阅读说明：本技术 一种(±)-肾上腺素的制备方法 (Method for preparing (+/-) -adrenaline ) 是由 路佛云 靳磊 王全刚 杜振军 廖健宇 黄浩喜 苏忠海 于 2021-10-26 设计创作，主要内容包括：本发明将甲酸盐作为氢供体,钯碳作为催化剂,在反应液pH为2.0～4.0,氮气条件下,将肾上腺酮盐酸盐还原为(±)肾上腺素。这种合成方法具有收率高、简易安全、生产成本低、可大规模工业生产的特点。(The method takes formate as a hydrogen donor, palladium carbon as a catalyst, and reduces the adrenal ketone hydrochloride into (+/-) epinephrine under the conditions that the pH of a reaction liquid is 2.0-4.0 and nitrogen gas. The synthesis method has the characteristics of high yield, simplicity, safety, low production cost and large-scale industrial production.)

1. A process for preparing (+/-) -adrenaline features that the adrenalone compound is used as raw material, hydrogen donor and Pd catalyst are added, and the (+/-) -adrenaline is synthesized under acidic condition.

2. The method of claim 1, comprising the steps of:

(1) an adrenone compound, a hydrogen donor, and water; (2) adjusting the pH value to 2.0-4.0 by using acid liquor; (3) reacting under inert atmosphere by using a palladium catalyst; (4) filtering out the palladium catalyst, adjusting the pH value of the reaction system to 8.2-8.5 by using alkali liquor under an inert atmosphere, stirring, and removing liquid to obtain the (+/-) -adrenaline.

3. The process according to claim 1 or 2, wherein the adrenergic compound is an free base of adrenergic, a hydrochloride salt of adrenergic, a formate salt of adrenergic, a tartrate salt of adrenergic, a sulfate salt of adrenergic, a phosphate salt of adrenergic, a camphorsulfonate salt of adrenergic, an ascorbate salt of adrenergic, a malate salt of adrenergic, a methanesulfonate salt of adrenergic, a nitrate salt of adrenergic, an aspartate salt of adrenergic, a hydroiodide salt of adrenergic, a hydrobromide salt of adrenergic, preferably a hydrochloride salt of adrenergic.

4. The method according to claim 1 or 2, wherein the hydrogen donor is one of sodium formate, ammonium formate, potassium formate and calcium formate, preferably sodium formate.

5. The method according to claim 1 or 2, wherein the pH in the step (2) is 2.0 to 4.0, preferably 2.6 to 3.9, more preferably 3.6 to 3.8.

6. The production method according to claim 1 or 2, wherein the palladium catalyst is palladium on carbon.

7. The method according to claim 1 or 2, wherein the mass ratio of the palladium catalyst to the adrenal ketone hydrochloride is 0.08:1 to 0.15:1, preferably 0.08: 1.

8. The method according to claim 1 or 2, wherein the mass ratio of the adrenal ketone hydrochloride to the formate is 1:1.2 to 1:3.5, preferably 1: 3.1.

9. The process according to claim 1 or 2, wherein the acid solution is concentrated hydrochloric acid, formic acid solution, acetic acid solution, nitric acid solution, phosphoric acid solution, sulfuric acid solution, preferably concentrated hydrochloric acid.

10. The method according to claim 1 or 2, wherein in the step (4), the alkali solution is sodium hydroxide solution, potassium hydroxide solution, sodium bicarbonate solution, sodium carbonate solution, potassium carbonate solution, ammonia water, preferably ammonia water.

Technical Field

The invention relates to the technical field of medicines, in particular to a method for preparing (+/-) -epinephrine.

Background

Adrenaline (Adrenaline or Epinephrine), also known as rennin and rennin, is extracted from the adrenal medulla of domestic animals (cattle and sheep) or synthesized by artificial method, is white or quasi-white crystalline powder, and has agonistic effect on alpha and beta receptors. The traditional Chinese medicine composition is mainly used for treating anaphylactic shock, cardiac arrest, bronchial asthma, urticaria, hay fever and nasal mucosa or gingival bleeding in clinic, and can also relieve symptoms such as weak heartbeat, blood pressure reduction and dyspnea. The structural formula is shown as (I):

