CN111138434A - Preparation method of levofolinic acid - Google Patents
Preparation method of levofolinic acid Download PDFInfo
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- CN111138434A CN111138434A CN201910880598.0A CN201910880598A CN111138434A CN 111138434 A CN111138434 A CN 111138434A CN 201910880598 A CN201910880598 A CN 201910880598A CN 111138434 A CN111138434 A CN 111138434A
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- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
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Abstract
The invention relates to a preparation method of levofolinic acid, belonging to the technical field of pharmaceutical synthesis processes. The preparation method provided by the invention comprises the following steps: (1) dispersing calcium levofolinate in a solvent, slowly mixing the calcium levofolinate with carbonate at 0-60 ℃ for reaction, and removing solids after the reaction to obtain a levofolinate solution; (2) and (2) adding inorganic acid into the levofolinate solution obtained in the step (1) at the temperature of-20-30 ℃ for acidification reaction, and separating out solids after reaction to obtain the levofolinate solution. The method provided by the invention effectively improves the yield, reduces the cost and the discharge of waste liquid, the obtained wet product has good granularity and is easy to filter, calcium levofolinate ions obtained by freeze-drying are less than 0.1%, the purity is more than 99.2%, the chloride is less than 0.5%, and other indexes all meet the standard requirements.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical synthesis processes, and particularly relates to a preparation method of levofolinic acid.
Background
Levorotatory folinic acid is used as an antidote for resisting tumors and an auxiliary medicine for resisting megaloblastic anemia, the dose of the levorotatory folinic acid is 1/2 of folinic acid, the levorotatory folinic acid can participate in a reaction of utilizing folate as a carbon unit source without being reduced by dihydrofolate reductase, and the levorotatory folinic acid can actively or passively pass through a cell membrane; the levorotatory folinic acid has the same basic effect as folic acid, but the effect is better than folic acid, and meanwhile, the levorotatory folinic acid also has the effect of stimulating the growth and maturation of leucocytes, and can improve megaloblastic anemia.
At present, the products on the market with the main components of the sodium folinate for injection, the calcium folinate for injection and the calcium folinate injection are sold in China, the products on the market at abroad comprise the calcium folinate injection and the calcium levofolinate injection sold in the American Whitman company, and the sodium folinate injection and the sodium levofolinate injection sold in the Germany MEDAC company.
The calcium salt of the levorotatory calcium folinate preparation has low water solubility, is not easy to prepare a high-concentration preparation, and is limited in usage and dosage; on the other hand, too high a calcium ion concentration in plasma may cause unnecessary side effects, and therefore, calcium levofolinate often needs to be instilled slowly. Therefore, the sodium salt prepared from the levorotatory folinic acid has good water solubility and biocompatibility, the drug effect and safety of the sodium levorotatory folinate are obviously superior to those of the sodium folinate and the calcium levorotatory folinate, and the sodium salt has more advantages in clinical application.
Chinese patent CN101229167A, Chinese patent CN101780084A and CN102743331A all report that levofolinic acid is used as a raw material drug to be prepared into a sodium salt form injection administration preparation, so that the quality of the raw material drug levofolinic acid is crucial to the stability of the injection. The reports on the preparation process of the levofolinic acid are less, and Chinese patents CN88102709A, CN101792444A and US2008/0153849A1 all report that the levofolinic acid calcium is obtained by acidification of hydrochloric acid in an aqueous medium. The former method is to drop hydrochloric acid into the dissolved calcium levofolinate solution, while the U.S. patent adopts different acidification modes, the dissolved calcium levofolinate and hydrochloric acid are dropped into water according to a certain dropping speed, wet levofolinate obtained by the two methods is in a slurry state and is difficult to filter or centrifuge, so that related substances of the wet levofolinate are increased, and the residues of calcium ions and chloride ions after drying seriously exceed the standard.
Therefore, it is very important to develop a new technology suitable for the industrial production of levofolinic acid.
Disclosure of Invention
The invention aims to provide a preparation method of levofolinic acid based on the prior art.
