CN115403476A - Citrate and tartrate salts of 5-aminolevulinic acid and methods for making the same - Google Patents
Citrate and tartrate salts of 5-aminolevulinic acid and methods for making the same Download PDFInfo
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Abstract
The invention discloses citrate and tartrate of 5-aminolevulinic acid and a preparation method thereof. The tartrate and citrate salts of 5-aminolevulinic acid of the invention are less skin irritating than the hydrochloride salt of 5-aminolevulinic acid. The citrate and tartrate salts of 5-aminolevulinic acid of the invention can be used for preparing photodynamic medicaments or plant growth regulators.
Description
Technical Field
The present invention relates to citrates and tartrates of 5-aminolevulinic acid and methods for their preparation.
Background
5-aminolevulinic acid is a common precursor of endogenous substances (vitamin B12, heme) and the like in organisms, has important physiological activity, is widely applied to the treatment of brain cancer and skin cancer as a photodynamic medicament, and is also used as a photosynthesis promoter for regulating the growth of plants. The salt commonly used at present is 5-aminolevulinic acid hydrochloride. The clinical application of the 5-aminolevulinic acid hydrochloride has strong skin irritation (an Ela drug instruction), and the long-term storage stability of the raw material is poor (patent CN 201310144703.7).
The desalting process of 5-aminolevulinic acid hydrochloride generally adopts diluted solution (about 10 g/L) prepared and is absorbed by hydrogen type strongly acidic ion exchange resin, then an alkaline solution is used for elution (CN 201310144703.7), acid is added for salt formation, and the salt is concentrated and crystallized at 60 ℃. The method produces more than 100 kg of acidic wastewater per kg of 5-aminolevulinic acid phosphate, the process has poor environmental protection property, and the dilute solution concentration process can cause adverse conditions such as decomposition of the 5-aminolevulinic acid phosphate.
Disclosure of Invention
The invention aims to solve the technical problem of providing tartrate and citrate of 5-aminolevulinic acid with low irritation and a preparation method thereof aiming at the defect of high skin irritation of the existing 5-aminolevulinic acid hydrochloride.
The invention provides a salt of 5-aminolevulinic acid, which is citrate or tartrate.
In some embodiments, the citrate salt is
In some embodiments, the tartrate salt is
In some embodiments, the tartaric acid salt is L-tartaric acid.
In some embodiments, the tartrate salt is
The invention also provides a preparation method of the salt of 5-aminolevulinic acid, which comprises the following steps: reacting 5-aminolevulinic acid hydrochloride with acid in water in the presence of an acid-binding agent to obtain the salt of 5-aminolevulinic acid;
the acid-binding agent is triethylamine, pyridine or a mixture thereof;
the acid is citric acid or tartaric acid.
In some embodiments, the tartaric acid can be L-tartaric acid.
In some embodiments, the molar ratio of the acid to 5-aminolevulinic acid hydrochloride can be (1.2-1.3): 1.
In some embodiments, the molar ratio of the acid scavenger to 5-aminolevulinic acid hydrochloride can be (1.05-1.2): 1, e.g., (1.1-1.2): 1.
In some embodiments, the concentration of the hydrochloride salt of 5-aminolevulinic acid in water can be from 550g to 650g/L, preferably 550g/L.
In some embodiments, the operation of the reaction may include the steps of: adding an acid-binding agent into an aqueous solution of 5-aminolevulinic acid hydrochloride and citric acid, and then carrying out reaction. Preferably, the temperature of the process control system for adding the acid binding agent is 10-15 ℃. Preferably, the acid scavenger is added in portions, e.g. dropwise.
In some embodiments, the temperature of the reaction may be 10-15 ℃.
In some embodiments, the time of the reaction may be 30min.
In some embodiments, the preparation method may further comprise a post-treatment step after the reaction, and the post-treatment step may comprise: adding a mixed solvent of ethanol and acetone into the reaction solution to crystallize, and separating out a solid to obtain a crude product of the salt of the 5-aminolevulinic acid. In the mixed solvent of ethanol and acetone, the volume ratio of ethanol to acetone may be 2. The volume of the mixed solvent may be 12 to 15 times, preferably 13 times, the volume of the water. The temperature of the crystallization may be 0 to 10 ℃. The time for the crystallization may be 6 to 10 hours, for example 8 hours.