there is one chiral center in the epinephrine molecule, so there are two enantiomers, R-epinephrine and S-epinephrine, among which R-epinephrine, which is physiologically active, is generally obtained by resolution of (±) -epinephrine. Therefore, it is necessary to develop a safe, efficient and industrial process route for producing (+/-) -epinephrine. Patent WO2016038422a1 discloses a process for the preparation of (+/-) -epinephrine by direct reduction of an epinephrine hydrochloride to (+/-) -epinephrine using hydrogen as a reducing agent under the action of palladium hydroxide. In the route, the raw materials contain hydrochloride, so that the raw materials have a corrosion effect on a hydrogenation kettle, and the direct use of hydrogen requires the professional to carry out post operation on a special operation certificate in a hydrogenation workshop, so that great potential safety hazards exist in industrial production. In addition, the reaction time of the process is long, and more than 16 hours are needed; the molar yield is low, only 64%. The reaction formula is as follows:

therefore, the development of a simple and safe synthesis process for the (+/-) -adrenaline with low production cost and large-scale industrial production has very important practical significance.

Disclosure of Invention

The invention provides a method for preparing (+/-) -epinephrine aiming at the defects of the synthesis process.

Firstly, the invention screens the types of non-hydrogen reduction systems commonly used in industrial production:

1. sodium borohydride or potassium borohydride is used for reducing adrenalone, although the system can react, the reaction yield is low (20.8 percent, the comparative example 1), and the main reason is that borane and a substrate adrenalin are subjected to complexation, so that the borane cannot be completely dissociated during the post-treatment;

2. formic acid and formate thereof are used as non-hydrogen donors to reduce adrenal ketone hydrochloride, wherein the non-hydrogen donors comprise sodium formate, potassium formate, formic acid, ammonium formate and the like. The results of the experiments show that, when formic acid is used as the non-hydrogen donor, the system is not able to react (example 5), and that ammonium formate and sodium formate, although both can react, react faster than ammonium formate at the same reaction time (examples 3 and 4). In addition, the production cost of the sodium formate is low, the post-treatment is simple, and the redundant sodium formate can be removed by washing;

after comparing the two experimental schemes, the invention decides to adopt the second scheme. Namely, the (+/-) -adrenalin is generated by taking an adrenalone compound as a raw material in a hydrogen donor, a palladium catalyst and an acid environment.

The preparation method of (+/-) -adrenaline comprises the following steps:

(1) dissolving the adrenalone compound and the hydrogen donor in water;

(2) adjusting the pH value to 2.0-4.0 by using acid liquor;

(3) adding a palladium catalyst, and reacting in inert atmosphere;

(4) filtering out the palladium catalyst and inert atmosphere, adjusting the pH value of the reaction system to 8.2-8.5 by using alkali liquor, stirring, and removing liquid to obtain the (+/-) -adrenaline.

The invention takes the formate as the hydrogen donor, avoids the operation risk when taking the hydrogen as the hydrogen source, ensures safer process production, does not need special equipment, a special workshop and special operators when using the hydrogen source, and is more convenient for realizing large-scale production.

The inert atmosphere according to the present invention can prevent oxygen or other gases from participating in the reaction, and as the protective atmosphere, for example, nitrogen, argon, or the like can be used.

Preferably, the adrenalone compound is adrenalone free base, adrenalone hydrochloride, adrenalone formate, adrenalone tartrate, adrenalone sulfate, adrenalone phosphate, adrenalone camphor sulfonate, adrenalone ascorbate, adrenalone malate, adrenalone methanesulfonate, adrenalone nitrate, adrenalone aspartate, adrenalone hydroiodide, adrenalone hydrobromide, preferably adrenalone hydrochloride.

In the specific embodiment of the invention, the experimental results show that formate is a desirable hydrogen source for catalytic transfer hydrogenation. Since the formate is soluble in water, excess formate can be removed by post-treatment. While the formic acid system did not react, it is hypothesized that the likely reason is that at lower pH, the substrate underwent enolization.

Therefore, as a preferable scheme, the formate is one of sodium formate, ammonium formate, potassium formate and calcium formate, and sodium formate is preferable.

As a further improvement of the method, the pH value of the reaction system in the step (2) is 2.0-4.0, and when the pH value of the reaction system is less than 2.0, the reaction does not occur; when the pH is more than 4.0, the reaction system cannot be dissolved clearly. When the pH value is 2.6-3.9, the reaction rate is increased along with the increase of the pH value of the reaction system, and the effect is best when the pH value of the system is 3.6-3.8.