The technical scheme of the invention is as follows:
a preparation method of levofolinic acid comprises the following steps:
(1) dispersing calcium levofolinate in a solvent, slowly mixing the calcium levofolinate with carbonate at 0-60 ℃ for reaction, and removing solids after the reaction to obtain a levofolinate solution;
(2) and (2) adding inorganic acid into the levofolinate solution obtained in the step (1) at the temperature of-20-30 ℃ for acidification reaction, and separating out solids after reaction to obtain the levofolinate solution.
The present invention can adopt specific carbonate which does not affect the method, and the carbonate mentioned in the present invention is not limited to carbonate solid, but can also be carbonate aqueous solution prepared by dissolving carbonate in water. The carbonate aqueous solution adopted by the invention is a specific carbonate aqueous solution which does not influence the method, and in a preferred scheme, the carbonate is one or more of sodium carbonate, potassium carbonate, lithium carbonate, rubidium carbonate, cesium carbonate or corresponding aqueous solutions thereof, for example, the sodium carbonate aqueous solution, the potassium carbonate aqueous solution, the rubidium carbonate aqueous solution or the cesium carbonate aqueous solution; in a more preferred embodiment, the carbonate is sodium carbonate, potassium carbonate or their corresponding aqueous solutions, for example, sodium carbonate aqueous solution or potassium carbonate aqueous solution.
In the current prior art, the acidification mechanism of calcium levofolinate with the addition of mineral acid (e.g. hydrochloric acid) is as follows:
the inventor of the present invention further studies the calcium acidification mechanism of levofolinate based on the prior art, and as a result, finds that: when inorganic acid (such as hydrochloric acid) is added, part of the calcium levofolinate does exist, and the acidification reaction is carried out according to the acidification mechanism disclosed in the prior art to generate the levofolinic acid, but because the organic reaction process is complex, other related reaction processes also exist to interfere the formation of the main product levofolinic acid. After a great deal of research work we found that: 1 molecule of levofolinic acid calcium, two carboxyl groups of which are combined with 1 calcium ion, in the process of adding inorganic acid (such as hydrochloric acid) to carry out acidification reaction, because of the special structure of levofolinic acid calcium, the dissociation capability of two carboxyl groups is different, wherein one carboxyl group is dissociated first to generate carboxylic acid, and the other carboxyl group is still combined with calcium ion without dissociation, so as to form an intermediate structure 1, which is shown in detail as follows:
however, intermediate structure 1 produced in the reaction can further react with the generated levofolinic acid to form intermediate structure 2 of monocalcium salt structure (similar to 2 molecules of levofolinic acid combined with 1 calcium ion to form monocalcium salt), as shown below:
the mesostructure 2 of the monocalcium salt structure can slowly separate out from the solvent due to extremely poor water solubility, and then continuously reacts with hydrochloric acid to completely dissociate to form two independent levofolinic acid molecules. In the process of separating out the levofolinic acid, the water solubility of the intermediate structure 2 of the monocalcium salt structure is poorer than that of the levofolinic acid, and the monocalcium salt structure is more easily separated out, so that the intermediate structure 2 is easily wrapped by the separated-out levofolinic acid solid, in order to reduce calcium ion residue, the intermediate structure 2 of the monocalcium salt structure is completely acidified, the amount of inorganic acid needs to be increased, the acidification time needs to be prolonged, and the levofolinic acid is unstable in a strongly acidic solution, so that the content of related substances of the levofolinic acid is increased, and finally the content of the calcium ions and related substances.
In order to overcome the defects, carbonate (such as sodium carbonate) and calcium levofolinate are subjected to ion exchange reaction to remove calcium carbonate precipitate to obtain sodium levofolinate with good water solubility, and then acidification is carried out to form an intermediate structure 3 of a monosodium salt structure. The mesostructure 3 of the monosodium salt structure has good water solubility, so that the monosodium salt structure is not easy to wrap in the process of separating out the levofolinic acid, further dissociation is facilitated, the problems are avoided, in addition, the solubility of the sodium salt is good, the dosage of a solvent can be reduced, and the discharge of waste water or waste liquid is effectively reduced. The details are as follows:
in the step (1), the molar ratio of the carbonate to the calcium levofolinate is 0.8-2.5: 1, preferably 1-2: 1, and more preferably 1.5-2: 1.