In some embodiments, the preparation method may further comprise a purification step after the post-treatment, and the purification step may comprise: and recrystallizing the crude product of the salt of the 5-aminolevulinic acid by using a mixed solvent of ethanol and water. The recrystallization method can be a hot melt cold separation method. In the mixed solvent of ethanol and water, the volume ratio of ethanol to water may be 1. In the hot-melting cold separation method, the dissolving temperature can be 30-40 ℃, and the crystallization temperature can be 0-10 ℃.
In some embodiments, the method of preparing the salt of 5-aminolevulinic acid may comprise the steps of:
(1) Reacting 5-aminolevulinic acid hydrochloride with acid in water in the presence of an acid-binding agent;
(2) Adding a mixed solvent of ethanol and acetone into the reaction solution obtained in the step (1) for crystallization, and separating out solids to obtain a crude product of the salt of the 5-aminolevulinic acid;
(3) Recrystallizing the crude product of the 5-aminolevulinic acid salt prepared in the step (2) by using a mixed solvent of ethanol and water to obtain a salt product of the 5-aminolevulinic acid.
The invention also provides a pharmaceutical composition which comprises the salt of 5-aminolevulinic acid and pharmaceutically acceptable auxiliary materials.
The invention also provides an application of the salt of 5-aminolevulinic acid in preparing photodynamic medicaments or plant growth regulators.
In the present invention, the citrate or tartrate salt of 5-aminolevulinic acid is intended to include salts of 5-aminolevulinic acid and acid in various possible ratios, when the ratio of 5-aminolevulinic acid and acid in the molecule is not limited.
The above preferred conditions may be combined arbitrarily to obtain preferred embodiments of the present invention without departing from the general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the invention synthesizes the tartrate and the citrate of the 5-aminolevulinic acid with low irritation.
The invention also provides a method for preparing tartrate and citrate of 5-aminolevulinic acid, which has at least one of the following advantages:
(1) Pyridine or triethylamine is adopted in the desalting process, so that a large amount of waste water containing chloride ions generated in a hydrogen type strong-acid ion exchange resin adsorption process is avoided;
(2) The high-concentration solution is adopted, the amount of the used organic solvent is low, and the product degradation in the high-temperature concentration process is avoided;
(3) The ethanol-acetone mixed solvent precipitation crystallization method ensures high yield, simultaneously enables salt formed by an acid-binding agent and chloride ions or a small amount of excessive acid to be dissolved in the solution, and ensures the quality of products while ensuring green process.
Drawings
FIG. 1 is a high performance liquid chromatography purity analysis chart of tartrate salt of 5-aminolevulinic acid obtained in example 2.
FIG. 2 is a high performance liquid chromatography purity analysis chart of citrate 5-aminolevulinic acid obtained in example 1.
FIG. 3 is a photograph of the tartrate salt of 5-aminolevulinic acid obtained in example 2.
FIG. 4 is a photograph of citrate 5-aminolevulinic acid crystal form prepared in example 1.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. Experimental procedures without specifying specific conditions in the following examples were selected in accordance with conventional procedures and conditions, or in accordance with commercial instructions.
