Preparation method of epinephrine

Abstract

The invention provides a novel method for preparing epinephrine, which comprises the following steps of: condensing catechol serving as an initial raw material with 2-(benzyl-methyl-amino) acetic acid to obtain 2-(benzyl methyl amino)-3 ', 4'-dihydroxyacetophenone hydrochloride, performing hydrogenation reduction to obtain racemic epinephrine, performing salification resolution with L-tartaric acid, and finally regulating the pH value to 8-9 by using ammonia water to obtain the epinephrine. According to the method, 2-(benzyl-methyl-amino) acetic acid is selected as a starting material instead of chloroacetic acid in a traditional process, and two steps of chloroacetylation and methylamine in the traditional process are combined into one step, so that the environmental problem caused by the use of chloroacetic acid and monomethylamine is avoided, the reaction steps are reduced, and the yield is increased; in addition, benzyl serving as a protecting group can be synchronously removed along with reduction of carbonyl in the catalytic reduction process, so that the risk caused by multi-step hydrogenation is avoided; and finally, the racemized isomer is obtained by recycling the resolution mother liquor and then salified with L-tartaric acid for resolution and recovery of the product, so that the yield is increased, the cost is reduced, and the method has excellent industrial production and application prospects.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of adrenaline. Starting from catechol, it is condensed with 2-(benzyl-methyl-amino) acetic acid to obtain 2-(benzylmethylamino)-3’,4’-dihydroxyacetophenone hydrochloride, which is then catalytically hydrogenated and reduced to obtain racemic adrenaline, and then L resolved by salification with (-)-tartaric acid, and finally the pH is adjusted to 8-9 with ammonia water to obtain adrenaline. Background Art

[0002] Adrenaline, also known as epinephrine and suprarenine, is a hormone secreted by chromaffin cells in the adrenal medulla. This product directly acts on adrenaline α and β receptors, producing a strong, rapid and short-lived excitement. The excitement of the β1-receptor of the heart can enhance myocardial contractility, increase heart rate and myocardial oxygen consumption. At the same time, it acts on the β2-receptor of vascular smooth muscle, dilates blood vessels, reduces peripheral vascular resistance and decreases diastolic blood pressure. Exciting the β2-receptor can relax bronchial smooth muscle, dilate the bronchi and relieve bronchospasm; exciting the α-receptor can constrict the blood vessels of the skin, mucous membranes and internal organs. Clinically, it is mainly used for cardiac arrest, bronchial asthma, anaphylactic shock, and can also treat urticaria, hay fever and nasal or gingival bleeding. It is an essential product for saving dying people or animals. Its biosynthesis mainly first forms norepinephrine in each cell of the medulla, and then further undergoes the action of N -methyltransferase ( phenylethanolamine N-methyl transferase, PNMT ), which methylates norepinephrine to form adrenaline. The structural formula of adrenaline is as follows: .

[0003] Adrenaline has two chiral isomers, namely R- adrenaline and S- adrenaline. Research has found that the biological activities of these two isomers are different, R- adrenaline is the isomer with the strongest biological activity, while S- adrenaline has no biological activity.

[0004] Currently, the reported synthetic routes of adrenaline are mainly as follows: Route 1: (Compilation of National API Processes, State Medicine Administration, 1980, 491, 502): Catechol and chloroacetic acid react in the presence of phosphorus oxychloride to form chloroacetylcatechol, which then undergoes an amination reaction with monomethylamine and salifies with hydrochloric acid to obtain adrenaline ketone hydrochloride. After catalytic hydrogenation with palladium-carbon and pH adjustment, racemic adrenaline is formed, and then it is resolved by L-tartaric acid and the pH is adjusted with ammonia water to obtain adrenaline. The synthetic route is as follows: .

[0005] Route 1 has a long route, cumbersome operation and low yield. In addition, phosphorus oxychloride and monomethylamine are used, which pollute the environment and are not conducive to labor operation.

[0006] Route 2: (CN1368949A) Asymmetric reduction is carried out with [Rh(COD)Cl2]2 / (2R,4R)-4-(dicyclohexylphosphino)-2-(diphenylphosphino-toluene)-N-methyl-aminocarbonyl-pyrrolidine as the catalyst, and then palladium on carbon is used for reduction to remove the benzyl protection. This synthesis process requires two-step hydrogenation, and the rhodium catalyst is difficult to obtain, so the cost is high and the safety risk is large, which is not suitable for large-scale industrial production.

