A method for chiral resolution of racemic norepinephrine

Abstract

The present invention belongs to the technical field of drug preparation, and specifically discloses a method for chiral resolution of racemic norepinephrine. In the method of the present invention, an ethanol aqueous solution is used as a solvent, and racemic norepinephrine and D-tartaric acid are salted out in the solvent. By utilizing the different solubilities of its isomers in the solvent after salting out, solid L-norepinephrine-D-tartrate is separated, and then it is dissociated with a base to obtain L-norepinephrine with high purity. This method has a simple technological process, is easy to operate, can obtain L-norepinephrine isomers with high purity in one resolution, the solvent can be recycled and reused, has low cost, is green and environmentally friendly, is suitable for large-scale industrial production, and has good industrial application prospects.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation, and particularly relates to a chiral separation method for racemic norepinephrine. Background Art

[0002] Norepinephrine, also known as noradrenaline, norrepinephrine, noradrenaline, left arterial phenol, etc., English name Noradrenaline, Noradrenaline Bitartrate, chemical name 1-(3,4-dihydroxyphenyl)-2-aminoethanol, is the substance formed after removing the N-methyl group of adrenaline, and it also belongs to catecholamines in chemical structure.

[0003] Norepinephrine is an adrenergic receptor α and β-receptor stimulant, with the α-receptor acting primarily. Compared with adrenaline, it has stronger vasoconstriction and pressor effects, and reflexively causes a slowing of the heart rate, but weaker effects on the heart and bronchial dilation. Clinically, it is mainly used for its pressor effect, and intravenous drip is used for various shocks (contraindicated for hemorrhagic shock) to increase blood pressure and ensure blood supply to important organs (such as the brain).

[0004] Norepinephrine contains one chiral carbon and has two optical isomers, S and R. R-norepinephrine is the active ingredient and its tartrate is commonly used, with a molecular formula of C 8 H 11 NO 3 ·C 4 H 6 O 6 , the structural formula is as follows:

[0005]

[0006] At present, most chiral separation methods of racemic norepinephrine are to use norepinephrine and L-tartaric acid to form salts, and then perform multiple recrystallizations. For example, Chinese patent CN111004136B discloses a method for purifying norepinephrine bitartrate, which is to repeatedly recrystallize norepinephrine bitartrate in a solution. Since the amount of solvent used is less than the weight of the product in most cases, the operation is more difficult and more complicated due to the large number of times, and the yield is often not high after multiple recrystallizations. Chinese patent application CN112225665A discloses a chiral resolution method of racemic norepinephrine, comprising: racemic norepinephrine is resolved in an alcohol aqueous solution (the alcohol in the alcohol aqueous solution is methanol, ethanol, isopropanol) by D-tartaric acid to obtain L-norepinephrine D-tartrate, specifically, before resolution, racemic norepinephrine and D-tartaric acid are dissolved in water to form a salt, and the amount of water is 2 times (m / m) of racemic norepinephrine, and a methanol / ethanol mixed solvent is added dropwise during the resolution process; L-norepinephrine D-tartrate is neutralized in water by alkali (the alkali is selected from organic amines such as triethylamine, or inorganic alkalis such as ammonia water, lithium hydroxide, sodium hydroxide) to obtain L-norepinephrine. According to experiments, the method precipitates a small amount of milky viscous material, which is easy to form a mass and difficult to filter, and L-norepinephrine is not obtained after ammonia water dissociation.

[0007] In view of this, it is necessary to develop a new chiral separation method to prepare L-norepinephrine, which has practical significance for optimizing the drug synthesis process. Summary of the invention

[0008] In order to solve one of the above-mentioned technical problems existing in the prior art, the present invention provides a chiral separation method for racemic norepinephrine, which uses a mixed solution of water and alcohol as a solvent, has a simple process and is easy to operate. High-purity L-norepinephrine can be obtained by one separation, and the solvent can be recycled and reused, which is low-cost and green and environmentally friendly.