The HPLC test conditions of the invention are as follows:
the chromatographic column is as follows: waters Xbridge C18,5 μm,4.6 mm. Times.150 mm
The mobile phase is as follows: sodium octane sulfonate solution (0.02 mol/1 sodium octane sulfonate solution, using HClO 4 Adjusting the pH to 1.3) -acetonitrile (90: 10)
The flow rate is: 1ml/min
The detection wavelength is as follows: 205nm
The chromatographic column temperature is: at normal temperature
The sample injection amount is as follows: 10 μ l
Example 1: preparation of citrate 5-aminolevulinic acid
Adding 550g of appropriate amount of 5-aminolevulinic acid hydrochloride into a 20L three-neck reaction bottle, adding 1L of purified water, and stirring for dissolving; 760g of citric acid is added in batches and stirred for dissolution; starting refrigeration to reduce the temperature in the reaction system to 10-15 ℃, dropwise adding 360g of triethylamine, and controlling the temperature of the system to 10-15 ℃ in the dropwise adding process; after dropping, continuously cooling to 0-10 ℃, and adding 13L of ethanol-acetone solution mixed according to the ratio of 2:1 (V: V); stirring and crystallizing for 8 hours at the temperature; filtering, adding filter cake into 5L three-necked bottle, adding mixed solution of ethanol and water (1: 1) 2L, stirring at 30-40 deg.C for 2 hr, cooling to 0-10 deg.CCrystallizing for 2h, vacuum filtering, and vacuum drying the filter cake at 35-40 deg.C for 24h to obtain white crystalline powder 960.5g (picture shown in FIG. 4), with molar yield of 90.6%, purity of 97.31% (HPLC purity shown in FIG. 2 and table below), and melting point of 111-112 deg.C. 1 H NMR(500M，DMSO)δ：2.46(t，J＝6.5Hz，2H)，2.72(t，J＝6.5Hz，2H)，3.60(brs，2H)，3.91(s，2H)，4.80(m，2H)，8.30(brs，4H)，12.25(brs，1H)。
| Number of peak | Retention time | Height | Degree of separation (USP) | Area of | |
| 1 | 3.520 | 1188 | -- | 5721 | 0.20 |
| 2 | 4.191 | 802 | 3.98 | 4884 | 0.17 |
| 3 | 8.489 | 217790 | 16.00 | 2882794 | 99.03 |
| 4 | 9.224 | 193 | 1.55 | 3679 | 0.13 |
| 5 | 10.542 | 761 | 2.47 | 13918 | 0.48 |
| In total | 220734 | 2910996 | 100.00 |
Example 2: preparation of tartrate salt of 5-aminolevulinic acid
An appropriate amount of 550g of 5-aminolevulinic acid hydrochloride was added to a 20L three-necked reaction flask, and purified water was added thereto1L, stirring and dissolving; then adding 600g of L-tartaric acid in batches, stirring and dissolving; starting refrigeration to reduce the temperature in the reaction system to 10-15 ℃, dropwise adding 290g of pyridine, and controlling the temperature of the system to 10-15 ℃ in the dropwise adding process; after dropping, continuously cooling to 0-10 ℃, and adding 13L of ethanol-acetone solution mixed according to the ratio of 2:1 (V: V); stirring at the temperature for crystallization for 8 hours; filtering, putting the filter cake into a 5L three-necked bottle, adding 1.5L of ethanol-water (1) mixed solution, stirring at 30-40 ℃ for 2h, cooling to 0-10 ℃ for crystallization for 2h, performing suction filtration, and drying the filter cake at 35-40 ℃ for 24h in vacuum to obtain 710g of white crystalline powder (shown in figure 3), wherein the molar yield is 91.2%, the purity is 99.0% (shown in figure 1 and the following table for HPLC purity), and the melting point is 101-103 ℃. 1 H NMR(500M，DMSO)δ：2.49(t，J＝6.5Hz，2H)，2.77(t，J＝6.5Hz，2H)，3.96(s，2H)，4.25(brs，1H)，8.30(brs，5H)，12.35(brs，1H)。
| Peak number | Retention time | Height | Degree of separation (USP) | Area of | |
| 1 | 7.999 | 284713 | -- | 3790815 | 97.32 |
| 2 | 8.878 | 955 | 1.81 | 22312 | 0.57 |
| 3 | 9.690 | 3048 | 1.53 | 54816 | 1.41 |
| 4 | 10.510 | 195 | 1.79 | 2782 | 0.07 |
| 5 | 14.193 | 860 | 5.76 | 24347 | 0.63 |
| Total of | 289772 | 3895072 | 100.00 |
Example 3
5-Aminolevulinic acid hydrochloride, 5-aminolevulinic acid tartrate according to example 2, and 5-aminolevulinic acid citrate according to example 1 were each formulated into a gel having a 5-aminolevulinic acid content of 1.5% (matrix is 2% xanthan gum, salt is in a dissolved state in the gel). Removing 24 rabbits, and randomly dividing into 4 groups including blank matrix group, hydrochloride group, citrate group, and tartrate group; removing hair and preparing skin at 3 x 5cm back of rabbit, coating corresponding gel 1g on each group, covering and fixing with non-irritating membrane, keeping for 4h, and observing skin irritation at 0, 4, 8, 16, and 24h after removing medicine. Skin reactions were evaluated according to the following scores:
0 minute: no irritation is seen;
1 minute: slight erythema, barely observable;
and 2, dividing: a marked erythema, macroscopic, mild edema or mild papular reaction;
and 3, dividing: erythema and papules;
and 4, dividing: significant edema;
and 5, dividing: erythema, edema and papules;
and 6, dividing into: water bubble
7, dividing: strongly reacting, distribution range beyond the test site.