[0007] Therefore, it is urgent to research and develop a new method for preparing adrenaline with a short synthesis route, high yield, environmental friendliness, convenient operation, etc. Summary of the Invention

[0008] To overcome the defects existing in the prior art, the present invention provides a new method for preparing adrenaline. This method uses catechol as the starting material, condenses with 2-(benzyl-methyl-amino)acetic acid under the action of auxiliary reagents, then undergoes catalytic hydrogenation and deprotection to obtain racemic adrenaline, and finally L- is salted and resolved with tartaric acid, and the pH is adjusted to 8-9 to obtain adrenaline. This method has the characteristics of short synthesis route, high yield, environmental friendliness, convenient operation, etc. Especially, the yield is greatly improved by recovering the racemized isomers from the mother liquor, which is suitable for industrial production.

[0009] To achieve the above object, the present invention adopts the following technical scheme: A method for preparing adrenaline, which uses catechol as the starting material, condenses with 2-(benzyl-methyl-amino)acetic acid under the action of auxiliary reagents, then undergoes catalytic hydrogenation and deprotection with palladium on carbon, etc. to obtain racemic adrenaline, and then L- is salted and resolved with tartaric acid, and finally the pH is adjusted to 8-9 with ammonia water to obtain adrenaline; the mother liquor after resolution is racemized in an acidic system to recover the racemate, and the product can also be obtained by continuing the resolution. The specific steps are as follows: 1) Under the protection of an inert gas (such as nitrogen, argon, etc.), catechol and 2-(benzyl-methyl-amino)acetic acid are condensed in a first reaction solvent under the action of auxiliary reagents to obtain 2-(benzylmethylamino)-3',4'-dihydroxyacetophenone hydrochloride; 2) Under the conditions of an inert gas (such as nitrogen, argon, etc.) and purified water, 2-(benzylmethylamino)-3',4'-dihydroxyacetophenone hydrochloride is catalytically hydrogenated and reduced to obtain racemic adrenaline; 3) Under the conditions of an inert gas (such as nitrogen, argon, etc.) and a second reaction solvent, racemic adrenaline reacts with L-The tartaric acid is used for salt formation and resolution, and finally the pH is adjusted to 8-9 with ammonia water to obtain epinephrine.

[0010] The synthesis route of the epinephrine described in the present invention is as follows: 。

[0011] Specifically, the auxiliary reagent in step 1) can be phosphorus oxychloride, thionyl chloride, etc., preferably phosphorus oxychloride; the molar ratio of the auxiliary reagent to catechol can be 0.6-0.8:1, preferably 0.7:1. In step 1), the molar ratio of 2-(benzyl-methyl-amino)acetic acid to catechol can be 1.05-1.25:1, preferably 1.1:1.

[0012] Furthermore, in step 1), the first reaction solvent can be one or a mixture of two or more of inert solvents such as chloroform, dichloromethane, dichloroethane, etc., preferably chloroform. The addition amount of the first reaction solvent is 2-5 times the mass of catechol. In step 1), the condensation reaction temperature can be 60-70 °C, and the reaction time can be 6-8 hours.

[0013] Specifically, in step 2), the catalyst used in the catalytic hydrogenation reduction is a noble metal such as palladium on carbon, platinum or nickel, preferably palladium on carbon. The addition amount of the catalyst can be 3-7% of the mass of 2-(benzylmethylamino)-3',4'-dihydroxyacetophenone hydrochloride, preferably 5%. The addition amount of purified water can be 1.5-4 times the mass of 2-(benzylmethylamino)-3',4'-dihydroxyacetophenone hydrochloride. Furthermore, in step 2), the pressure during the catalytic hydrogenation reduction is 0.2-1.0 MPa, preferably 0.5-0.8 MPa; the reaction temperature is 40-50 °C; the reaction time is 5-7 hours.

