CN108047136B - Refining method of benzydac - Google Patents
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- CN108047136B CN108047136B CN201711381799.3A CN201711381799A CN108047136B CN 108047136 B CN108047136 B CN 108047136B CN 201711381799 A CN201711381799 A CN 201711381799A CN 108047136 B CN108047136 B CN 108047136B
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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Abstract
The invention belongs to the field of chemical medicine preparation, and particularly relates to a refining method of benzydac. The refining method provided by the invention comprises the following steps: A) mixing the crude product of the benzydac with amide to obtain a benzydac solution; B) and mixing the benzydac solution with water, and crystallizing to obtain a refined benzydac product. The refining method provided by the invention adopts an amide solvent, can effectively remove the 3-hydroxy-1-benzyl indazozole impurity in the benzydac, and has a good removal effect on other impurities. In addition, the method for refining the benzydac provided by the invention has the advantages of small solvent usage amount, environmental friendliness and low cost, and is very suitable for industrial production. Experimental results show that in the refined product of the benzydac obtained by the refining method, the content of the 3-hydroxy-1-benzyl inddazole impurities is only 0.03%, and the total impurities are 0.06%.
Description
Technical Field
The invention belongs to the field of chemical medicine preparation, and particularly relates to a refining method of benzydac.
Background
Bendazac lysine (1-benzyl-1H-indazozole-3-oxy) acetate, a chemical name, is a drug developed by Angelini, italy, and is approved to be marketed in 80 th century, italy and argentina, and is subsequently marketed in grapevine, spain, korea, and other countries, and is formally marketed in China at the end of 90 th century: the bendazac lysine is an aldose reductase inhibitor, not only has the effect of preventing and treating the diabetic cataract, but also has the effect of preventing and treating various early senile cataracts, can delay the development of the cataract, improve and maintain the eyesight, has slight adverse reaction, and is a truly effective medicament for preventing and treating the cataract which is widely applied at home and abroad at present.
The synthesis of bendazac lysine and analogs thereof has more literature data, and the difference mainly focuses on the difference of the synthesis methods of key intermediates of 3-hydroxy-1-benzylindazozole and bendazole.
The bendazac acid and L-lysine are subjected to salt-forming reaction in an ethanol solution to obtain a final product. During the research and production process, we found that: the main reason influencing the purity of the bendazac lysine is the purity of the raw material of the bendazac acid, the salt-forming reaction system of the ethanol solution cannot effectively remove the 3-hydroxy-1-benzylindazozole and other impurities in the bendazac acid, and the impurities cannot be completely removed even if the impurities are recrystallized for many times, and because the impurities and the bendazac lysine are crystallized and separated out from the alcohol-water system at the same time, the quality of a final product is seriously influenced, so that a new refining method needs to be developed to obtain the high-purity bendazac acid.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for refining benzydac, which can effectively remove 3-hydroxy-1-benzylindazozole and other impurities in benzydac, and improve purity.
The invention provides a refining method of benzydate, which comprises the following steps:
A) mixing the crude product of the benzydac with amide to obtain a benzydac solution;
B) and mixing the benzydac solution with water, and crystallizing to obtain a refined benzydac product.
Preferably, the amide comprises one or more of N, N-dimethylformamide, N-dimethylacetamide, N-dimethylpropionamide, and N, N-dimethylbutanamide.
Preferably, the amides include N, N-dimethylformamide, N-dimethylacetamide and N, N-dimethylpropionamide.
Preferably, the dosage ratio of the crude benzydate to the amide is 1 g: (3-5) mL.
Preferably, in the step A), the mixing temperature is 20-30 ℃.
Preferably, the step a) is:
mixing the crude product of the benzydac, the amide and the active carbon, and filtering to obtain a benzydac solution.
Preferably, the mass of the activated carbon is 0.5-5% of the mass of the crude benzydate.
Preferably, the dosage ratio of the crude benzydate acid to water is 5 g: (15-30) mL.
Preferably, the temperature of the crystallization is 20-30 ℃.
Preferably, the step B) further comprises:
and (3) carrying out solid-liquid separation on the solid-liquid mixture obtained after crystallization, and then washing and drying the solid obtained by separation in sequence.
Compared with the prior art, the invention provides a refining method of benzydate. The refining method provided by the invention comprises the following steps: A) mixing the crude product of the benzydac with amide to obtain a benzydac solution; B) and mixing the benzydac solution with water, and crystallizing to obtain a refined benzydac product. The refining method provided by the invention adopts an amide solvent, can effectively remove the 3-hydroxy-1-benzyl indazozole impurity in the benzydac, and has a good removal effect on other impurities. In addition, the method for refining the benzydac provided by the invention has the advantages of small solvent usage amount, environmental friendliness and low cost, and is very suitable for industrial production. Experimental results show that in the refined product of the benzydac obtained by the refining method, the content of the 3-hydroxy-1-benzyl inddazole impurities is only 0.03%, and the total impurities are 0.06%.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.