[0009] The object of the present invention is achieved through the following technical solutions:

[0010] A chiral resolution method for racemic norepinephrine comprises the following steps:

[0011] The racemic norepinephrine is salified with D-tartaric acid in a solvent to obtain L-norepinephrine-D-tartrate solid;

[0012] The solvent is a mixed solution of water and alcohol;

[0013] The L-norepinephrine-D-tartrate is dissociated with an alkali in water to obtain L-norepinephrine.

[0014] As an embodiment of the present invention, the alcohol is selected from one or more of methanol, ethanol, and isopropanol, preferably ethanol.

[0015] As an embodiment of the present invention, the solvent is a 60% to 75% ethanol aqueous solution, and the concentration is mass percentage concentration.

[0016] As an embodiment of the present invention, the molar ratio of racemic norepinephrine to D-tartaric acid is 1:(1.0-1.3);

[0017] And / or, the mass ratio of the racemic norepinephrine to the solvent is 1:(6-8).

[0018] As an embodiment of the present invention, the chiral resolution method of racemic norepinephrine comprises: mixing racemic norepinephrine, D-tartaric acid and a solvent, performing a salt-forming reaction, adding L-norepinephrine-D-tartaric acid seed crystals (a small amount is sufficient) for crystallization, and then filtering to obtain L-norepinephrine-D-tartrate solid.

[0019] Wherein, the reaction temperature of the salt-forming reaction is 20-30°C.

[0020] As an embodiment of the present invention, when the L-norepinephrine-D-tartrate is dissociated in water with an alkali, the mass ratio of the L-norepinephrine-D-tartrate to water is 1:(6-8).

[0021] As an embodiment of the present invention, the base used for the alkaline dissociation is selected from one or more of triethylamine, ammonia water, lithium hydroxide, and sodium hydroxide, preferably ammonia water.

[0022] As an embodiment of the present invention, the amount of the base used is to adjust the pH value of the solution to 8-9.

[0023] As an embodiment of the present invention, the obtained L-norepinephrine is salted with L-tartaric acid in a reaction solvent to obtain norepinephrine bitartrate; wherein the reaction solvent is a mixed solution of water and alcohol.

[0024] As an embodiment of the present invention, the alcohol in the reaction solvent is selected from one or more of methanol, ethanol, and isopropanol, preferably ethanol.

[0025] As an embodiment of the present invention, the molar ratio of L-norepinephrine to L-tartaric acid is 1:(1.0-1.1);

[0026] And / or, the mass ratio of L-norepinephrine to the reaction solvent is 1:(6-8).

[0027] As an embodiment of the present invention, the reaction solvent is 70%-80% ethanol aqueous solution, preferably 75% ethanol aqueous solution, and the concentration is mass percentage concentration.

[0028] The chiral separation method of racemic norepinephrine provided by the present invention uses an ethanol aqueous solution of a specific concentration as a solvent, racemic norepinephrine and D-tartaric acid are salified therein, and the difference in solubility of its isomers in the solvent after salification is utilized to separate L-norepinephrine-D-tartrate solid, and D-norepinephrine-D-tartrate is dissolved in the solvent. Then, L-norepinephrine-D-tartrate is dissociated with ammonia water to obtain high-purity L-norepinephrine. The method of the present invention has a simple process, and high-purity L-norepinephrine isomers can be obtained by one-time separation, and the operation is simple, the solvent can be recycled and reused, the cost is low, it is green and environmentally friendly, suitable for large-scale industrial production, and has good industrial application prospects. DETAILED DESCRIPTION

[0029] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with embodiments. The specific embodiments described herein are only used to explain the present invention and are not intended to constitute any limitation of the present invention. In addition, in the following description, the description of the known technology is omitted to avoid unnecessary confusion of concepts. Such technology is also described in many publications.

[0030] definition

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly used in the art to which this invention belongs.