[0014] Specifically, in step 3), L- The molar ratio of tartaric acid to racemic epinephrine can be 1.1-1.2:1, preferably 1.15:1. Furthermore, in step 3), the second reaction solvent can be one of methanol, acetone, ethanol, etc., preferably methanol. The addition amount of the second reaction solvent can be 3-5 times the mass of racemic epinephrine.

[0015] As a preference, the preparation method of the epinephrine further includes step 4) recycling the epinephrine in the mother liquor of salt formation and resolution through racemization, and the specific operation is as follows: under the protection of an inert gas (such as nitrogen, argon, etc.), the mother liquor of resolution is adjusted to pH 8-9 with a weak base, cooled, crystallized, and filtered to obtain epinephrine S- isomers, which generate epinephrine racemates under the catalysis of strong acid, and then S- are re-salt-formed and resolved with tartaric acid to obtain the recycled epinephrine; the reaction is as follows: L- 。 。

[0016] Further, in step 4), the weak base used can be ammonia water or sodium carbonate, etc., preferably ammonia water; the strong acid used for racemization can be strong acids such as hydrochloric acid or sulfuric acid, preferably hydrochloric acid.

[0017] Compared with the prior art, the synthesis method of the present invention has the following advantages and beneficial effects: 1) In the present invention, 2-(benzyl-methyl-amino)acetic acid is selected as the starting material instead of chloroacetic acid in the traditional process. In this way, the two steps of chloroacetylation and methylamination in the traditional process can be combined into one step, avoiding the environmental problems caused by the use of chloroacetic acid and monomethylamine, reducing the reaction steps, and improving the reaction yield (it is found that phenolic compounds are easily oxidized into quinone substances under alkaline conditions, and the yield of the amination reaction in the traditional process is only about 30%); 2) The present invention selects benzyl as the protecting group. During the catalytic hydrogenation process, as the carbonyl group is reduced, the benzyl group naturally falls off, making full use of the characteristics of catalytic reduction and avoiding the risks brought by multi-step hydrogenation; 3) Epinephrine has optical isomerism. Only R- isomer has physiological effects ，S- isomer has no biological activity. During the hydrogenation reduction process, the R configuration and S configuration are theoretically each 50%. Therefore, half of the S configuration epinephrine will be contained in the mother liquor obtained by resolution. This is also the main reason for the low synthesis yield of epinephrine. If the S configuration epinephrine in the mother liquor can be recovered and converted into R configuration, the yield will increase significantly. The present invention converts the S configuration isomer into R configuration through racemization, thereby improving the yield and output and saving costs; 4) The materials used in the present invention are environmentally friendly and non-toxic, and have the characteristics of short route, economic practicality, high yield, etc. during the synthesis process, and are suitable for industrial production. Specific Embodiments

[0018] The technical solutions of the present invention are further described in detail below in combination with the following examples, but the protection scope of the present invention is not limited thereto.

[0019] In the following examples, unless otherwise specified, the raw materials used are all ordinary commercially available products that can be directly purchased or can be prepared by using conventional techniques in the art. Room temperature refers to 25 ± 5 °C.

[0020] In the following examples, the synthesis route of epinephrine is shown as follows: 。

[0021] Example 1 Preparation of Compound 4 (2-(Benzylmethylamino)-3’,4’-dihydroxyacetophenone Hydrochloride) Under nitrogen protection, 100 g (0.91 mol) of catechol (Compound 2), 179.2 g (1.0 mol) of 2-(Benzyl-methyl-amino)acetic acid (Compound 3), and 300 g of chloroform were added to a dry 1000 ml three-necked flask. The temperature was raised to reflux, and 97.7 g (0.64 mol) of phosphorus oxychloride was slowly added dropwise to the system. After the addition was complete, the temperature was controlled at 60 - 70 °C and the reaction was carried out for 6 hours. Then a sample was taken for TLC monitoring until the reaction was completed (Developing agent: Dichloromethane:Methanol = 30:1, V:V, and the disappearance of the catechol spot was the end point of the reaction). After the reaction was completed, 200 ml of purified water was added to the system and stirred for 30 minutes. After standing for liquid separation, the chloroform layer was separated. The pH of the aqueous layer was adjusted to 8 - 9 with ammonia water (about 21 g), and the temperature was lowered to 0 - 10 °C. Stirring and crystallization were carried out for 4 hours, followed by suction filtration. The filter cake was washed with water and then added to 100 g of absolute ethanol. It was heated to 65 °C to dissolve completely, and the pH was adjusted to 1 - 2 with hydrochloric acid (about 60 g). Stirring was carried out for 2 hours, followed by suction filtration. The filter cake was dried in vacuo at 50 °C to obtain 182 g of 2-(Benzylmethylamino)-3’,4’-dihydroxyacetophenone Hydrochloride (Compound 4), with a yield of 65%.