FIG. 1 is an HPLC chart of benzydate used in the examples of the present invention;
FIG. 2 is an HPLC chart of benzydac purified in example 6 of the present invention;
FIG. 3 is an enlarged view of a portion of benzydac purified according to example 6 of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides a refining method of benzydate, which comprises the following steps:
A) mixing the crude product of the benzydac with amide to obtain a benzydac solution;
B) and mixing the benzydac solution with water, and crystallizing to obtain a refined benzydac product.
In the present invention, the crude benzydate and the amide are first mixed. In the present invention, the source of the crude benzydate is not particularly limited, and may be commercially available benzydate or benzydate self-made by those skilled in the art. In an embodiment provided by the present invention, the purity of the crude benzydac is 95-99 wt%, specifically 98.89 wt%; the content of 3-hydroxy-1-benzyl indazozole (impurity) is 0.1-1 wt%, and specifically can be 0.35 wt%. In the present invention, the amide includes, but is not limited to, one or more of N, N-dimethylformamide, N-dimethylacetamide, N-dimethylpropionamide, and N, N-dimethylbutanamide. In one embodiment provided herein, the amide comprises N, N-dimethylformamide and N, N-dimethylpropionamide, preferably in a volume ratio of 1: (0.5-2), specifically 1: 1; in another embodiment provided by the present invention, the amide comprises N, N-dimethylformamide, N-dimethylacetamide and N, N-dimethylpropionamide, and the volume ratio of N, N-dimethylformamide, N-dimethylacetamide and N, N-dimethylpropionamide is preferably 1: (0.1-1): (0.1-1), specifically 1:0.5: 0.5; the dosage ratio of the crude benzydate and the amide is preferably 1 g: (3-5) mL, which may be specifically 1 g: 3mL, 1 g: 4mL or 1 g: 5 mL; the mixing temperature is preferably 20-30 ℃, and more preferably 25 ℃; the mixing time is not particularly limited, and the crude benzydate can be completely dissolved in the amide; the mixing is preferably carried out with stirring. After mixing, a benzydate solution is obtained.
In the present invention, the decolouring treatment of the crude benzydate is preferably performed in the process of preparing the benzydate solution, which comprises the following specific processes: mixing the crude product of the benzydac, the amide and the active carbon, and filtering to obtain a benzydac solution. Wherein the pH value of the activated carbon can be 5-7; the mesh number of the active carbon can be 50-200 meshes, and specifically can be 100 meshes; the mass of the activated carbon is preferably 0.5-5% of the mass of the crude product of the benzydate acid, and specifically can be 1%. The mixing mode is not particularly limited, and the crude benzydate, the amide and the activated carbon can be simultaneously mixed; alternatively, the crude benzydate and the amide may be mixed to form a solution and the solution may be mixed with activated carbon. In one embodiment of the present invention, in which the crude benzydate and the amide are mixed to form a solution, and the solution is then mixed with activated carbon, the mixing conditions of the crude benzydate and the amide are the same as above; the temperature of the solution and the activated carbon is preferably 20-30 ℃, more preferably 25 ℃, the mixing time is preferably 15-30 min, specifically 20min, and the mixing is preferably carried out under stirring.
After obtaining the benzydac solution, the benzydac solution is mixed with water. Wherein the water is preferably deionized water; the preferable dosage ratio of the water to the crude benzydac is (15-30) mL: 5g, specifically 25 mL: 5g of the total weight of the mixture; the mixing is preferably carried out by adding water to the benzydate solution, more preferably by adding water to the benzydate solution with stirring. The benzydate solution and water are mixed and then crystallized. Wherein the crystallization temperature is preferably 20-30 ℃, and specifically can be 25 ℃; the time for the crystallization is not particularly limited, and the crystals can be completely precipitated; the crystallization is preferably carried out with stirring. And after crystallization, carrying out solid-liquid separation on a solid-liquid mixture obtained after crystallization, and then sequentially washing and drying the solid obtained by separation. Wherein, the solid-liquid separation mode is preferably suction filtration; the washing mode is preferably water washing; the drying mode is preferably reduced pressure drying; the drying temperature is preferably 50-70 ℃, and specifically can be 60 ℃; the drying time is preferably 8-12 h, and specifically can be 8h, 10h or 12 h. And after drying, obtaining a refined product of the benzydac.
