CN111848427A - Purification method of L-alanine-2-ethyl butyl ester hydrochloride - Google Patents
Purification method of L-alanine-2-ethyl butyl ester hydrochloride Download PDFInfo
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- DEAGOVGXNPHPIJ-FJXQXJEOSA-N 2-ethylbutyl (2s)-2-aminopropanoate;hydrochloride Chemical compound Cl.CCC(CC)COC(=O)[C@H](C)N DEAGOVGXNPHPIJ-FJXQXJEOSA-N 0.000 title claims abstract description 105
- 238000000034 method Methods 0.000 title claims abstract description 30
- 238000000746 purification Methods 0.000 title claims abstract description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 66
- 239000000047 product Substances 0.000 claims abstract description 52
- 239000002904 solvent Substances 0.000 claims abstract description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000012043 crude product Substances 0.000 claims abstract description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000001953 recrystallisation Methods 0.000 claims abstract description 18
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000001816 cooling Methods 0.000 claims description 44
- 239000013078 crystal Substances 0.000 claims description 28
- 238000002425 crystallisation Methods 0.000 claims description 25
- 230000008025 crystallization Effects 0.000 claims description 25
- 238000001291 vacuum drying Methods 0.000 claims description 8
- 238000004090 dissolution Methods 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- 239000007787 solid Substances 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 9
- 238000001514 detection method Methods 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000002245 particle Substances 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 230000006866 deterioration Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 231100000956 nontoxicity Toxicity 0.000 description 2
- 238000013094 purity test Methods 0.000 description 2
- 238000010583 slow cooling Methods 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- BBDQDTSBXDTVIF-ZETCQYMHSA-N 2-ethylbutyl (2s)-2-aminopropanoate Chemical class CCC(CC)COC(=O)[C@H](C)N BBDQDTSBXDTVIF-ZETCQYMHSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- MMSGWPLJAYFEQJ-UHFFFAOYSA-N ethanol;n-ethylethanamine;hexane Chemical compound CCO.CCNCC.CCCCCC MMSGWPLJAYFEQJ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 150000003384 small molecules Chemical group 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
- C07C227/42—Crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A purification method of L-alanine-2-ethyl butyl ester hydrochloride belongs to the field of pharmacy. The purification method comprises the following steps: and recrystallizing the crude product of the L-alanine-2-ethyl butyl ester hydrochloride and a dissolved solution formed by the solvent to obtain a finished product of the L-alanine-2-ethyl butyl ester hydrochloride. Wherein the solvent comprises at least one of ethanol, ethyl acetate, toluene, methyl tertiary butyl ether and dichloromethane. In the implementation process, the relative purity and the chiral purity of the finished product of the L-alanine-2-ethylbutyl ester hydrochloride are effectively improved by combining the selection of a specific solvent with a recrystallization mode, so that the relative purity and the chiral purity can be more than 99.5%.
Description
Technical Field
The application relates to the field of pharmacy, and particularly relates to a purification method of L-alanine-2-ethylbutyl ester hydrochloride.
Background
RudeSeivir is a small-molecule broad-spectrum antiviral drug developed by Gilidard scientific Inc.
The chiral purity and the relative purity of the L-alanine-2-ethyl butyl ester hydrochloride serving as a Reidesciclovir intermediate have great influence on the curative effect of finally prepared Reidesciclovir, the chiral purity and the relative purity of the existing L-alanine-2-ethyl butyl ester hydrochloride are generally lower than 99.5%, and impurities with similar structures and the same properties, namely chiral isomeric impurities, which are difficult to purify and remove are difficult to effectively remove, can seriously influence the purity of the L-alanine-2-ethyl butyl ester hydrochloride.
Meanwhile, most of the existing L-alanine-2-ethyl butyl ester hydrochloride is mixed crystals, and the structure of the mixed crystals has strong hygroscopicity, so that the mixed crystals are easy to absorb moisture after being stored for a long time, and the falling of ester groups is caused, thereby causing the deterioration of products.
In view of this, the present application is hereby presented.