[0022] Example 2 Preparation of Compound 5 (Racemic Epinephrine) Under nitrogen protection, 182 g (0.59 mol) of 2-(Benzylmethylamino)-3’,4’-dihydroxyacetophenone Hydrochloride (Compound 4) and 364 g of purified water were added to a 1000 ml hydrogenation autoclave. The temperature was raised until it was completely dissolved. 9.1 g of 10% palladium on carbon catalyst was added. After the air in the autoclave was replaced and sealed, hydrogen was introduced until the pressure in the autoclave reached 0.7 MPa. The temperature was raised to 45 °C and stirring reaction was carried out until no more hydrogen was absorbed (about 6 hours). After the reaction was completed, the hydrogen in the autoclave was replaced. The palladium on carbon was washed with 50 g of purified water, and the filtrates were combined and transferred to a 1000 ml three-necked flask. Under nitrogen protection, the temperature was stirred and lowered to below 30 °C. The pH was adjusted to 8 - 9 with ammonia water (about 13 g), and crystallization was carried out by stirring at 0 - 10 °C for 1 h. Filtration was carried out, and the filter cake was washed with 75 g of purified water and then with 60 g of absolute ethanol. It was dried in vacuo at 45 °C for 8 hours to obtain 78.2 g of Racemic Epinephrine (Compound 5), with a yield of 71.1%.

[0023] Example 3 Preparation of Compound 1 (Epinephrine) Under nitrogen protection, 78 g (0.43 mol) of Racemic Epinephrine (Compound 5) and 75 g L-Tartaric acid (0.50 mol) and 280 g of methanol were stirred and dissolved. The temperature was controlled at 15 - 20 °C for crystallization for 10 - 12 hours, then filtered, and the filter cake was washed thoroughly with 156 g of methanol (the filtrate was recovered, i.e., the mother liquor 1 for splitting was separated). Under nitrogen protection, the above-mentioned filter cake and 200 g of purified water were added to a three-necked flask, heated to 50 °C, 3 g of medicinal charcoal was added for decolorization for 30 min, filtered while it was hot, the filtrate was cooled to below 20 °C, and the pH was adjusted to 8 - 9 with ammonia water (about 9 g), then filtered, and the filter cake was washed with 135 g of purified water to obtain the wet product of the epinephrine split product. To improve the product purity, the obtained wet product of the epinephrine split product was salified and split again with L- tartaric acid as follows: Under nitrogen protection, the wet product of the split product, 48 g of L- tartaric acid and 175 g of methanol were added to a 250 ml three-necked flask. After stirring and dissolving, the temperature was controlled at 15 - 20 °C for crystallization for 8 - 10 hours, then filtered, and the filter cake was washed thoroughly with 93 g of methanol (the filtrate was recovered, i.e., the mother liquor 2 for splitting was separated). Under nitrogen protection, the above-mentioned filter cake and 150 g of purified water were added to a three-necked flask, heated to 50 °C, and then 2 g of medicinal charcoal was added for decolorization for 30 min, filtered while it was hot, the filtrate was cooled to below 20 °C, and the pH was adjusted to 8 - 9 with ammonia water (about 5 g), then filtered, first washed with 120 g of purified water, and then washed with 85 g of methanol to obtain the wet product of epinephrine. It was dried in vacuum at 40 - 50 °C for 8 - 10 hours to obtain 17 g of pure epinephrine with a yield of 22%. Tested according to the second part of the Chinese Pharmacopoeia 2020 standard: the content was 99.5%, and the specific rotation was -52.0°.