Table description: the first row 0-7 of the table is the score, 0h,4h,8h, 169h and 24h are the grouping according to time, and the middle data of the table is the number of the rabbits in the group which meet the specific score.
And (4) conclusion: the skin irritation test scores of the tartrate salt of 5-aminolevulinic acid and the citrate salt group are lower than that of the hydrochloride salt group, and the irritation of the two salts is lower than that of the hydrochloride salt group.
Claims (10)
1. A salt of 5-aminolevulinic acid, which salt is a citrate or tartrate salt.
2. The salt of 5-aminolevulinic acid according to claim 1, wherein the citric acid salt is
And/or the tartrate salt is
3. The salt of 5-aminolevulinic acid as claimed in claim 1 or 2, wherein in the tartaric acid salt, the tartaric acid is L-tartaric acid.
4. The salt of 5-aminolevulinic acid as claimed in claim 1 or 2, wherein the tartaric acid salt is a salt of tartaric acid
5. A process for the preparation of a salt of 5-aminolevulinic acid as claimed in claim 1, comprising the steps of: reacting 5-aminolevulinic acid hydrochloride with acid in water in the presence of an acid-binding agent to obtain the salt of 5-aminolevulinic acid;
the acid-binding agent is triethylamine, pyridine or a mixture thereof;
the acid is citric acid or tartaric acid.
6. The method of claim 5, wherein the tartaric acid is L-tartaric acid;
and/or the molar ratio of the acid to 5-aminolevulinic acid hydrochloride is (1.2-1.3) to 1;
and/or the molar ratio of the acid-binding agent to the 5-aminolevulinic acid hydrochloride is (1.05-1.2): 1, such as (1.1-1.2): 1;
and/or the concentration of the 5-aminolevulinic acid hydrochloride in water is 550g-650g/L;
and/or the reaction temperature is 10-15 ℃;
and/or the operation of the reaction comprises the following steps: adding an acid-binding agent into an aqueous solution of 5-aminolevulinic acid hydrochloride and citric acid, and then carrying out reaction.
7. The production method according to claim 5 or 6, further comprising a post-treatment step after the reaction, the post-treatment comprising: adding a mixed solvent of ethanol and acetone into the reaction solution for crystallization, and separating out solids to obtain a crude product of the salt of the 5-aminolevulinic acid; in the mixed solvent of ethanol and acetone, the volume ratio of ethanol to acetone is preferably 2.
8. The method of claim 7, further comprising a purification step after the post-treatment, the purification step comprising: recrystallizing the crude product of the salt of the 5-aminolevulinic acid by using a mixed solvent of ethanol and water;
preferably, in the mixed solvent of ethanol and water, the volume ratio of ethanol to water is 1;
preferably, the recrystallization method is a hot melt cold separation method; preferably, in the hot-melt cold separation method, the dissolving temperature is 30-40 ℃, and the crystallization temperature is 0-10 ℃.
9. A pharmaceutical composition comprising a salt of 5-aminolevulinic acid as claimed in any one of claims 1 to 4 and a pharmaceutically acceptable excipient.
10. Use of a salt of 5-aminolevulinic acid as defined in any one of claims 1 to 4 for the preparation of a photodynamic drug or a plant growth regulator.
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