Further, in the step (1), the temperature for dispersing the calcium levofolinate in the solvent is-20 to 100 ℃; preferably 55 to 60 ℃.
Further, in the step (1), the reaction temperature is 0-30 ℃; further, it is preferably 0 to 10 ℃.
In the step (1), the solvent for dispersing the calcium levofolinate is water and C1～C4Alcohol or a mixed solvent thereof, and further, water and C1～C4In a mixed solvent of alcohol, water and C1～C4The alcohols may be miscible in any volume ratio. Wherein, C1～C4The alcohol is alcohol with 1-4 carbon atoms, such as methanol, ethanol, propanol, isopropanol or butanol. In a preferred scheme, the solvent for dispersing the calcium levofolinate is water, methanol, ethanol, propanol, isopropanol, n-butanol or a mixed solvent of the water, the methanol, the ethanol, the propanol, the isopropanol and the n-butanol; more preferably, the solvent is water, methanol or ethanol; particularly more preferably, the solvent is water.
The concentration of the calcium levofolinate dispersed in the solvent can be adjusted according to actual conditions, and in a preferable scheme, the mass ratio of the calcium levofolinate to the solvent is 1: 1-1: 10000, preferably 1: 5-1: 100, and further preferably 1: 5-1: 50.
A more specific operation of the step (1) is as follows: dissolving calcium levofolinate in a solvent under the condition of heating or not, slowly mixing the calcium levofolinate with a carbonate solution at 0-15 ℃ for reaction, filtering to remove precipitated solids after the reaction, wherein the filtrate is the levofolinate solution. The precipitated solid may be further washed with a solvent, and the washed washing solution may be incorporated into the levofolinate solution. The solvent in the levofolinate solution mentioned in the invention can be only water, or water and C1～C4A mixed solution of alcohol.
The inorganic acid adopted in the step (2) is one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or carbonic acid.
In the step (2), inorganic acid is added to adjust the pH value of a reaction system to 2.0-3.5; preferably, the pH value is 2.0-2.5.
In the invention, the inorganic acid in the step (2) does not need to be a high-concentration inorganic acid, but only needs to be a dilute inorganic acid, such as 0.2-4N inorganic acid, especially 0.5-1.5N inorganic acid. Specifically, the inorganic acid may be 0.2 to 4N hydrochloric acid, particularly 0.5 to 1.5N hydrochloric acid.
Further, in the step (2), the reaction temperature is 0-20 ℃; further, it is preferably 0 to 5 ℃.
In the step (2), stirring for reaction in the acidification reaction, standing for aging, filtering after reaction, and washing and drying a filter cake to obtain the levofolinic acid solid.
By adopting the technical scheme of the invention, the advantages are as follows:
the preparation method of the levofolinic acid provided by the invention overcomes the defects and shortcomings of the prior art, and provides a new method suitable for industrial production of the levofolinic acid. The method effectively improves the yield, reduces the cost and the discharge of waste liquid, the obtained wet product has good granularity and is easy to filter, calcium levofolinate obtained by freeze-drying has less than 0.1 percent of calcium ion, the purity of more than 99.2 percent and the chloride of less than 0.5 percent, and other indexes all meet the standard requirements.
Detailed Description
The preparation process of the present invention is further illustrated by the following examples, which are not intended to limit the invention in any way.
