CN115850095A - Preparation method of noradrenaline bitartrate - Google Patents
Preparation method of noradrenaline bitartrate Download PDFInfo
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- CN115850095A CN115850095A CN202211687044.7A CN202211687044A CN115850095A CN 115850095 A CN115850095 A CN 115850095A CN 202211687044 A CN202211687044 A CN 202211687044A CN 115850095 A CN115850095 A CN 115850095A
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- WNPNNLQNNJQYFA-UHFFFAOYSA-N [2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]azanium;2,3,4-trihydroxy-4-oxobutanoate Chemical compound OC(=O)C(O)C(O)C(O)=O.NCC(O)C1=CC=C(O)C(O)=C1 WNPNNLQNNJQYFA-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims description 10
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Abstract
The invention relates to the technical field of medicines, in particular to a method for preparing noradrenaline bitartrate by splitting a noradrenaline racemate. The method comprises the steps of firstly salifying D-tartaric acid and racemic noradrenaline, and then separating R-type noradrenaline by controlling crystallization temperature under the action of a mixed solvent of alcohol and water; then the chiral purity of the product can be improved to 99 percent by pulping; decolorizing with active carbon and dissociating with ammonia water; and finally salifying the obtained noradrenaline and L-tartaric acid to obtain noradrenaline bitartrate. The method has the advantages of simple process, easy operation, safety, environmental protection and higher chiral purity of the product.
Description
Technical Field
The invention relates to the technical field of medicines, relates to an isomer separation technology of a known compound, and particularly relates to a method for separating noradrenaline isomers.
Background
Norepinephrine, also known as norepinephrine, is a substance formed by removing N-methyl from epinephrine, belongs to catecholamine in chemical structure, is a synthetic levorotatory isomer currently used for medicine, and is usually bitartrate salt thereof. Norepinephrine bitartrate (norpinephrine bitartrate) with the chemical name (R) -4- (2-amino-1-hydroxyethyl) -1, 2-benzenediol bitartrate monohydrate, the structure of which is shown in the following formula:
norepinephrine bitartrate, the name of western medicine. The common dosage form is injection. Is an adrenoceptor agonist. Can be used for treating hypotension caused by acute myocardial infarction and extracorporeal circulation; for shock caused by hypovolemia, hypotension or hypotension after pheochromocytoma resection, the product is used as adjuvant therapy for supplementing blood volume during emergency treatment, so as to raise blood pressure, and temporarily maintain perfusion of brain and coronary artery until blood volume supplementing therapy is performed; it can also be used for hypotension during intravertebral block and blood pressure maintenance after resuscitation of cardiac arrest. Therefore, the research on the synthesis process has great economic value and social significance.
At present, many relevant documents about the synthetic route of noradrenaline bitartrate are available, and most of the documents are obtained by taking catechol as a raw material and performing chloroacetylation, ammoniation, palladium-carbon catalytic hydrogenation and L-tartaric acid resolution and salt formation. The resolution mode mainly uses purified water as a solvent and obtains the product by resolution for many times. In a newly reported method (8 th stage of 2014 of chemical technology and development, research on synthesis of (-) -noradrenaline bitartrate, liangda Wei and Wangyue), the chiral purity is 88.9% at the highest, and the method has low yield and insufficient chiral purity. The resolution method reported in the related patent at present is to re-resolve commercially available levonoradrenaline, and the resolution of racemate cannot be completed (see patent application CN 201911367929.7).
At present, in pharmacopoeia standards (chp/ep/jp/ip/usp) of various countries, there is no isomer restriction standard. Therefore, the technology still has great promotion space for obtaining the noradrenaline bitartrate with lower content of pharmaceutical grade isomer while improving the yield.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a method for preparing noradrenaline bitartrate by resolving noradrenaline racemate. The method comprises the steps of salifying D-tartaric acid and racemic noradrenaline, and separating R-type noradrenaline under the action of a mixed solvent of alcohol and water and by controlling crystallization temperature; then the chiral purity of the product can be improved to 99 percent by pulping; decolorizing with active carbon, and dissociating with ammonia water; and finally salifying the obtained noradrenaline and L-tartaric acid to obtain noradrenaline bitartrate.
The specific purification method is as follows:
(1) After salifying the noradrenaline racemate and D-tartaric acid, resolving the salt in a mixed solution of alcohol and water to obtain a compound 1 (noradrenaline D-tartrate, wherein the proportion of R configuration is more than or equal to 85%):
adding noradrenaline (wherein the ratio of (S) to (R) is about 50), D-tartaric acid and purified water into a reaction vessel, stirring at room temperature for dissolving, adding alcohol, heating to 50-80 ℃, keeping the temperature and stirring for 0.5-1 hour, cooling to 5-45 ℃, keeping the temperature and crystallizing, carrying out suction filtration, washing and drying the obtained product, and obtaining the compound 1.