Disclosure of Invention
The application provides a method for purifying L-alanine-2-ethyl butyl ester hydrochloride, which aims to solve at least one technical problem.
The embodiment of the application is realized as follows:
the application example provides a method for purifying L-alanine-2-ethyl butyl ester hydrochloride, which comprises the following steps:
and recrystallizing the crude product of the L-alanine-2-ethyl butyl ester hydrochloride and a dissolved solution formed by the solvent to obtain a finished product of the L-alanine-2-ethyl butyl ester hydrochloride.
Wherein the solvent comprises at least one of ethanol, ethyl acetate, toluene, methyl tertiary butyl ether and dichloromethane.
In the implementation process, the relative purity and the chiral purity of the finished product of the L-alanine-2-ethylbutyl ester hydrochloride are effectively improved by combining the selection of a specific solvent with a recrystallization mode, so that the relative purity and the chiral purity can be more than 99.5%.
In some possible examples of the present application, the solvent is ethyl acetate.
In some possible examples of the present application, when the solvent is ethyl acetate and the recrystallization is gradient cooling crystallization, the finished product of the L-alanine-2-ethylbutyl ester hydrochloride comprises single crystals of the L-alanine-2-ethylbutyl ester hydrochloride with a regular shape.
In the implementation process, the specific solvent ethyl acetate is selected and combined with a specific recrystallization mode, so that the relative purity and the chiral purity of the finished product of the L-alanine-2-ethyl butyl ester hydrochloride are remarkably improved and can reach 99.9%, meanwhile, the single crystal L-alanine-2-ethyl butyl ester hydrochloride can be obtained, and the single crystal L-alanine-2-ethyl butyl ester hydrochloride has large particle size, reduces the surface area of the material, can be stored for a longer time, is more stable in structure and is less prone to moisture absorption and deterioration compared with a mixed crystal structure.
In some possible examples of the present application, the recrystallization means includes any one of concentration crystallization under reduced pressure, gradient temperature-decreasing crystallization, and slow temperature-decreasing crystallization.
In some possible examples of the present application, the gradient temperature-decreasing crystallization comprises: cooling at a gradient of 1.5-3 deg.C every 15-25min and maintaining the temperature for at least 15min every time until the temperature is 25-35 deg.C.
Optionally, cooling at 1.5-2.5 deg.C every 20min, and maintaining the temperature for 15-25min after each cooling, until the temperature is 25-35 deg.C.
Optionally, the gradient temperature-decreasing crystallization comprises: cooling at 2 deg.C every 20min and maintaining the temperature for 15-25min until the temperature is 25-35 deg.C.
In the implementation process, through the matching of the parameters of the gradient cooling crystallization and the reasonable matching of the parameters and the solvent, the crude product is effectively purified, and the relative purity and the chiral purity of the finished product of the L-alanine-2-ethylbutyl ester hydrochloride are improved.
In one possible example of the application, the temperature of the dissolution solution before recrystallization is 45-50 ℃.
At the above temperature, the crude product has good solubility in ethyl acetate.
In one possible example of the present application, the weight ratio of crude L-alanine-2-ethylbutyl ester hydrochloride to solvent is 1: 2-3.
The above proportion ensures good solubility of the crude product in the solvent.
In one possible example of the present application, the chiral purity of the crude product is 90.0% to 99.5%, and the relative purity of the crude product is 90.0% to 99.5%.
Under the set conditions, the impurity interference is small, and the crude product is effectively purified, so that the relative purity and the chiral purity of the crude product are improved to be more than 99.5 percent.
In one possible example of the present application, after recrystallization, the purification method further comprises collecting the crystals and vacuum drying to obtain the finished product of L-alanine-2-ethylbutyl ester hydrochloride.
The purification method of L-alanine-2-ethyl butyl ester hydrochloride provided by the application has the beneficial effects that:
the purification purity of the L-alanine-2-ethyl butyl ester hydrochloric acid finished product is greatly improved through the synergistic effect of the specific solvent and the purification mode of recrystallization, and the solvent can be recycled, so that the method is suitable for industrial production, and has the advantages of no toxicity, no harm, environmental protection, safety and low production cost.