[0032] Example 1

[0033] This embodiment provides a method for chiral resolution of racemic norepinephrine, comprising the following steps:

[0034] 33.8 g of racemic norepinephrine and 30 g of D-tartaric acid were added to a 500 mL single-mouth bottle, and 270 g of 65% ethanol aqueous solution was added. The mixture was stirred at room temperature (temperature 20-30° C.) until it was clear. 0.2 g of L-norepinephrine-D-tartaric acid was added as a seed crystal. A large amount of solid was precipitated later. The reaction was continued for 2 h and then filtered to obtain L-norepinephrine-D-tartrate wet product.

[0035] 40 g of L-norepinephrine-D-tartrate was added to 200 g of purified water, stirred to dissolve, and then slowly added with ammonia water to adjust the pH value of the solution to 8-9. A large amount of solid precipitated, which was filtered and dried to obtain 8.5 g of L-norepinephrine.

[0036] 8.5 g of L-norepinephrine and 7.6 g of L-tartaric acid were added to a reaction bottle, and 60 g of 75% by mass ethanol aqueous solution was added. The solid quickly dissolved and a new solid was quickly precipitated. The salt-forming reaction was stirred at room temperature for 1 hour and filtered to obtain 13.6 g of norepinephrine bitartrate.

[0037] After testing, the content of the obtained norepinephrine bitartrate is: 101.0%, the specific rotation is: -11.7°, the content of D-norepinephrine isomer is 0.62%, the related substances are qualified, the ketone body is 0.011 (absorbance value), and the melting point is 101.5°C.

[0038] Example 2

[0039] This embodiment provides a method for chiral resolution of racemic norepinephrine, comprising the following steps:

[0040] 16.9 g of racemic norepinephrine and 15 g of D-tartaric acid were added to a 500 mL single-mouth bottle, and 130 g of 65% ethanol aqueous solution was added. The mixture was stirred at room temperature (temperature 20-30° C.) until it was clear. 0.1 g of L-norepinephrine-D-tartaric acid was added as a seed crystal. A large amount of solid was precipitated later. The reaction was continued for 2 h and then filtered to obtain L-norepinephrine-D-tartrate wet product.

[0041] 19.5 g of L-norepinephrine-D-tartrate was added to 100 g of purified water, stirred to dissolve, and then slowly added with ammonia water to adjust the pH value of the solution to 8-9. A large amount of solid precipitated, which was filtered and dried to obtain 4.0 g of L-norepinephrine.

[0042] 4.0 g of L-norepinephrine and 3.6 g of L-tartaric acid were added to a reaction bottle, and 24 g of 75% ethanol aqueous solution was added. The solid quickly dissolved and a new solid was quickly precipitated. The salt-forming reaction was stirred at room temperature for 1 hour and filtered to obtain 6.6 g of norepinephrine bitartrate.

[0043] After testing, the content of the obtained norepinephrine bitartrate is: 101.0%, the specific rotation is: -11.6°, the content of D-norepinephrine isomer is 0.73%, the related substances are qualified, the ketone body is 0.012, and the melting point is: 101.0℃.

[0044] Embodiment 3-6

[0045] The chiral resolution method of racemic norepinephrine provided in Example 3-6 is the same as that in Example 2, except that different resolution solvents are used when racemic norepinephrine reacts with D-tartaric acid. The details are as follows:

[0046] 16.9 g of racemic norepinephrine and 15 g of D-tartaric acid were added to a 500 mL single-mouth bottle, 135 g of ethanol aqueous solution was added, and the reaction was stirred at room temperature (temperature 20-30° C.) until it was clarified, 0.1 g of L-norepinephrine-D-tartaric acid was added as a seed crystal, and a large amount of solid precipitated later. The reaction was continued for 2 hours and then filtered to obtain L-norepinephrine-D-tartrate wet product; the subsequent operations were the same as in Example 2.

[0047] The mass percentage concentrations of the added 135 g ethanol aqueous solution are 55%, 60%, 65% and 75% respectively.

[0048] Different resolution solvents were used to investigate the effect of ethanol content in the solvent on the chiral resolution effect. The specific rotation of the finished product norepinephrine bitartrate was used as the evaluation index. The experimental results are shown in Table 1 below.

