A mixed solvent for purifying L-adrenaline and its salts, and a method for purifying L-adrenaline and its salts

Abstract

The present invention relates to the technical field of chemical drug purification, specifically discloses a mixed solvent for purifying L-epinephrine and its salts, and a method for purifying L-epinephrine and its salts. The mixed solvent for purifying L-epinephrine and its salts provided by the present invention, the mixed solvent is composed of water, methanol and ethanol, wherein the volume ratio of water, methanol and ethanol is 1: (1-3): (3-6). When a specific proportion of water, methanol and ethanol is used as a mixed solvent to purify L-epinephrine and its salts, the crystal form of L-epinephrine and its salts can be affected, the growth rate of L-epinephrine and its salt crystallization can be increased, so as to facilitate the smooth crystallization of L-epinephrine and its salts, realize chiral separation, significantly improve the chiral purity of L-epinephrine and its salts, and apply it to L-epinephrine and its salt purification method, the chiral purity and yield of L-epinephrine and its salts can be significantly improved.

Description

Technical Field

[0001] The invention relates to the technical field of chemical drug purification, and in particular to a mixed solvent for purifying L-adrenaline and its salt, and a method for purifying L-adrenaline and its salt. Background Art

[0002] Adrenaline is a hormone secreted by the human body. It is mainly used for rescue of cardiac arrest and anaphylactic shock. It can also be used to treat other allergic diseases.

[0003] Epinephrine is generally synthesized according to the following synthesis method:

[0004]

[0005] The synthesized adrenaline is DL-adrenaline (racemic adrenaline), which exists in two enantiomers, L-adrenaline and D-adrenaline, of which L-adrenaline meets the requirements for pharmaceutical use. It is very necessary to study the chiral purity of L-adrenaline and its salts. Summary of the invention

[0006] In view of this, the present invention provides a mixed solvent for purifying L-adrenaline and its salts. By selecting water, methanol and ethanol in a specific ratio as the mixed solvent for purifying L-adrenaline and its salts, the crystal morphology of L-adrenaline and its salts can be affected, and the growth rate of the crystals of L-adrenaline and its salts can be increased, thereby facilitating the smooth crystallization and precipitation of L-adrenaline and its salts, achieving chiral separation, and further significantly improving the chiral purity of L-adrenaline and its salts.

[0007] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0008] A mixed solvent for purifying L-adrenaline and its salts, wherein the mixed solvent is a mixed solution of water, methanol and ethanol in a volume ratio of 1:(1-3):(3-6).

[0009] At present, there are many methods to improve the chiral purity of L-epinephrine and its salts, such as selecting specific catalysts or enzymes for catalysis to convert one chiral molecule in a chiral compound into other chiral molecules to achieve the purpose of separation; or using column chromatography with a chiral stationary phase to achieve chiral separation by utilizing the interaction between the chiral product and the chiral stationary phase; however, the method using catalysts or enzymes is costly and cumbersome to operate; although the column chromatography method has a good separation effect, it is complicated to operate and requires precise operating skills and equipment, which increases the difficulty and cost of production; therefore, it is very necessary to study how to improve the chiral purity of L-epinephrine and its salts.

[0010] Compared with the prior art, the present invention breaks away from the idea of ​​purifying L-epinephrine and its salts in the prior art, and by selecting water, methanol and ethanol as a mixed solvent for purifying L-epinephrine and its salts, the yield of L-epinephrine and its salts can be significantly improved; further, the inventors have found through a large number of experiments that when a specific proportion of water, methanol and ethanol are selected as a mixed solvent for purifying L-epinephrine and its salts, the crystal morphology of L-epinephrine and its salts can be affected, and the growth rate of L-epinephrine and its salt crystals can be increased, thereby facilitating the smooth crystallization and precipitation of L-epinephrine and its salts, achieving chiral separation, and significantly improving the chiral purity of L-epinephrine and its salts; the mixed solvent for purifying L-epinephrine and its salts provided by the present invention is applied to the method for purifying L-epinephrine and its salts, and can significantly improve the chiral purity and yield of L-epinephrine and its salts.

[0011] Further preferably, the volume ratio of water, methanol and ethanol in the mixed solvent is 1:2:4.

[0012] The preferred ratio is beneficial to further improve the chiral purity and yield of L-adrenaline and its salts.

[0013] A method for preparing the above-mentioned mixed solvent for purifying L-adrenaline and its salts comprises the following steps:

[0014] Weigh each component according to the mass ratio, mix water, methanol and ethanol evenly to obtain the mixed solvent.

[0015] A method for purifying L-adrenaline and its salts comprises the following steps:

[0016] S1. Evenly mix the crude adrenaline tartrate with the mixed solvent according to claim 1 or 2 at 30°C to 40°C, cool and crystallize, and filter to obtain primary L-adrenaline tartrate;

[0017] S2. Repeat the above S1 operation 1 to 3 times with the primary L-tartrate adrenaline, dry it, and obtain L-tartrate adrenaline.