Through tests, by the purification method, when the solvent is ethyl acetate and a gradient cooling crystallization mode is adopted, the L-alanine-2-ethylbutyl ester hydrochloride with a single crystal structure can be obtained, the relative purity is higher than 99.5%, the chiral purity is higher than 99.5%, the product performance is very excellent, and the method has unexpected beneficial effects.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings that are required to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present application and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained from the drawings without inventive effort.
FIG. 1 is a relative purity profile of crude L-alanine-2-ethylbutyl ester hydrochloride;
FIG. 2 is a chiral purity profile of a crude L-alanine-2-ethylbutyl ester hydrochloride;
FIG. 3 is an electron microscope scan of the L-alanine-2-ethylbutyl ester hydrochloride product of example 1;
FIG. 4 is a graph of the relative purity of the L-alanine-2-ethylbutyl ester hydrochloride product of example 1;
FIG. 5 is a chiral purity map of the L-alanine-2-ethylbutyl ester hydrochloride product of example 1;
FIG. 6 is an electron microscope scan of the product L-alanine-2-ethylbutyl ester hydrochloride of example 5.
Detailed Description
Embodiments of the present application will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present application and should not be construed as limiting the scope of the present application. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The applicant finds that when the solvent is at least one of ethanol, ethyl acetate, toluene, methyl tertiary butyl ether and dichloromethane, the relative purity and chiral purity of the finished L-alanine-2-ethyl butyl ester hydrochloride can be obviously improved by adopting a recrystallization mode, and particularly, when the solvent is ethyl acetate and the gradient decompression condition is adopted, the finished single-crystal L-alanine-2-ethyl butyl ester hydrochloride can be obtained.
The following is a detailed description of the purification method of L-alanine-2-ethylbutyl ester hydrochloride according to the examples of the present application:
a method for purifying L-alanine-2-ethylbutyl ester hydrochloride, comprising:
s1, obtaining a dissolving solution formed by a crude product of L-alanine-2-ethyl butyl ester hydrochloride and a solvent.
Wherein the solvent comprises at least one of ethanol, ethyl acetate, toluene, methyl tertiary butyl ether and dichloromethane. Specifically, the solvent may be ethanol, ethyl acetate, toluene, methyl tertiary butyl ether or dichloromethane, or may be a mixture of ethanol and ethyl acetate, or a mixture of ethanol and methyl tertiary butyl ether, which is not limited herein.
Wherein the temperature of the dissolving solution is 45-50 deg.C, such as 45 deg.C, 47 deg.C, 48 deg.C, 49 deg.C or 50 deg.C.
The method for obtaining the dissolved solution formed by the crude product of the L-alanine-2-ethyl butyl ester hydrochloride and the solvent comprises the following steps: mixing the crude product of L-alanine-2-ethyl butyl ester hydrochloride with ethyl acetate, stirring and heating to obtain a solution at 45-50 ℃.
In addition to the above manner, the crude L-alanine-2-ethylbutyl ester hydrochloride can be dissolved in a solvent at 45-50 ℃ to obtain the above solution at 45-50 ℃.
Alternatively, the weight ratio of the crude L-alanine-2-ethylbutyl ester hydrochloride to the solvent is 1: 2-3. For example, the weight ratio of the crude L-alanine-2-ethylbutyl ester hydrochloride to the solvent is 1:2, 1:2.2, 1:2.5, 1:2.7 or 1: 3.
It should be noted that the chiral purity and the relative purity of the crude product of L-alanine-2-ethylbutyl ester hydrochloride are equal to or less than 99.5%, for example, 80% to 99.5%, optionally, the crude product of L-alanine-2-ethylbutyl ester hydrochloride is a mixed crystal, and the chiral purity of the crude product is 90.0% to 99.5%, optionally, the relative purity of the crude product is 90.0% to 99.5%, under the above purity conditions, the purification by the method of the present application is facilitated, and the relative purity and the chiral purity of the purified L-alanine-2-ethylbutyl ester hydrochloride finished product are high.
S2, recrystallizing the 45-50 ℃ dissolved solution.