Example 1: preparation of levofolinic acid
Adding 45L of pure water into a 100L glass reaction kettle, heating to 55-60 ℃ under stirring, adding 1.5kg (2.45mol, 16.4% of water) of calcium levofolinate, keeping the temperature at 55-60 ℃, stirring to be basically dissolved, cooling to 0-10 ℃ firstly, dropwise adding a sodium carbonate aqueous solution (520.0g of sodium carbonate (4.9mol) is dissolved in 7.0L of pure water), keeping the temperature at 0-10 ℃, stirring for 1 hour under heat preservation, filtering out precipitated solids, washing a filter cake once with 200ml of pure water, and obtaining a filtrate, namely the sodium levofolinate solution. Putting the filtrate into a 100L glass reaction kettle, cooling to 0-5 ℃ under stirring, controlling the temperature of a reaction system to be 0-5 ℃, uniformly dropwise adding 1N dilute hydrochloric acid, stopping dropwise adding when the pH of an acidification end point is 2.0-2.5, stirring for about 30min, standing and aging for 30min, filtering, washing a filter cake for 2 times by using 7.5L pure water, and freeze-drying a wet product to obtain 0.98kg of levofolinic acid, wherein the yield is as follows: 85% (purity 99.6%, calcium ion 0.07%, chloride less than 0.5%). The data corresponding to the substance profile of example 1 are shown in Table 1.
TABLE 1 data corresponding to the relevant substance profile of example 1
Example 2: preparation of levofolinic acid
Adding 0.45L of pure water into a 1L reaction bottle, heating to 55-60 ℃ under stirring, adding 15g (0.0245mol, water content is 16.4%) of calcium levofolinate, keeping the temperature at 55-60 ℃, stirring to be basically dissolved, cooling to 0-10 ℃, dropwise adding a sodium carbonate aqueous solution (2.6g of sodium carbonate (0.0245mol) is dissolved in 45mL of pure water), keeping the temperature at 0-10 ℃, stirring for 1 hour under heat preservation after dropwise adding, filtering out separated solids, washing a filter cake once with 20mL of pure water, and obtaining a filtrate, namely the sodium levofolinate solution. Putting the filtrate into a 1L reaction bottle, cooling to 0-5 ℃ under stirring, controlling the temperature of a reaction system to be 0-5 ℃, uniformly dropwise adding 1N dilute hydrochloric acid, stopping dropwise adding when the pH of an acidification end point is 2.0-2.5, stirring for about 30min, standing and aging for 30min, filtering, washing a filter cake for 2 times by using 75mL pure water, and freeze-drying a wet product to obtain 9.1g of levofolinic acid, wherein the yield is as follows: 78% (purity 99.5%, calcium ion 0.065%, chloride less than 0.5%).
Example 3: preparation of levofolinic acid
Adding 0.45L of ethanol or methanol into a 1L reaction bottle, adding 15g (0.0245mol, water content is 16.4%) of calcium levofolinate, cooling to 0-10 ℃, dropwise adding a sodium carbonate aqueous solution (5.2g of sodium carbonate (0.049mol) is dissolved in 50mL of pure water), keeping the temperature at 0-10 ℃, stirring for 1 hour under heat preservation after dropwise adding, filtering out separated solid, washing a filter cake with 20mL of ethanol once, and obtaining a filtrate, namely the sodium levofolinate solution. Putting the filtrate into a 1L reaction bottle, cooling to 0-5 ℃ under stirring, controlling the temperature of a reaction system to be 0-5 ℃, uniformly dropwise adding 1N dilute hydrochloric acid, stopping dropwise adding when the pH of an acidification end point is 2.0-2.5, stirring for about 30min, standing and aging for 30min, filtering, washing a filter cake for 2 times by using 75mL pure water, and freeze-drying a wet product to obtain 8.1g of levofolinic acid, wherein the yield is as follows: 70% (purity 99.4%, calcium ion 0.075%, chloride less than 0.5%).
Example 4: preparation of levofolinic acid
Adding 0.45L of water into a 1L reaction bottle, adding 15g (0.0245mol, water content is 16.4%) of calcium levofolinate, cooling to 0-10 ℃, dropwise adding a sodium carbonate aqueous solution (5.2g of sodium carbonate (0.049mol) is dissolved in 50mL of pure water), keeping the temperature at 0-10 ℃, stirring for 1 hour under heat preservation after dropwise adding, filtering out separated solid, washing a filter cake with 20mL of ethanol once, and obtaining a filtrate, namely the sodium levofolinate solution. Putting the filtrate into a 1L reaction bottle, cooling to 0-5 ℃ under stirring, controlling the temperature of a reaction system to be 0-5 ℃, uniformly dropwise adding 1N dilute hydrochloric acid, stopping dropwise adding when the pH of an acidification end point is 3.0-3.5, stirring for about 30min, standing and aging for 30min, filtering, washing a filter cake for 2 times by using 75mL pure water, and freeze-drying a wet product to obtain 7.5g of levofolinic acid, wherein the yield is as follows: 64% (purity 99.3%, calcium ion 0.08%, chloride less than 0.5%).