[0018] The invention provides a method for purifying L-adrenaline and its salts. A specific mixed solvent is selected at a specific temperature to purify L-adrenaline tartrate. The specific solvent and temperature can affect the crystal form of L-adrenaline and its salts, and improve the growth rate of the crystals of L-adrenaline and its salts, thereby facilitating the smooth crystallization and precipitation of L-adrenaline and its salts, realizing chiral separation, and significantly improving the chiral purity and yield of L-adrenaline and its salts. The method provided by the invention is simple to operate, low in cost, has both high chiral purity and high yield, is suitable for factory production, and has extremely high promotion and application value.

[0019] Preferably, in S1, the mass volume ratio of the crude adrenaline tartrate and the mixed solvent is 1 g: (6-8) mL.

[0020] Preferably, in S1, the temperature of the cooling crystallization is 20°C to 30°C, and the time of the cooling crystallization is 8h-16h.

[0021] The preferred crystallization temperature and crystallization time are beneficial to the chiral purity and yield of L-adrenaline tartrate.

[0022] Preferably, in S1, the preparation of the crude adrenaline tartrate comprises the following steps:

[0023] At 30° C. to 40° C., DL-adrenaline and L-tartaric acid are added to an alcohol solvent for reaction to obtain the crude tartaric acid adrenaline.

[0024] Preferably, the alcohol solvent is methanol.

[0025] Preferably, the molar ratio of DL-adrenaline to L-tartaric acid is 1:(1.5-3).

[0026] Preferably, the reaction time is 20 h to 30 h.

[0027] Preferably, the mass volume ratio of the DL-adrenaline to the alcohol solvent is 1 g:(5-10) mL. DETAILED DESCRIPTION

[0028] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0029] In order to better illustrate the present invention, further examples are given below.

[0030] The chiral purity of L-adrenaline tartrate is determined by high performance liquid chromatography (General Rule 0512 of the 2020 edition of the Chinese Pharmacopoeia), as follows:

[0031] The diluent was: n-hexane-anhydrous ethanol-trifluoroacetic acid (50:50:0.2);

[0032] Test solution: Take an appropriate amount of the product, weigh accurately, dissolve in diluent and quantitatively dilute to make a solution containing about 1 mg per 1 ml;

[0033] Reference solution: Take an appropriate amount of impurity I reference substance, dissolve it in diluent and dilute it to make a solution containing about 30 μg per 1 ml;

[0034] Chromatographic conditions: Use amylose-tris (3,5-dimethylphenylcarbamate) coated silica gel as filler (CHIRAL PAK AD-H 4.6mm×250mm, 5μm or chromatographic column with equivalent performance); use n-hexane-isopropanol-methanol-ethanolamine-trifluoroacetic acid (88:7:5:0.1:0.2) as mobile phase; flow rate is 1.0ml per minute; column temperature is 20℃; detection wavelength is 280nm; injection volume is 10μL.

[0035] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram to twice the retention time of the main component;

[0036] Limit: Calculated by peak area using the external standard method, impurity I shall not exceed 3.0%.

[0037] Example 1

[0038] This embodiment provides a method for purifying L-adrenaline and its salts, comprising the following steps:

[0039] S1. Add DL-epinephrine (1 mol, 183.20 g) and L-tartaric acid (1.5 mol, 225.14 g) to methanol (916.02 mL) at 40°C and react for 20 h to obtain tartrate of epinephrine;

[0040] S2. At 30°C, mix the adrenaline tartrate (10 g) and a mixed solvent (60 mL) uniformly, cool to 20°C and crystallize for 8 hours, filter, repeat the above operation 3 times, and dry to obtain L-adrenaline tartrate with a chiral purity of 99.4% and a yield of 48.9%; wherein the mixed solvent is a mixture of water, methanol and ethanol in a volume ratio of 1:2:4.

[0041] Example 2

[0042] This embodiment provides a method for purifying L-adrenaline and its salts, comprising the following steps:

[0043] S1. Add DL-epinephrine (1 mol, 183.20 g) and L-tartaric acid (3 mol, 450.27 g) to methanol (1832.04 mL) at 30°C and react for 30 h to obtain tartrate of epinephrine;

[0044] S2. At 40°C, mix the adrenaline tartrate (10 g) and a mixed solvent (80 mL) uniformly, cool to 30°C and crystallize for 16 hours, filter, repeat the above operation 3 times, and dry to obtain L-adrenaline tartrate with a chiral purity of 98.7% and a yield of 53.3%; wherein the mixed solvent is a mixture of water, methanol and ethanol in a volume ratio of 1:1:6.

[0045] Example 3

[0046] This embodiment provides a method for purifying L-adrenaline and its salts, comprising the following steps:

[0047] S1. Add DL-epinephrine (1 mol, 183.20 g) and L-tartaric acid (2 mol, 300.18 g) to methanol (1465.63 mL) at 35°C and react for 25 h to obtain tartrate of epinephrine;

[0048] S2. At 35°C, mix the adrenaline tartrate (10 g) and a mixed solvent (70 mL) uniformly, cool to 25°C and allow to crystallize for 10 hours, filter, repeat the above operation 3 times, and dry to obtain L-adrenaline tartrate with a chiral purity of 99.7% and a yield of 45.4%; wherein the mixed solvent is a mixture of water, methanol and ethanol in a volume ratio of 1:3:3.