(2) Pulping the compound 1 in a mixed solution of alcohol and water to obtain a compound 2 (noradrenaline D-tartrate, wherein the proportion of R configuration can reach 99%):
adding the compound 1 and purified water into a reaction container, stirring at normal temperature for dissolving, adding alcohol (the same as the alcohol in the step (1)), heating to 10-45 ℃, keeping the temperature and stirring for 1 hour, slowly cooling to 10 +/-5 ℃, and performing suction filtration to obtain a compound 2, wherein the step can be repeated for n (n is more than or equal to 0) times. The chiral purity can reach 99%.
(3) Decolorizing the compound 2 with activated carbon and dissociating with ammonia water to obtain a compound 3 (R configuration norepinephrine):
adding the compound 2 into 5g/L sodium metabisulfite aqueous solution, adding activated carbon, heating to 15-45 ℃, keeping the temperature and stirring for 0.5 hour, and then carrying out suction filtration to obtain filtrate. And cooling the filtrate to 10 +/-5 ℃, adjusting the pH to 9-10 by using ammonia water, carrying out suction filtration, washing a filter cake by using purified water and absolute ethyl alcohol in sequence, and drying to obtain a compound 3.
(4) Salifying the compound 3 and L-tartaric acid in an alcohol-water solution to obtain noradrenaline bitartrate
Adding the compound 3 into a reaction container, adding purified water and L-tartaric acid, stirring at normal temperature for dissolving, slowly adding methanol or ethanol to obtain a large amount of solid, stirring at 5 +/-5 ℃ for 2 hours, performing suction filtration, washing a filter cake, and drying to obtain the norepinephrine bitartrate.
Preferably, the alcohol in the step (1) is methanol or ethanol, and the proportion of the norepinephrine, the D-tartaric acid, the purified water and the alcohol is 1g, (0.8-1.1) g, (2-3) mL, (10-15) mL.
Preferably, the proportion of the compound 1, purified water and alcohol in the step (2) is 1g (1-1.5) mL (5-7.5) mL.
Preferably, the proportion of the compound 2, the sodium metabisulfite aqueous solution and the activated carbon in the step (3) is 1g (2-10) mL (0.03-0.05) g.
Preferably, the ratio of the compound 3, the purified water, the L-tartaric acid and the methanol/ethanol in the step (4) is 1g (1-3) mL (0.8-1.1) g (10-20) mL.
Compared with the prior art, the method has the advantages and beneficial effects that:
compared with the prior art, the method can directly split the norepinephrine racemate, and has the advantages of simple process, easy operation, safety and environmental protection. The content of the isomer can be adjusted according to the beating times, the content of the S-noradrenaline can be stably controlled within 2 percent, and the isomer can be controlled within 1.0 percent after multiple beating.
Drawings
FIG. 1 is a chiral HPLC plot of noradrenaline bitartrate from the control purchased in the middle (lot number: 100169-201404, ID.
Fig. 2 is a chiral purity chart of compound 1 prepared in example 1.
Figure 3 is a chiral purity plot of compound 2 prepared in example 1.
FIG. 4 is an HPLC chart of noradrenaline bitartrate prepared in example 1.
Figure 5 is a chiral purity plot of compound 1 prepared in example 2.
Figure 6 is a chiral purity plot of compound 2 prepared in example 2.
FIG. 7 is an HPLC chart of noradrenaline bitartrate prepared in example 2.
Figure 8 is a chiral purity profile for compound 1 prepared in example 3.
Figure 9 is a chiral purity plot for compound 2 prepared in example 3.
FIG. 10 is an HPLC plot of noradrenaline bitartrate prepared in example 3.
Detailed Description
Applicants will now further describe the method of the present invention in detail with reference to specific examples, but it should be understood that the following examples are only illustrative and not intended to limit the scope of the invention as claimed in the claims. The experimental methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are commercially available unless otherwise specified. The concentration of the ammonia water is 25.0 to 28.0 weight percent.
Norepinephrine racemate: reference Journal of the American Pharmaceutical Association (Scientific), 1946, 35 (10): 306-309.
Example 1:
a preparation method of noradrenaline bitartrate comprises the following steps:
the method comprises the following steps: adding 10g (59.11 mmol) of norepinephrine racemate into a reactor, adding 9.05g (60.30 mmol) of D-tartaric acid and 25ml of purified water, stirring at room temperature for 0.5h until the solution is clear, adding 125ml of anhydrous methanol, heating to reflux, stirring at constant temperature for 0.5h, slowly cooling to 20 +/-2 ℃, stirring at constant temperature for 1 h, performing suction filtration, washing the product with 10ml of anhydrous ethanol, and drying to obtain 5.5g of compound 1, wherein the yield is 29.14%, and the chiral purity HPLC (figure 2) is 93.26%.