Further, the pH value in the step (2) is 2.0-4.0, preferably 2.6-3.9, and more preferably 3.6-3.8.

Preferably, the palladium catalyst is palladium on carbon.

In a specific embodiment of the invention, the mass ratio of the palladium carbon to the adrenal ketone hydrochloride is 0.08: 1-0.15: 1, and when the mass ratio of the palladium carbon to the adrenal ketone hydrochloride is less than 0.08:1, the reaction is slow and the adrenal ketone remains more. In a specific embodiment (example 11), when the pH of the system is between 3.5 and 3.9, the mass ratio of palladium on carbon to the adrenal ketone hydrochloride is reduced to 0.08:1, the reaction can still be efficiently performed, and the purity is greater than 99.6%. In view of production cost, the mass ratio of palladium on carbon to adrenal ketone hydrochloride is preferably 0.08: 1.

Preferably, the mass ratio of the adrenal ketone hydrochloride to the formate is 1: 1.2-1: 3.5, preferably 1: 3.1.

Preferably, the acid solution is formic acid solution, acetic acid solution, nitric acid solution, phosphoric acid solution, sulfuric acid solution, concentrated hydrochloric acid, and preferably concentrated hydrochloric acid.

The reaction time of the invention can be determined by a conventional means, so that the reasonable reaction time length is determined. In the present invention, the reaction time in step (3) may be generally selected from 5 to 20 hours, preferably 6 to 7 hours.

Preferably, the alkali solution in step (4) is sodium hydroxide solution, potassium hydroxide solution, sodium bicarbonate solution, sodium carbonate solution, potassium carbonate solution, or ammonia water, preferably ammonia water.

The step (4) of removing the liquid means removing the liquid in the reaction system by a conventional operation means such as filtration and centrifugation, and these means may be used alone or in combination.

After the reaction is finished, the purity of the product is detected by adopting a high performance liquid chromatography.

The invention has the beneficial effects that:

1. catalytic hydrogenation process, corrosion hydrogenation kettle, introduction of iron ion, so that the product autoxidation to become light red brown, long reaction time (16 hours), 93.5% yield (comparative example 2). The process developed by the invention avoids the use of a hydrogenation kettle, the reaction time is short (6-7 hours), the yield is more than 92%, the purity is more than 99.6%, and the color of the product is white.

2. Compared with the hydrogen source of hydrogen, the hydrogen source of formate is higher in safety, simpler and more convenient, lower in production cost and more friendly to operators in the technical production process.

Drawings

FIG. 1 is a HPLC chart of the product of example 1;

FIG. 2 is a HPLC chart of the product of example 2;

FIG. 3 is a HPLC chart of the product of example 3;

FIG. 4 is a HPLC chart of the product of example 4;

FIG. 5 is a HPLC chart of the product of example 5;

FIG. 6 is an HPLC chart of the product of example 6;

FIG. 7 is an HPLC chart of the product of example 7;

FIG. 8 is an HPLC chart of the product of example 8;

FIG. 9 is an HPLC chart of the product of example 9;

FIG. 10 is an HPLC plot of the product of example 10;

FIG. 11 is an HPLC chart of the product of example 11;

FIG. 12 is a HPLC chart of the product of comparative example 1.

Detailed Description

The technical solution of the present invention is further defined below with reference to the specific embodiments, but the scope of the claims is not limited to the description.

Example 1

2.0g of adrenal ketone hydrochloride and 6.25g of sodium formate are sequentially added into 30.0g of pure water to be stirred, 5.2g of concentrated hydrochloric acid is slowly dripped to adjust the pH value of the system to be 3.2-3.9, 0.2g of palladium-carbon is added, a nitrogen replacement system is added, and the reaction is carried out for 6-7 hours under liquid seal. Filtering to remove palladium carbon, transferring the filtrate into a 100mL three-necked bottle, replacing the system with nitrogen, dropwise adding ammonia water to adjust the pH of the system to be between 8.2 and 8.5, stirring for 10 minutes, and filtering to obtain 1.53g of white solid with the yield of 91.1%. The purity of the product is 99.78% by HPLC (see the figure 1 in the specification and the attached drawing), and the purity of the adrenalone is 0.13%.