Wherein, the recrystallization mode comprises any one of decompression concentration crystallization, gradient cooling crystallization and slow cooling crystallization.
For example, the slow cooling crystallization includes: slowly cooling to 25-30 ℃ within 2-3 h.
Optionally, the gradient temperature-decreasing crystallization comprises: cooling at a gradient of 1.5-3 deg.C every 15-25min and maintaining the temperature for at least 15min every time until the temperature is 25-35 deg.C. For example, the temperature is reduced by 1.5 ℃, 1.7 ℃, 1.9 ℃, 2 ℃, 2.1 ℃, 2.4 ℃, 2.6 ℃ or 3 ℃ every 15min, 17min, 18min, 20min, 22min, 24min or 25min, and the temperature is preserved for at least 15min after each temperature reduction until the temperature is reduced to 25 ℃, 26 ℃, 27 ℃, 28 ℃, 30 ℃, 33 ℃ or 35 ℃.
Further, the gradient cooling crystallization comprises: cooling at 1.5-2.5 deg.C every 20min and maintaining the temperature for 15-25min until the temperature is 25-35 deg.C.
Further, the gradient cooling crystallization comprises: cooling at 2 deg.C every 20min and maintaining the temperature for 15-25min until the temperature is 25-35 deg.C.
Optionally, when the solvent is ethyl acetate and the recrystallization mode is the gradient temperature-reduction crystallization, the finished product of the L-alanine-2-ethyl butyl ester hydrochloride comprises single crystals of the L-alanine-2-ethyl butyl ester hydrochloride with a regular shape; that is, the single-crystal L-alanine-2-ethylbutyl ester hydrochloride in which the crystal particle size of the single-crystal L-alanine-2-ethylbutyl ester salt was > 800. mu.m was obtained in the above manner.
It should be noted that the selection of the solvent and the specific mode of recrystallization have significant influence on the crystalline phase, chiral purity and relative purity of the finished product of L-alanine-2-ethylbutyl ester hydrochloride, in the embodiment of the present application, in addition to the fact that the solvent is ethyl acetate-gradient cooling crystallization mode, the finished product of single-crystal L-alanine-2-ethylbutyl ester hydrochloride can be obtained, the rest of solvents and/or different recrystallization modes are combined, the obtained finished product of L-alanine-2-ethylbutyl ester hydrochloride is mixed crystal, and the crystal particle size of the mixed crystal L-alanine-2-ethylbutyl ester hydrochloride is lower than 50 μm.
S3, collecting the solid, and drying in vacuum to obtain the finished product of the L-alanine-2-ethyl butyl ester hydrochloride.
Optionally, the temperature of vacuum drying is 30-50 ℃.
The purification process of L-alanine-2-ethylbutyl ester hydrochloride according to the present application is further described in detail with reference to examples.
In the following examples, the relative purity and chiral purity of the crude and finished product of L-alanine-2-ethylbutyl ester hydrochloride were determined by HPLC, wherein: indicates the relative purity of the compound; EE value indicates the chiral purity of the compound. The L value represents the particle size of the crystals of L-alanine-2-ethylbutyl ester hydrochloride.
Detecting the relative purity of the product by high performance liquid chromatography: agilent 1200 liquid chromatograph, column: agilent SB-C18 (4.6X 150mm, 5 μm), detection wavelength 265nm, column temperature 25 ℃, flow rate 1.0ml/min, mobile phase: 0.1% aqueous phosphoric acid solution-acetonitrile (70: 30 by volume), and a sample amount of 5. mu.l was introduced.
Detecting the chiral purity of the product by high performance liquid chromatography: the detection conditions are as follows: shimadzu LC-20A/UV; a chromatographic column: CHIRALCEL OD-H (4.6 mm. times.250 mm, 5 μm), mobile phase: n-hexane-ethanol-diethylamine (volume ratio 40:60:0.2), flow rate: 1mL/min, column temperature: 25 ℃, detection wavelength: 210nm, and the sample size is 5 μ l.