Comparative example 1: preparation of levofolinic acid (refer to US2008/0153849A1)
290g of calcium levofolinate is added into a 10L three-necked bottle, 4.9L of purified water is added, the temperature is heated to 58 ℃, and the temperature is cooled to 45 ℃ for standby. Adding 4L of purified water into a 20L reaction kettle, cooling to 6 ℃, then dropwise adding the calcium levofolinate solution and 18% of dilute hydrochloric acid solution, controlling the speed of dropwise adding the calcium levofolinate solution, keeping the reaction temperature at 6-10 ℃, simultaneously controlling dropwise adding the 18% of dilute hydrochloric acid solution to make the pH of the system between 2.8-3.2, filtering after dropwise adding, washing with purified water at 5-10 ℃, and performing vacuum drying at room temperature to obtain 146g of product with the yield of 65% (the purity is 96.85%, the calcium ions are 0.25%, and the chloride is more than 0.5%). The data on the substance profile of comparative example 1 are shown in Table 2.
TABLE 2 data relating to the substance profile of comparative example 1
Comparative example 2: preparation of levofolinic acid (refer to Chinese patent CN101792444A)
Adding 5g of calcium levofolinate into 50ml of water, heating to 50 ℃, dropwise adding 5N hydrochloric acid, adjusting the pH value to 1-2, cooling at 0-5 ℃ in an ice bath, standing overnight at the temperature, gradually separating out a white solid from a water layer, filtering, washing with 10ml of water, washing with ethanol, and drying to obtain 3.4g of levofolinate, wherein the yield is as follows: 88% (purity 97.78%, calcium ion 0.30%, chloride greater than 0.5%). The data on the substance profile of comparative example 2 are shown in Table 3.
TABLE 3 data relating to the substance profile of comparative example 2
Comparative example 3: preparation of levofolinic acid
Adding 1.70Kg of calcium levofolinate into a reactor, adding 102L of water, cooling to 1-5 ℃, slowly dripping 0.3MHCl to adjust the pH value to be about 2.5-3, stirring for 2 hours, then preserving heat, aging for 3-5 hours, performing suction filtration, respectively stirring and washing filter cakes for 6 times by 15L of ice water, then performing suction filtration, and performing vacuum drying at room temperature to obtain 1.12Kg of yellow solid with the yield of 71.2% (the purity is 99.14%, the calcium ion is 0.18%, and the chloride is less than 0.5%). The data corresponding to the substance profile of comparative example 3 are shown in Table 4.
TABLE 4 data relating to the substance profile of comparative example 3
Compared with the prior art, the method obviously improves the yield, has smaller calcium ions and related substances, is easy to filter products, and has the specific data shown in the following table 2 and the impurity structure shown in the following table 3.
Table 2 comparison of different acidification methods
TABLE 3 different impurity Structure
The preparation method of the levofolinic acid provided by the invention overcomes the defects and shortcomings of the prior art, and provides a new method suitable for industrial production of the levofolinic acid. The method effectively improves the yield, reduces the cost and the discharge of waste liquid, the obtained wet product has good granularity and is easy to filter, calcium levofolinate obtained by freeze-drying has less than 0.1 percent of calcium ion, the purity of more than 99.2 percent and the chloride of less than 0.5 percent, and other indexes all meet the standard requirements.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (10)
1. The preparation method of the levofolinic acid is characterized by comprising the following steps:
(1) dispersing calcium levofolinate in a solvent, slowly mixing the calcium levofolinate with carbonate at 0-60 ℃ for reaction, and removing solids after the reaction to obtain a levofolinate solution;
(2) and (2) adding inorganic acid into the levofolinate solution obtained in the step (1) at the temperature of-20-30 ℃ for acidification reaction, and separating out solids after reaction to obtain the levofolinate solution.