The refining method provided by the invention adopts an amide solvent, can effectively remove the 3-hydroxy-1-benzyl indazozole impurity in the benzydac, and has a good removal effect on other impurities. In addition, the method for refining the benzydac provided by the invention has the advantages of small solvent usage amount, environmental friendliness and low cost, and is very suitable for industrial production. Experimental results show that in the refined product of the benzydac obtained by the refining method, the content of the 3-hydroxy-1-benzyl inddazole impurities is only 0.03%, and the total impurities are 0.06%.
For the sake of clarity, the following examples are given in detail.
The following examples relate to the detection conditions:
the high performance liquid chromatography method comprises the following steps: shimadzu high performance liquid chromatograph, C18(250 × 4.6mm, 5 μm); mobile phase A: 0.1% acetic acid solution; mobile phase B: acetonitrile; the ratio of mobile phase A to mobile phase B is 53: 47; detection wavelength: 227 nm; flow rate: 1.0 ml/min; sample introduction amount: 20 mu l of the mixture; column temperature: at 30 ℃. The benzydac produces a peak in about 12min, and the 3-hydroxy-1-benzyl inddazole impurity produces a peak in about 6 min.
The following examples refer to the sources of benzydate: the results of HPLC (high performance liquid chromatography) detection of commercially available benzydac are shown in FIG. 1, and FIG. 1 is an HPLC chart of benzydac used in the examples of the present invention. As can be seen from FIG. 1, the purity of the benzydac is 98.89%, the maximum single impurity is 0.35% (3-hydroxy-1-benzylindazozole impurity), and the total impurity is 1.11%.
The following examples refer to activated carbon sources: market purchase, analytical purity, pH: 5.0 to 7.0, and 100 meshes.
Example 1
Adding 5.0g of commercially available benzydac into 20mLN, N-dimethylformamide, stirring at room temperature (25 ℃), dissolving and clarifying, adding 0.05g of activated carbon, keeping the temperature, stirring for 20min, filtering, slowly adding 25mL of deionized water while stirring, stirring at 25 ℃, crystallizing, filtering, washing a filter cake with 5mL of deionized water, drying at 60 ℃ under reduced pressure for 10h to obtain 4.3g of white powder, wherein the yield is as follows: 86.0 percent.
The white powder obtained was subjected to HPLC detection and the results showed: the purity of the refined product of the benzydac is 99.92 percent, the maximum single impurity is 0.035 percent (3-hydroxy-1-benzyl indazozole impurity), and the total impurity is 0.08 percent.
Example 2
Adding 5.0g of commercially available benzydac into 15mLN, N-dimethylacetamide, stirring at room temperature (25 ℃), dissolving and clarifying, adding 0.05g of activated carbon, keeping the temperature and stirring for 20min, filtering, slowly adding 25mL of deionized water while stirring, stirring at 25 ℃, crystallizing, filtering, washing a filter cake with 5mL of deionized water, drying at 60 ℃ under reduced pressure for 10h to obtain 4.4g of white powder, wherein the yield is as follows: 88.0 percent.
The white powder obtained was subjected to HPLC detection and the results showed: the purity of the refined product of the benzydac is 99.91 percent, the maximum single impurity is 0.033 percent (3-hydroxy-1-benzyl inddazole impurity), and the total impurity is 0.09 percent.
Example 3
Adding 5.0g of commercially available benzydac into 25mL of LN, N-dimethylpropionamide, stirring at room temperature (25 ℃), dissolving and clarifying, adding 0.05g of activated carbon, keeping the temperature, stirring for 20min, filtering, slowly adding 25mL of deionized water while stirring, stirring at 25 ℃, crystallizing, filtering, washing a filter cake with 5mL of deionized water, drying at 60 ℃ under reduced pressure for 8 hours to obtain 4.35g of white powder, wherein the yield is as follows: 87.0 percent.
The white powder obtained was subjected to HPLC detection and the results showed: the purity of the refined product of the benzydac is 99.91 percent, the maximum single impurity is 0.04 percent (3-hydroxy-1-benzyl inddazole impurity), and the total impurity is 0.09 percent.
Example 4
Adding 5.0g of commercially available benzydac into 25mLN, N-dimethylbutanamide, stirring at room temperature (25 ℃), dissolving and clarifying, adding 0.05g of activated carbon, keeping the temperature and stirring for 20min, filtering, slowly adding 25mL of deionized water while stirring, stirring at 25 ℃, crystallizing, filtering, washing a filter cake with 5mL of deionized water, drying at 60 ℃ under reduced pressure for 8h to obtain 4.4g of white powder, wherein the yield is as follows: 88.0 percent.
The white powder obtained was subjected to HPLC detection and the results showed: the purity of the refined product of the benzydac is 99.90 percent, the maximum single impurity is 0.05 (3-hydroxy-1-benzyl inddazole impurity), and the total impurity is 0.10 percent.