In the following examples, the same crude L-alanine-2-ethylbutyl ester hydrochloride is used, wherein FIG. 1 and FIG. 2 show the relative purity and chiral purity of the crude L-alanine-2-ethylbutyl ester hydrochloride, respectively, wherein Table 1 shows the detection results corresponding to FIG. 1, Table 2 shows the detection results corresponding to FIG. 2, wherein Peak No. 5 in Table 1 shows L-alanine-2-ethylbutyl ester hydrochloride, and Peak No. 2 in Table 2 shows L-alanine-2-ethylbutyl ester hydrochloride.
TABLE 1 results of relative purity measurements
TABLE 2 relative purity test results
That is, HPLC: 99.262%, EE: 92.78 percent.
Example 1
Dissolving the crude product of 25g L-alanine-2-ethylbutyl ester hydrochloride in 50g of ethyl acetate, heating to 45 ℃, dissolving and clarifying, performing gradient cooling in a manner of cooling to 2 ℃ every 20min and preserving heat for 15min after cooling every time until the temperature is reduced to 25 ℃, stopping cooling and completely crystallizing, filtering and collecting solids, and performing vacuum drying at 40 ℃ to obtain the finished product of L-alanine-2-ethylbutyl ester hydrochloride.
Wherein, an electron microscope scanning image of the finished product of the L-alanine-2-ethylbutyl ester hydrochloride is shown in fig. 3, and according to fig. 3, it can be seen that the finished product of the L-alanine-2-ethylbutyl ester hydrochloride in the application is a single crystal, and the grain size L of the single crystal is: 802.121 μm.
Meanwhile, the purity and chiral purity of the finished product of the L-alanine-2-ethylbutyl ester hydrochloride are shown in FIG. 4 and FIG. 5.
Wherein, table 3 corresponds to the detection results of fig. 4, table 4 corresponds to the detection results of fig. 5, wherein, peak number 2 in table 3 represents L-alanine-2-ethyl butyl ester hydrochloride, and peak number 2 in table 4 represents L-alanine-2-ethyl butyl ester hydrochloride.
TABLE 3 results of relative purity measurements
TABLE 4 chiral purity test results
According to tables 3 and 4, in the finished product of L-alanine-2-ethylbutyl ester hydrochloride in this example, HPLC: 99.87%, EE: 99.98 percent.
Example 2
Dissolving the crude product of 25g L-alanine-2-ethylbutyl ester hydrochloride in 75g of ethyl acetate, heating to 45 ℃, dissolving and clarifying, performing gradient cooling in a manner of cooling to 2 ℃ every 20min and preserving heat for 15min after cooling every time until the temperature is reduced to 25 ℃, stopping cooling and completely crystallizing, filtering and collecting solids, and performing vacuum drying at 40 ℃ to obtain the finished product of L-alanine-2-ethylbutyl ester hydrochloride. In the finished product of L-alanine-2-ethyl butyl ester hydrochloride, HPLC (high performance liquid chromatography) is 99.3 percent, and EE: 98.9%, L: 73.251 μm.
Example 3
Dissolving the crude product of 25g L-alanine-2-ethylbutyl ester hydrochloride in 60g of ethyl acetate, heating to 45 ℃, dissolving and clarifying, performing gradient cooling in a manner of cooling to 2 ℃ every 20min and preserving heat for 15min after cooling every time until the temperature is reduced to 25 ℃, stopping cooling and completely crystallizing, filtering and collecting solids, and performing vacuum drying at 40 ℃ to obtain the finished product of L-alanine-2-ethylbutyl ester hydrochloride.
In the finished product of L-alanine-2-ethyl butyl ester hydrochloride, HPLC (high performance liquid chromatography) is 99.2 percent, and EE: 98.7%, L: 83.281 μm.
Example 4
Dissolving the crude product of 25g L-alanine-2-ethylbutyl ester hydrochloride in 50g of ethyl acetate, heating to 45 ℃, dissolving and clarifying, performing gradient cooling in a manner of cooling to 2 ℃ every 19min and preserving heat for 17min after cooling every time until the temperature is reduced to 25 ℃, stopping cooling and completely crystallizing, filtering and collecting solids, and performing vacuum drying at 40 ℃ to obtain the finished product of L-alanine-2-ethylbutyl ester hydrochloride. 99.4% of L-alanine-2-ethyl butyl ester hydrochloride, 99.4% of HPLC, EE: 98.7%, L: 123.651 μm.