Example 2

Sequentially adding 2.0g of adrenal ketone hydrochloride and 5.80g of ammonium formate into 30.0g of pure water, stirring, slowly dropwise adding 5.2g of concentrated hydrochloric acid to adjust the pH value of the system to be 3.2-3.9, adding 0.2g of palladium-carbon, replacing the system with nitrogen, and reacting for 6-7 hours under a liquid seal condition. Filtering to remove palladium carbon, transferring the filtrate into a 100mL three-necked bottle, replacing the system with nitrogen, dropwise adding ammonia water to adjust the pH of the system to be between 8.2 and 8.5, stirring for 10 minutes, and filtering to obtain 1.43g of white solid with the yield of 85.1%. The purity of the product was 92.26% by HPLC (see the figure 2 in the specification for HPLC chart) and 7.64% for adrenalone.

Example 3

2.0g of adrenal ketone hydrochloride and 4.23g of formic acid are sequentially added into 30.0g of pure water to be stirred, 0.2g of palladium-carbon is added into the mixture, a nitrogen displacement system is added, and the mixture is reacted for 6 to 7 hours under liquid seal. The adrenalone content was 99.17% by HPLC (see the figure 3 in the figure of the specification), and no product was detected.

Example 4

2.0g of adrenal ketone hydrochloride and 2.50g of sodium formate are sequentially added into 30.0g of pure water and stirred, 5.2g of concentrated hydrochloric acid is slowly added dropwise to adjust the pH value of the system to be 0.5, 0.2g of palladium-carbon is added, the system is replaced by nitrogen, and the reaction is carried out for 20 hours under a liquid seal condition. The adrenalone content was 99.15% by HPLC (see the figure 4 in the figure of the specification), and no product was detected.

Example 5

2.0g of adrenal hydrochloride and 3.75g of sodium formate are sequentially added into 30.0g of pure water and stirred, then 5.2g of concentrated hydrochloric acid is slowly dropped to adjust the pH value of the system to be 2.07, 0.2g of palladium-carbon is added, a nitrogen replacement system is added, and the reaction is carried out for 20 hours under a liquid seal condition. The adrenalone content was 98.72% by HPLC (see the figure 5 in the figure of the specification), and no product was detected.

Example 6

2.0g of adrenal hydrochloride and 3.75g of sodium formate are sequentially added into 30.0g of pure water and stirred, 2.80g of concentrated hydrochloric acid is slowly added dropwise to adjust the pH value of the system to be 3.41, 0.2g of palladium-carbon is added, the system is replaced by nitrogen, and the reaction is carried out for 20 hours under a liquid seal condition. Filtering to remove palladium carbon, transferring the filtrate into a 100mL three-necked bottle, replacing the system with nitrogen, dropwise adding ammonia water to adjust the pH of the system to be between 8.2 and 8.5, stirring for 10 minutes, and filtering to obtain 1.54g of white solid with the yield of 91.7%. The purity of the product is 99.84% by HPLC (see the figure 6 in the specification and the drawing), and the adrenalone is not detected.

Example 7

2.0g of adrenal hydrochloride and 5.0g of sodium formate are sequentially added into 30.0g of pure water and stirred, then 5.2g of concentrated hydrochloric acid is slowly dropped to adjust the pH value of the system to be 2.87, 0.2g of palladium-carbon is added, a nitrogen replacement system is added, and the reaction is carried out for 20 hours under a liquid seal condition. Filtering to remove palladium carbon, transferring the filtrate into a 100mL three-necked flask, replacing the system with nitrogen, dropwise adding ammonia water to adjust the pH of the system to be 8.2-8.5, stirring for 10 minutes, and filtering to obtain 1.55g of white solid with the yield of 92.2%. The purity of the product is 99.85% by HPLC (see the figure 7 in the specification and the figure of HPLC), and the adrenalone is not detected.

Example 8

2.0g of adrenal ketone hydrochloride and 5.0g of sodium formate are sequentially added into 30.0g of pure water and stirred, then concentrated hydrochloric acid is slowly added dropwise to adjust the pH of the system to 3.28, then 0.2g of palladium carbon is added, a nitrogen replacement system is added, and the reaction is carried out for 13 hours under liquid seal. Filtering to remove palladium carbon, transferring the filtrate into a 100mL three-necked bottle, replacing the system with nitrogen, dropwise adding ammonia water to adjust the pH of the system to be 8.2-8.5, stirring for 10 minutes, and filtering to obtain 1.55g of white solid with the yield of 92.3%. The purity of the product is 99.90% by HPLC (see the figure 8 in the specification and attached drawing), and the adrenalone is not detected.