[0049] Table 1 Effect of ethanol content in solvent on chiral separation

[0050]

[0051] As can be seen from Table 1, the mass percentage concentration of ethanol in the chiral resolution solvent has a good resolution effect in a small range of 60% to 75%, and a high-purity L-norepinephrine isomer can be obtained after one chiral resolution. When the mass percentage concentration of ethanol in the chiral resolution solvent is reduced to 55%, no solid can be precipitated, and when the concentration is higher than 75%, no qualified product can be obtained.

[0052] Comparative Example 1

[0053] The chiral resolution method of racemic norepinephrine provided in this comparative example comprises the following steps:

[0054] 33.8g racemic noradrenaline and 15g D-tartaric acid are added to a single-mouth bottle, 85g water is added, stirring and dissolving is complete, and salt-forming reaction is carried out. After 0.5h, 345g of absolute ethanol is slowly added dropwise. During the dropping process, the reaction solution is gradually emulsified, but no obvious solid is precipitated. After completion of the dropwise addition, stirring is continued, and the solution is gradually clarified, and a small amount of viscous colloidal solid appears in the reaction flask, which is difficult to filter. After careful removal, ammonia water is dissociated to obtain a small amount of noradrenaline sample after splitting, and the specific rotation is detected. The specific rotation is close to zero, and there is basically no chiral splitting effect.

[0055] The chiral resolution method of racemic norepinephrine provided by the present invention uses a mixed solution of water and alcohol of a specific concentration as a resolution solvent, and racemic norepinephrine and D-tartaric acid are salified in a solvent, and L-norepinephrine-D-tartrate solid is separated by utilizing the difference in solubility of its isomers in the solvent after salification, and L-norepinephrine-D-tartrate is precipitated, and D-norepinephrine-D-tartrate is dissolved in the solvent; and then the L-norepinephrine-D-tartrate solid is dissociated with an alkali to obtain high-purity L-norepinephrine. The method has a simple process and is easy to operate. High-purity L-norepinephrine isomers can be obtained by one-time resolution, and the solvent can be recycled and reused, with low cost, green and environmentally friendly, suitable for large-scale industrial production, and has good industrial application prospects.

[0056] Although the present invention has been described in detail above with general descriptions and specific implementation schemes, it is obvious to those skilled in the art that some modifications or improvements can be made to the present invention. Therefore, the technical solution of the present invention is not limited to the above-mentioned specific embodiments, and all technical variations made according to the technical solution of the present invention fall within the protection scope of the present invention.

Claims

1. A chiral resolution method for racemic norepinephrine, It is characterized in that The following steps are involved: The racemic norepinephrine, D-tartaric acid and solvent are mixed to carry out a salt-forming reaction, L-norepinephrine-D-tartaric acid seed crystals are added to carry out crystallization, and then filtered to obtain L-norepinephrine-D-tartrate solid; wherein the reaction temperature of the salt-forming reaction is 20-30° C., and the solvent is a 60%-75% ethanol aqueous solution; Dissociating the L-norepinephrine-D-tartrate with alkali in water to obtain L-norepinephrine; and The obtained L-norepinephrine is salified with L-tartaric acid in a reaction solvent to obtain norepinephrine bitartrate; wherein the reaction solvent is a 70%-80% ethanol aqueous solution; The molar ratio of racemic norepinephrine to D-tartaric acid is 1:(1.0-1.3); The mass ratio of racemic norepinephrine to solvent is 1:(6-8); The mass ratio of L-norepinephrine-D-tartrate to water is 1:(6-8); The molar ratio of L-norepinephrine to L-tartaric acid is 1:(1.0-1.1); The mass ratio of the L-norepinephrine to the reaction solvent is 1:(6-8).

2. The chiral separation method according to claim 1, It is characterized in that The base is selected from one or more of triethylamine, ammonia water, lithium hydroxide and sodium hydroxide; And / or, the base is used in an amount to adjust the pH value of the solution to 8-9.

3. The chiral separation method according to claim 1, It is characterized in that The reaction solvent is 75% ethanol aqueous solution.

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