[0024] 1 HNMR (Bruker, 400 MHz, D2O, δ ): 6.71 - 6.82 (3H, m), 4.79 - 4.81 (1H, m), 3.13 - 3.14 (2H, m), 2.64 (3H, t). Note: The sample used for NMR was epinephrine tartrate.

[0025] Example 4 S- Racemization and recovery of epinephrine The mother liquor for splitting obtained in Example 3 (combining mother liquor 1 and 2 for splitting) was adjusted to pH 8 - 9 with ammonia water under nitrogen protection, cooled to 0 - 10 °C, stirred for crystallization for 1 hour, and filtered to obtain the filter cake of epinephrine S-Isomer. The filter cake, 115 g of purified water, and 66 g of concentrated hydrochloric acid were added to a three-necked flask, heated to 100 °C under nitrogen protection, stirred and refluxed for 24 hours, cooled to 0 - 10 °C, adjusted to pH 8 - 9 with ammonia water, stirred and crystallized for 6 - 8 hours, filtered, and the filter cake was washed with 90 g of methanol to obtain racemic adrenaline. Resolution was carried out by referring to the method for preparing Compound 1 (Example 3), and vacuum dried at 40 - 50 °C for 8 - 10 hours to obtain 13 g of recovered pure adrenaline with a content of 99.2% and a specific rotation of -51.7°.

[0026] Through the above racemization recovery, the resolution yield of adrenaline was increased to 38% (calculated based on Compound 5).

Claims

1. A method for preparing adrenaline, characterized in that: The following steps are involved: 1) Under the protection of inert gas, catechol and 2-(benzyl-methyl-amino)acetic acid are subjected to condensation reaction in the first reaction solvent with the help of auxiliary reagents to obtain 2-(benzylmethylamino)-3',4'-dihydroxyacetophenone hydrochloride; 2) In the presence of inert gas and purified water, 2-(benzylmethylamino)-3',4'-dihydroxyacetophenone hydrochloride is catalytically hydrogenated and reduced to obtain racemic epinephrine; 3) In the presence of an inert gas and a second reaction solvent, racemic adrenaline reacts with L- The tartaric acid salt is split and the pH is adjusted to 8-9 to obtain adrenaline.

2. The method for preparing adrenaline according to claim 1, characterized in that: The auxiliary reagent in step 1) is phosphorus oxychloride or thionyl chloride; the molar ratio of the auxiliary reagent to catechol is 0.6-0.8:

1.

3. The method for preparing adrenaline according to claim 1, characterized in that: In step 1), the molar ratio of 2-(benzyl-methyl-amino)acetic acid to catechol is 1.05-1.25:

1.

4. The method for preparing adrenaline according to claim 1, characterized in that: In step 1), the first reaction solvent is one of chloroform, dichloromethane, and dichloroethane, or a mixture of two or more of them in any proportion.

5. The method for preparing adrenaline according to claim 1, characterized in that: In step 1), the condensation reaction temperature is 60-70° C., and the reaction time is 6-8 hours.

6. The method for preparing adrenaline according to claim 1, characterized in that: In step 2), the catalyst used in the catalytic hydrogenation reduction is palladium on carbon, platinum or nickel.

7. The method for preparing adrenaline according to claim 1, characterized in that: In step 2), the pressure during catalytic hydrogenation reduction is 0.2-1.0 MPa; the reaction temperature is 40-50° C.; and the reaction time is 5-7 hours.

8. The method for preparing adrenaline according to claim 1, characterized in that: In step 3), L- The molar ratio of tartaric acid to racemic adrenaline is 1.1-1.2:

1.

9. The method for preparing adrenaline according to claim 1, characterized in that: In step 3), the second reaction solvent is one of methanol, acetone and ethanol.

10. The method for preparing adrenaline according to claim 1, characterized in that: The method also includes step 4), wherein the pH value of the split mother liquor is adjusted to 8-9 with a weak base under the protection of an inert gas, and the mixture is cooled, crystallized, and filtered to obtain adrenaline. S- Isomers, under the catalysis of strong acid to generate adrenaline racemate, and then L- The adrenaline can be recovered by re-salting tartaric acid; The weak base used is ammonia water or sodium carbonate; the strong acid used is hydrochloric acid or sulfuric acid.