Example 9

2.0g of adrenal ketone hydrochloride and 5.0g of sodium formate are sequentially added into 30.0g of pure water and stirred, then concentrated hydrochloric acid is slowly added dropwise to adjust the pH of the system to 3.90, then 0.2g of palladium carbon is added, a nitrogen replacement system is added, and the reaction is carried out for 5 hours under liquid seal. Filtering to remove palladium carbon, transferring the filtrate into a 100mL three-necked bottle, replacing the system with nitrogen, dropwise adding ammonia water to adjust the pH of the system to be 8.2-8.5, stirring for 10 minutes, and filtering to obtain 1.55g of white solid with the yield of 92.3%. The purity of the product was 99.94% by HPLC (see the figure 9 in the figure of the specification for HPLC), and no adrenalone was detected.

Example 10

2.0g of adrenal ketone hydrochloride and 6.25g of sodium formate are sequentially added into 30.0g of pure water and stirred, then concentrated hydrochloric acid is slowly added dropwise to adjust the pH of the system to 3.69, then 0.16g of palladium carbon is added, a nitrogen replacement system is added, and the reaction is carried out for 7 hours under a liquid seal condition. Filtering to remove palladium carbon, transferring the filtrate into a 100mL three-necked bottle, replacing the system with nitrogen, dropwise adding ammonia water to adjust the pH of the system to be between 8.2 and 8.5, stirring for 10 minutes, and filtering to obtain 1.54g of white solid with the yield of 91.7%. The purity of the product is 99.75% by HPLC (see the figure 10 in the specification and attached drawing), and the adrenalone is not detected.

Example 11

12.0g of adrenal hydrochloride and 37.5g of sodium formate are sequentially added into 180.0g of pure water and stirred, 18g of concentrated hydrochloric acid is slowly added dropwise to adjust the pH value of the system to 3.86, 0.96g of palladium-carbon is added, a nitrogen replacement system is added, and the reaction is carried out for 7 hours under a liquid seal condition. Filtering to remove palladium carbon, transferring the filtrate into a 500mL three-necked bottle, replacing the system with nitrogen, dropwise adding ammonia water to adjust the pH of the system to be 8.2-8.5, stirring for 10 minutes, and filtering to obtain 9.39g of white solid with the yield of 93.0%. The purity of the product was 99.68% by HPLC (see the figure 11 in the figure of the specification for HPLC), and no adrenalone was detected.

Comparative example 1

Add 2.0g of adrenone hydrochloride to 30.0g of purified water and stir under nitrogen protection and in dark. And cooling the mixture to 5-10 ℃ in an ice water bath, slowly adding 1.02g of sodium borohydride, raising the temperature of the system to 20-30 ℃ after the addition is finished, and carrying out heat preservation reaction for 12 hours. After the reaction is completed, cooling the reaction system to 5-10 ℃, dropwise adding 3% hydrochloric acid to adjust the pH of the system to 5.06, heating to 50 ℃, keeping the temperature, stirring for 2 hours, cooling to 5-10 ℃, adjusting the pH of the system to 8 by using 20% sodium carbonate solution, separating out solids, and filtering to obtain 0.35g of white solids, wherein the yield is 20.8%. The purity of the product is 100% by HPLC (see the figure 12 in the specification and attached drawing), and the adrenalone is not detected.

Comparative example 2

Respectively adding 2.0g of adrenal ketone hydrochloride and 0.2g of palladium-carbon into 30.0g of pure water, stirring, introducing hydrogen to 1.5MPa in a nitrogen displacement system, and carrying out heat preservation reaction at 20-30 ℃ for 16 hours. Filtering to remove palladium carbon, transferring the filtrate into a 100mL three-necked bottle, replacing the system with nitrogen, dropwise adding ammonia water to adjust the pH of the system to be between 8.2 and 8.5, stirring for 10 minutes, and filtering to obtain 1.57g of light reddish brown solid with the yield of 93.5%. The purity of the product was 99.03% by HPLC.

The above description is further intended to describe the present invention in detail with reference to specific embodiments, and it should not be construed that the specific embodiments of the present invention are limited to these descriptions. It will be apparent to those skilled in the art that various changes, substitutions and alterations can be made without departing from the spirit and scope of the invention.