Step two: adding 5g (15.66 mmol) of the compound 1 into a reactor, adding 6.25ml of purified water, stirring at normal temperature for dissolving, adding 31.25ml of anhydrous methanol, stirring at 20 +/-2 ℃ for 1 hour, slowly cooling to 10 +/-2 ℃, performing suction filtration to obtain a filter cake, repeating the operation of the second step, and drying the obtained product to obtain 3.6g of the compound 2, wherein the yield is 72.00%, and the chiral purity is 98.61% by HPLC (figure 3).
Step three: 3g (9.40 mmol) of Compound 2 was added to 20ml of a 5g/L aqueous solution of sodium metabisulfite, 0.15g of activated carbon (3 wt%) was added thereto, and the mixture was stirred at 20. + -. 2 ℃ for 0.5 hour and then filtered under suction to obtain a filtrate. And cooling the filtrate to 10 +/-2 ℃, adjusting the pH to 9-10 by using ammonia water, performing suction filtration, sequentially washing a filter cake by using 4ml of purified water and 4ml of absolute ethyl alcohol, and drying to obtain 1.51g of a compound 3, wherein the yield is 94.98%.
Step four: adding 1.5g (8.86 mmol) of the solid obtained in the third step into a reaction bottle, adding 1.5ml of purified water, adding 1.33g (8.86 mmol) of L-tartaric acid, stirring at normal temperature for dissolving, adding 15ml of anhydrous methanol, stirring at 5 +/-2 ℃ for 2 hours, performing suction filtration, leaching a filter cake by using methanol, and drying to obtain 2.6g of noradrenaline bitartrate, wherein the yield is 86.67%, and the liquid phase HPLC (figure 4) has the liquid phase purity of 99.65%.
Example 2:
a preparation method of noradrenaline bitartrate comprises the following steps:
the method comprises the following steps: adding 10g (59.11 mmol) of noradrenaline racemate into a reactor, adding 9.05g (60.30 mmol) of D-tartaric acid and 25ml of purified water, stirring at room temperature for 0.5h until the solution is clear, adding 125ml of absolute ethyl alcohol, heating to 75 +/-2 ℃, keeping the temperature and stirring for 1 h, slowly cooling to 10 +/-2 ℃, keeping the temperature and stirring for 1.5 h, performing suction filtration, washing a product with 10ml of absolute ethyl alcohol, and drying to obtain 7.5g of a compound 1, wherein the yield is 39.74%, and the chiral purity is 89.61% by using chiral purity HPLC (figure 5).
Step two: adding 5g (15.66 mmol) of the compound 1 into a reactor, adding 6.25ml of purified water, stirring at normal temperature to dissolve, adding 31.25ml of absolute ethyl alcohol, heating to 40 +/-2 ℃, keeping the temperature and stirring for 1 hour, slowly cooling to 10 +/-2 ℃, carrying out suction filtration to obtain a filter cake, repeating the operation of the step two, and drying the obtained product to obtain 4.1g of the compound 2, wherein the yield is 82.00%, and the chiral purity is 99.18% by means of chiral purity HPLC (shown in figure 6).
Step three: 4g (12.53 mmol) of the compound 2 was added to 20ml of a 5g/L aqueous solution of sodium metabisulfite, 0.2g of activated carbon (3 wt%) was added thereto, and the mixture was heated to 40. + -. 2 ℃ and stirred for 0.5 hour under heat preservation, followed by suction filtration to obtain a filtrate. And cooling the filtrate to 10 +/-2 ℃, adjusting the pH to 9-10 by using ammonia water, performing suction filtration, sequentially washing a filter cake by using 4ml of purified water and 4ml of absolute ethyl alcohol, and drying to obtain 2.01g of a compound 3, wherein the yield is 94.86%.
Step four: and (3) adding 2.0g (11.82 mmol) of the solid obtained in the step three into a reaction bottle, adding 2ml of purified water, adding 1.77g (11.82 mmol) of L-tartaric acid, stirring at normal temperature for dissolving, adding 20ml of absolute ethanol, stirring at 5 +/-2 ℃ for 2 hours, carrying out suction filtration, leaching a filter cake with ethanol, and drying to obtain 3.6g of noradrenaline bitartrate, wherein the yield is 90.00%, and the liquid phase HPLC (figure 7) has the liquid phase purity of 100%.