2. The method for preparing levofolinic acid according to claim 1, wherein in step (1), the carbonate is one or more of sodium carbonate, potassium carbonate, lithium carbonate, rubidium carbonate, cesium carbonate or their corresponding aqueous solutions, preferably sodium carbonate, potassium carbonate or their corresponding aqueous solutions.
3. The method for preparing levofolinic acid according to claim 1 or 2, wherein in the step (1), the molar ratio of the carbonate to the calcium levofolinate is 0.8-2.5: 1, preferably 1-2: 1, and more preferably 1.5-2: 1.
4. The method for preparing levofolinic acid according to claim 3, wherein the temperature for dispersing in step (1) is-20 to 100 ℃; preferably 55-60 ℃; the reaction temperature is 0-30 ℃; preferably 0 to 10 ℃.
5. The method for producing levofolinic acid according to claim 4, wherein in step (1), the solvent is water, C1～C4An alcohol or a mixed solvent thereof; preferably, the solvent is water, methanol, ethanol, propanol, isopropanol, butanol or a mixed solvent thereof; further preferably, the solvent is water.
6. The method for preparing levofolinic acid according to claim 1, wherein in the step (1), calcium levofolinate is first dissolved in a solvent with or without heating, then slowly mixed with a carbonate solution at 0-15 ℃ for reaction, and after the reaction, the precipitated solid is removed by filtration, and the filtrate is the levofolinic acid salt solution.
7. The method for preparing levofolinic acid according to claim 1, wherein in step (2), the inorganic acid is one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or carbonic acid.
8. The method for preparing levofolinic acid according to claim 7, wherein the inorganic acid is added in the step (2) to adjust the pH value of the reaction system to 2.0-3.5; preferably, the pH value is 2.0-2.5.
9. The method for preparing levofolinic acid according to claim 1, wherein in the step (2), the reaction temperature is 0-20 ℃; preferably 0 to 5 ℃.
10. The method for preparing levofolinic acid as claimed in claim 1, wherein in the step (2), the reaction is performed by stirring during the acidification reaction, then the reaction is performed by standing and aging, the reaction is followed by filtering, and the filter cake is washed and dried to obtain the solid levofolinic acid.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN88102709A (en) * | 1987-05-15 | 1988-12-28 | 阿泼洛发公司 | Method for separating folinic acid |
| US20080153849A1 (en) * | 2004-02-20 | 2008-06-26 | Francese Giancarlo | Process for the Preparation of Crystalline (6Rrs)-N(5)-Formyl-5,6,7,8-Tetrahydrofolic Acid |
| CN101792444A (en) * | 2009-02-02 | 2010-08-04 | 天津康鸿医药科技发展有限公司 | Sodium levofolinate and preparation method and drug combination thereof |
| US20120245177A1 (en) * | 2011-03-21 | 2012-09-27 | Gmt Fine Chemicals Sa | Crystalline levofolinic acid and process for its preparation |
| CN104277044A (en) * | 2013-07-10 | 2015-01-14 | 上海汇伦生命科技有限公司 | Method for efficiently preparing low-calcium-content folinic acid |
-
2019
- 2019-09-18 CN CN201910880598.0A patent/CN111138434A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN88102709A (en) * | 1987-05-15 | 1988-12-28 | 阿泼洛发公司 | Method for separating folinic acid |
| US20080153849A1 (en) * | 2004-02-20 | 2008-06-26 | Francese Giancarlo | Process for the Preparation of Crystalline (6Rrs)-N(5)-Formyl-5,6,7,8-Tetrahydrofolic Acid |
| CN101792444A (en) * | 2009-02-02 | 2010-08-04 | 天津康鸿医药科技发展有限公司 | Sodium levofolinate and preparation method and drug combination thereof |
| US20120245177A1 (en) * | 2011-03-21 | 2012-09-27 | Gmt Fine Chemicals Sa | Crystalline levofolinic acid and process for its preparation |
| CN104277044A (en) * | 2013-07-10 | 2015-01-14 | 上海汇伦生命科技有限公司 | Method for efficiently preparing low-calcium-content folinic acid |
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