Example 5
The crude 25g L-alanine-2-ethylbutyl ester hydrochloride was dissolved in 50g of methyl tert-butyl ether containing 6% (by mass) of tert-butyl alcohol, and the solution was heated to 45 ℃ to dissolve and clarify. And (3) performing gradient cooling in a manner of cooling the solution to 2 ℃ every 20min and keeping the temperature for 15min after cooling every time until the solution is cooled to 25 ℃, stopping cooling and completely crystallizing, filtering and collecting solids, and performing vacuum drying at 40 ℃ to obtain the finished product of the L-alanine-2-ethylbutyl ester hydrochloride.
An electron microscope scanning image of the obtained L-alanine-2-ethylbutyl ester hydrochloride finished product is shown in FIG. 5, and according to FIG. 6, the L-alanine-2-ethylbutyl ester hydrochloride finished product in the application is a mixed crystal without a regular shape, and the particle size L of the mixed crystal is 35.545 μm.
And simultaneously, measuring, wherein in the finished product of the L-alanine-2-ethyl butyl ester hydrochloride, HPLC: 98.6 percent and EE 98.3 percent.
Example 6
25g of crude L-alanine-2-ethylbutyl ester hydrochloride was dissolved in 50g of methyl tert-butyl ether containing 6% by mass of ethanol, and the solution was dissolved and clarified by heating to 45 ℃. Cooling the mixture at 2 ℃ every 20min, keeping the temperature for 15min after cooling every time until the temperature is reduced to 25 ℃, stopping cooling and completely crystallizing, filtering and collecting solids, and drying the solids in vacuum at 40 ℃ to obtain the finished product of the L-alanine-2-ethyl butyl ester hydrochloride.
In the finished product of L-alanine-2-ethyl butyl ester hydrochloride, HPLC (high performance liquid chromatography) is 97.3 percent, and EE: 98.7%, L: 23.251 μm.
Example 7
Dissolving 25g of crude L-alanine-2-ethylbutyl ester hydrochloride in absolute ethyl alcohol, heating to 45 ℃, dissolving and clarifying, concentrating under reduced pressure at 40 ℃ until crystallization occurs, filtering and collecting solids, and drying in vacuum at 40 ℃ to obtain powdery solid of the finished product of L-alanine-2-ethylbutyl ester hydrochloride.
In the finished product of L-alanine-2-ethyl butyl ester hydrochloride, HPLC (high performance liquid chromatography) is 96.3 percent, and EE: 96.7%, L: 22.251 μm.
Example 8
Dissolving the crude product of 25g L-alanine-2-ethylbutyl ester hydrochloride in 50g of dichloromethane, heating to 45 ℃, dissolving and clarifying, and slowly cooling to 25 ℃ to obtain a powdery solid L-alanine-2-ethylbutyl ester hydrochloride finished product.
In the finished product of L-alanine-2-ethyl butyl ester hydrochloride, HPLC (high performance liquid chromatography) is 98.3 percent, and EE: 98.9%, L: 24.251 μm.
Example 9
Dissolving the crude product of 25g L-alanine-2-ethylbutyl ester hydrochloride in 50g of toluene, heating to 45 ℃, dissolving and clarifying, and slowly cooling to 25 ℃ to obtain a fine powder solid L-alanine-2-ethylbutyl ester hydrochloride finished product.
In the finished product of L-alanine-2-ethyl butyl ester hydrochloride, HPLC (high performance liquid chromatography) is 95.3 percent, and EE: 95.9%, L: 21.251 μm.
According to the above examples 1-9, it can be seen that the selection of different solvents has significant influence on the relative purity, chiral purity, particle size and crystal form of the final L-alanine-2-ethylbutyl ester hydrochloride product, but the relative purity and chiral purity can be effectively improved by adopting the purification method provided by any of the above examples.
