 1: Synthesis of Pyrocatechol
Step 1: Oxidation of resorcinol to benzoquinone
1000 mL of water was added to the three-necked flask, and then 0.05 mol of CuSO4 was added. Slowly add 1 mol of NaOH to pH 8 while stirring. Next, 0.25 mol of resorcinol was added to the flask and stirred, then heated to 80°C. Add 0.05mol of CuSO4 in batches 3 times, and continue heating and stirring. During the course of the reaction, a yellow-brown flocculent precipitate was observed. After the reaction was complete, the solid was filtered and washed, then dried and pulverized into a powder.
Step 2: Reduction of benzoquinone to Pyrocatechol
1000 mL of water was added into the three-necked flask, then 0.5 mol of NaBH4 was added, and the solution was stirred for 30 min. While stirring, 0.25 mol of benzoquinone was slowly added. As the addition progressed, changes in reaction kinetics and color were observed. When the reaction solution showed an obvious brown-red color, the pH value was adjusted to 4-5 with 1 mol of HCl. Then, the product is filtered and washed, and dried to obtain Pyrocatechol.
Part 2: Synthesis of Epinephrine Hydrochloride
Step 1: Convert Pyrocatechol to 3,4-dihydroxyphenylethanol
The reaction used the Cannizzaro reaction. Dissolve the calculated amount of Pyrocatechol in 500 mL of water, slowly add 1.2 mol of formaldehyde, and finally add 1 mol of NaOH. Stir and heat to 90°C and observe the color change of the sample. After the reaction was completed, the reactant was cooled and filtered, and then the solution was adjusted to pH 6-7. Then recrystallize with ethanol to get 3,4-dihydroxyphenylethanol.
Step 2: Convert 3,4-dihydroxyphenylethanol to Epinephrine Hydrochloride
First, dissolve 1mol of 3,4-dihydroxyphenylethanol in 1000ml of water, and then add an appropriate amount of NaOH to make it alkaline. Heat it to 60°C and stir, then slowly add an appropriate amount of I2, and observe the color change of the reaction solution during the reaction. When the reaction is over, it is heated to 90°C, and HCl is added to adjust it to acidity (pH≈4), and then recrystallized with ethanol to obtain Epinephrine Hydrochloride.
At this point, we have successfully prepared Epinephrine Hydrochloride. Purification, determination of its physical and chemical properties and comparison with known Epinephrine Hydrochloride can ensure that the quality of the prepared drug meets the requirements.
3. 2,5-Dihydroxybenzoic acid ester is the synthetic method of raw material:
The synthesis starts with 2,5-dihydroxybenzoate and esterifies it with Ac2O. Subsequently, it is converted to DL-epinephrine hydrochloride through a series of steps including hydroxyalkylation, deprotection, tautomerization, glutamination, etc. This method has a certain yield and purity.
The preparation method of the 2,5-dihydroxybenzoate of Epinephrine Hydrochloride can generally be divided into the following steps:
3. 1. Esterify 2,5-dihydroxybenzoic acid with HCl to obtain 2,5-dihydroxybenzoic acid oxychloride.
3. 2. Reaction of 2,5-dihydroxybenzoic acid hydroxychloride with CDI (1,1'-carbonyldiimidazole) in THF forms a CDI-activated intermediate.
3. 3. React Epinephrine with CDI intermediate in THF to generate 2,5-dihydroxybenzoate.
3. 4. Purification of 2,5-dihydroxybenzoate can be carried out by recrystallization or column chromatography.
It should be noted that the selection of chemical reagents, the control of operating conditions and other details will affect the selectivity and yield of the reaction, and the preparation of 2,5-dihydroxybenzoate of Epinephrine Hydrochloride needs to be handled carefully to ensure the yield and synthesis efficiency. At the same time, the reaction operation involving chemical reagents has certain risks, and it needs to be carried out in a professional laboratory, and the necessary safety measures should be paid attention to.
4. D, L-phenylalanine is the synthetic method of raw material:
This approach is based on the detection of the comfort of D,L-phenylalanine residues by Fourier transform infrared spectroscopy and other structural characterization methods. For example, first by esterifying D,L-phenylalanine to the corresponding methyl ester, and then through a series of reduction and hydroxylation reactions, 6-hydroxyadrenaline is transformed into the structure of DL-adrenaline. This method has the advantages of high yield and high purity.
Overall, DL-epinephrine hydrochloride is a very important compound widely used in biomedical, pharmaceutical and chemical research. Several synthetic methods listed above are all mainstream methods at present. When selecting a particular method, factors such as cost feasibility, yield, time required, and detection methods need to be considered.