[0049] Comparative Example 1

[0050] This comparative example provides a method for purifying L-adrenaline and its salts, which is different from Example 1 in that: water is replaced with an equal amount of methanol, and the other components and steps are the same as those in Example 1;

[0051] Results: The chiral purity of L-adrenaline tartrate was 96.3% and the yield was 40.1%.

[0052] Comparative Example 2

[0053] This comparative example provides a method for purifying L-adrenaline and its salts. Compared with Example 1, the difference is that methanol is replaced by an equal amount of ethanol, and the other components and steps are the same as those in Example 1;

[0054] Results: The chiral purity of L-adrenaline tartrate was 95.1% and the yield was 46.6%.

[0055] Comparative Example 3

[0056] This comparative example provides a method for purifying L-adrenaline and its salts. Compared with Example 1, the difference is that ethanol is replaced by an equal amount of methanol, and the other components and steps are the same as those in Example 1;

[0057] Results: The chiral purity of L-adrenaline tartrate was 96.2%, and the yield was 32.8%.

[0058] Comparative Example 4

[0059] This comparative example provides a method for purifying L-adrenaline and its salts, which is different from Example 1 in that water and methanol are replaced with an equal amount of ethanol, and the other components and steps are the same as those in Example 1;

[0060] Results: The chiral purity of L-adrenaline tartrate was 84.6%, and the yield was 50.3%.

[0061] Comparative Example 5

[0062] This comparative example provides a method for purifying L-adrenaline and its salts. Compared with Example 1, the difference is that water and ethanol are replaced by an equal amount of methanol, and the other components and steps are the same as those in Example 1;

[0063] Results: The chiral purity of L-adrenaline tartrate was 97.8%, and the yield was 30.1%.

[0064] Comparative Example 6

[0065] This comparative example provides a method for purifying L-adrenaline and its salts. Compared with Example 1, the difference is that methanol and ethanol are replaced by an equal amount of water, and the other components and steps are the same as those in Example 1;

[0066] Results: The chiral purity of L-adrenaline tartrate was 98.7% and the yield was 27.4%.

[0067] Comparative Example 7

[0068] This comparative example provides a method for purifying L-adrenaline and its salts, which is different from Example 1 in that: the mixed solvent is a mixed solution of water, methanol and ethanol in a volume ratio of 1:4:2, and the other components and steps are the same as those in Example 1;

[0069] Results: The chiral purity of L-adrenaline tartrate was 98.3% and the yield was 37.6%.

[0070] Comparative Example 8

[0071] This comparative example provides a method for purifying L-adrenaline and its salts, which is different from Example 1 in that: the mixed solvent is a mixed solution of water, methanol and ethanol in a volume ratio of 1:1:7, and the other components and steps are the same as those in Example 1;

[0072] Results: The chiral purity of L-adrenaline tartrate was 96.3% and the yield was 49.5%.

[0073] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for purifying L-adrenaline and its salts, characterized in that: The following steps are involved: S1. Evenly mix the crude adrenaline tartrate with a mixed solvent at 30°C to 40°C, cool and crystallize, and filter to obtain primary L-adrenaline tartrate; S2, repeating the above S1 operation 1 to 3 times with the primary L-tartrate adrenaline, drying, and obtaining L-tartrate adrenaline; Wherein, in S1, the mixed solvent is a mixed solution of water, methanol and ethanol in a volume ratio of 1:(1-3):(3-6); Wherein, the preparation of the crude adrenaline tartrate comprises the following steps: At 30° C. to 40° C., DL-adrenaline and L-tartaric acid are added to an alcohol solvent for reaction to obtain the crude adrenaline tartaric acid.

2. The method for purifying L-adrenaline and its salt as claimed in claim 1, characterized in that The volume ratio of water, methanol and ethanol in the mixed solvent is 1:2:

4.

3. The method for purifying L-adrenaline and its salt as claimed in claim 1, characterized in that In S1, the mass volume ratio of the crude adrenaline tartrate and the mixed solvent is 1 g: (6-8) mL.

4. The method for purifying L-adrenaline and its salts as claimed in claim 1, characterized in that: In S1, the temperature of the cooling crystallization is 20°C to 30°C, and the time of the cooling crystallization is 8h-16h.

5. The method for purifying L-adrenaline and its salts as claimed in claim 1, characterized in that: The alcohol solvent is methanol.

6. The method for purifying L-adrenaline and its salts as claimed in claim 1, characterized in that: The molar ratio of DL-adrenaline to L-tartaric acid is 1:(1.5-3).

7. The method for purifying L-adrenaline and its salts as claimed in claim 1, characterized in that: The reaction time is 20 h to 30 h.

8. The method for purifying L-adrenaline and its salts as claimed in claim 1, characterized in that: The mass volume ratio of the DL-adrenaline to the alcohol solvent is 1 g: (5-10) mL.

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