In conclusion, the purification method of the L-alanine-2-ethylbutyl ester hydrochloride provided by the application greatly improves the chiral purity and the relative purity of the L-alanine-2-ethylbutyl ester hydrochloride finished product through the synergistic effect of the specific solvent and the purification mode of recrystallization, and the solvent can be recycled, so that the method is suitable for industrial production and has the advantages of no toxicity, no harm, environmental protection, safety and low production cost. When the solvent is ethyl acetate and a gradient cooling crystallization mode is adopted, the purification method can be used for preparing the single crystal L-alanine-2-ethylbutyl ester hydrochloride, the relative purity is more than 99.5 percent, the chiral purity is more than 99.5 percent, the product performance is very excellent, and the method has unexpected beneficial effects.
The foregoing is merely exemplary of the present application and is not intended to limit the present application, which may be modified or varied by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims (10)
1. A method for purifying L-alanine-2-ethylbutyl ester hydrochloride is characterized by comprising the following steps:
recrystallizing a dissolved solution formed by the crude product of the L-alanine-2-ethyl butyl ester hydrochloride and the solvent to obtain a finished product of the L-alanine-2-ethyl butyl ester hydrochloride;
wherein the solvent comprises at least one of ethanol, ethyl acetate, toluene, methyl tertiary butyl ether and dichloromethane.
2. The purification process according to claim 1, wherein the solvent is ethyl acetate.
3. The purification method according to claim 1, wherein when the solvent is ethyl acetate and the recrystallization mode is gradient cooling crystallization, the finished product of the L-alanine-2-ethylbutyl ester hydrochloride comprises single crystals of the L-alanine-2-ethylbutyl ester hydrochloride with a regular shape.
4. The purification method according to claim 1, wherein the recrystallization means includes any one of concentration crystallization under reduced pressure, gradient temperature-reduction crystallization, and slow temperature-reduction crystallization.
5. The purification process according to claim 3 or 4, wherein the gradient temperature-decreasing crystallization comprises: cooling at a gradient of 1.5-3 deg.C every 15-25min and maintaining the temperature for at least 15min every time until the temperature is 25-35 deg.C.
6. The purification process according to claim 3 or 4, wherein the gradient temperature-decreasing crystallization comprises: cooling at 1.5-2.5 deg.C every 20min and maintaining the temperature for 15-25min until the temperature is 25-35 deg.C.
7. The purification method according to claim 1, wherein the temperature of the dissolution solution before recrystallization is 45 to 50 ℃.
8. The purification process according to claim 1, wherein the weight ratio of the crude L-alanine-2-ethylbutyl ester hydrochloride to the solvent is 1: 2-3.
9. The purification method of claim 1, wherein the chiral purity of the crude product is 90.0% to 99.5%, and the relative purity of the crude product is 90.0% to 99.5%.
10. The purification process according to claim 1, further comprising collecting the crystals after recrystallization and vacuum drying to obtain the final product of L-alanine-2-ethylbutyl ester hydrochloride.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1202481A (en) * | 1998-06-12 | 1998-12-23 | 南通市东昌化工实业公司 | Purified glycine ethyl ester hydrochloride and its producing process |
| CN106518694A (en) * | 2016-10-24 | 2017-03-22 | 浙江金伯士药业有限公司 | Novel preparation method of L-alanine isopropyl ester hydrochloride |
| CN111393314A (en) * | 2020-04-30 | 2020-07-10 | 安徽红杉生物医药科技有限公司 | Process for preparing 2-alkyl-2-aminopropionate hydrochloride |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1202481A (en) * | 1998-06-12 | 1998-12-23 | 南通市东昌化工实业公司 | Purified glycine ethyl ester hydrochloride and its producing process |
| CN106518694A (en) * | 2016-10-24 | 2017-03-22 | 浙江金伯士药业有限公司 | Novel preparation method of L-alanine isopropyl ester hydrochloride |
| CN111393314A (en) * | 2020-04-30 | 2020-07-10 | 安徽红杉生物医药科技有限公司 | Process for preparing 2-alkyl-2-aminopropionate hydrochloride |
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