Example 3:
a preparation method of noradrenaline bitartrate comprises the following steps:
the method comprises the following steps: adding 200g (1.182 mol) of noradrenaline racemate into a reactor, adding 178g (1.186 mol) of D-tartaric acid and 500ml of purified water, stirring for 0.5h at room temperature until the solution is clear, adding 2500ml of absolute ethyl alcohol, heating to 60 +/-2 ℃, keeping the temperature and stirring for 1 h, slowly cooling to 40 +/-2 ℃, keeping the temperature and stirring for 1.5 h, performing suction filtration, washing a product with 100ml of absolute ethyl alcohol, and drying to obtain 123g of compound 1, wherein the yield is 32.59%, the chiral purity is HPLC (figure 8), and the chiral purity is 93.26%.
Step two: adding 123g (0.385 mol) of the compound 1 into a reactor, adding 154ml of purified water, stirring at normal temperature for dissolving, adding 769ml of absolute ethyl alcohol, heating to 40 +/-2 ℃, keeping the temperature and stirring for 1 hour, slowly cooling to 10 +/-2 ℃, performing suction filtration to obtain a filter cake, and drying to obtain 107g of the compound 2, wherein the yield is 86.99%, the chiral purity is High Performance Liquid Chromatography (HPLC) (figure 9), and the chiral purity is 99.25%.
Step three: 107g (0.335 mol) of Compound 2 was added to 430ml of a 5g/L aqueous solution of sodium metabisulfite, 3.22g of activated carbon (3 wt%) was added, the temperature was raised to 40. + -. 2 ℃ and stirred for 0.5 hour under constant temperature, followed by suction filtration to obtain a filtrate. And cooling the filtrate to 10 +/-2 ℃, adjusting the pH to 9-10 by using 64.5g of ammonia water, performing suction filtration, sequentially soaking and washing a filter cake by using 107ml of purified water and 107ml of absolute ethyl alcohol, and drying to obtain 55g of a compound 3, wherein the yield is 97.00%.
Step four: and (3) adding 55g (0.325 mol) of the solid obtained in the third step into a reaction bottle, adding 55ml of purified water, adding 49g (0.326 mol) of L-tartaric acid, stirring at normal temperature for dissolving, adding 550ml of absolute ethanol, stirring at 2 +/-2 ℃ for 2 hours, carrying out suction filtration, leaching a filter cake with ethanol, and drying to obtain 105g of noradrenaline bitartrate, wherein the yield is 95.45%. Liquid phase HPLC (fig. 10), liquid phase purity 99.97%.
Claims (5)
1. A preparation method of noradrenaline bitartrate comprises the following steps:
(1) Adding a norepinephrine racemate, D-tartaric acid and purified water into a reaction container, stirring at room temperature for dissolving, adding alcohol, heating to 50-80 ℃, keeping the temperature, stirring for 0.5-1 hour, cooling to 5-45 ℃, keeping the temperature, crystallizing, performing suction filtration, washing and drying the obtained product to obtain a compound 1;
(2) Adding the compound 1 and purified water into a reaction container, stirring at normal temperature for dissolving, adding alcohol which is the same as the alcohol in the step (1), heating to 10-45 ℃, keeping the temperature and stirring for 1 hour, slowly cooling to 10 +/-5 ℃, carrying out suction filtration to obtain a filter cake, repeating the step (2) for n times, wherein n is more than or equal to 0, and obtaining a compound 2;
(3) Adding the compound 2 into a sodium metabisulfite aqueous solution, adding activated carbon, heating to 15-45 ℃, keeping the temperature, stirring for 0.5 hour, performing suction filtration to obtain a filtrate, cooling the filtrate to 10 +/-5 ℃, adjusting the pH to 9-10 by using ammonia water, performing suction filtration, washing and drying a filter cake to obtain a compound 3;
(4) Adding the compound 3 into a reaction container, adding purified water and L-tartaric acid, stirring at normal temperature for dissolving, slowly adding methanol or ethanol, stirring at 5 +/-5 ℃ for 2 hours, carrying out suction filtration, washing a filter cake, and drying to obtain the norepinephrine bitartrate.
2. The preparation method according to claim 1, wherein the alcohol added in the step (1) is methanol or ethanol, and the proportion of the norepinephrine racemate, the D-tartaric acid, the purified water and the alcohol is 1g, (0.8 to 1.1) g, (2 to 3) mL, (10 to 15) mL.
3. The preparation method according to claim 1, wherein the proportion of the compound 1, purified water and alcohol in the step (2) is 1g to 1.5mL to 5 to 7.5 mL.
4. The preparation method according to claim 1, wherein the concentration of the aqueous sodium metabisulfite solution in the step (3) is 5g/L, and the proportion of the compound 2, the aqueous sodium metabisulfite solution and the activated carbon is 1g (2-10) mL (0.03-0.05) g.
5. The preparation method according to claim 1, wherein the proportion of the compound 3, purified water, L-tartaric acid and methanol/ethanol in the step (4) is 1g (1 to 3) mL (0.8 to 1.1) g (10 to 20) mL.
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