Example 5
Adding 5.0g of commercially available benzydac into a mixed solution of 10mL of N, N-dimethylformamide and 10mL of N, N-dimethylpropionamide, stirring at room temperature (25 ℃), dissolving, clarifying, adding 0.05g of activated carbon, keeping the temperature, stirring for 20min, filtering, slowly adding 25mL of deionized water while stirring, stirring at 25 ℃, crystallizing, filtering, washing a filter cake with 5mL of deionized water, drying at 60 ℃ under reduced pressure for 10h to obtain 4.45g of white powder, wherein the yield is as follows: 89.0 percent.
The white powder obtained was subjected to HPLC detection and the results showed: the purity of the refined product of the benzydac is 99.93 percent, the maximum single impurity is 0.03 percent (3-hydroxy-1-benzyl indazozole impurity), and the total impurity is 0.07 percent.
Example 6
Adding 5.0g of commercially available benzydac into a mixed solution of 10mL of N, N-dimethylformamide, 5mL of N, N-dimethylacetamide and 5mL of N, N-dimethylpropionamide, stirring at room temperature (25 ℃) to dissolve and clarify, adding 0.05g of activated carbon, keeping the temperature and stirring for 20min, filtering, slowly adding 25mL of deionized water while stirring, stirring at 25 ℃ to crystallize, performing suction filtration, washing a filter cake with 5mL of deionized water, and drying under reduced pressure at 60 ℃ for 10h to obtain 4.5g of white powder, wherein the yield is as follows: 90.0 percent.
HPLC detection is performed on the obtained white powder, and the result is shown in FIGS. 2-3, and FIG. 2 is an HPLC chart of the benzydate purified in the embodiment 6 of the present invention; FIG. 3 is an enlarged view of a portion of benzydac purified according to example 6 of the present invention. According to the graphs in fig. 2-3, the purity of the refined benzydac is 99.94%, the maximum single impurity is 0.03% (3-hydroxy-1-benzyl inddazole impurity), and the total impurity is 0.06%.
Example 7
Adding 5.0g of commercially available benzydac into 20mLN, N-dimethylformamide, stirring at room temperature (25 ℃) to dissolve and clarify, slowly adding 25mL of deionized water while stirring, stirring at 25 ℃ to crystallize, performing suction filtration, washing a filter cake with 5mL of deionized water, and performing reduced pressure drying at 60 ℃ for 10 hours to obtain 4.5g of white powder, wherein the yield is as follows: 90.0 percent.
The white powder obtained was subjected to HPLC detection and the results showed: the purity of the refined product of the benzydac is 99.67 percent, the single impurity is 0.16 percent (3-hydroxy-1-benzyl inddazole impurity), and the total impurity is 0.33 percent.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (5)
1. A refining method of benzydate comprises the following steps:
A) mixing the crude product of the benzydac, the amide and the active carbon, and filtering to obtain a benzydac solution;
the amide is one or more of N, N-dimethylformamide, N-dimethylacetamide, N-dimethylpropionamide and N, N-dimethylbutanamide;
the mixing temperature is 20-30 ℃;
B) mixing the benzydac solution with water, crystallizing, carrying out solid-liquid separation, and then sequentially washing and drying the separated solid to obtain a refined benzydac product;
the temperature of the crystallization is 20-30 ℃.
2. The purification process according to claim 1, wherein the amide is N, N-dimethylformamide, N-dimethylacetamide or N, N-dimethylpropionamide.
3. The refining method of claim 1, wherein the ratio of the amount of the crude benzydate to the amount of the amide is 1 g: (3-5) mL.
4. The refining method according to claim 1, wherein the mass of the activated carbon is 0.5 to 5% of the mass of the crude benzydate.
5. The refining method of claim 1, wherein the ratio of the amount of the crude benzydate to the amount of water is 5 g: (15-30) mL.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1044810A (en) * | 1989-02-07 | 1990-08-22 | 方济各安吉利克化学联合股份有限公司 | The ether of 1-benzyl-3-methylol-indazole and aliphatic series-2-alcohol acid |
| CN102206185A (en) * | 2011-04-15 | 2011-10-05 | 吉林大学 | Process for refining bendazac lysine and analogs thereof |
| CN103641784A (en) * | 2013-12-03 | 2014-03-19 | 杭州民生药业有限公司 | Bendazac lysine synthesis process |
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2017
- 2017-12-20 CN CN201711381799.3A patent/CN108047136B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1044810A (en) * | 1989-02-07 | 1990-08-22 | 方济各安吉利克化学联合股份有限公司 | The ether of 1-benzyl-3-methylol-indazole and aliphatic series-2-alcohol acid |
| CN102206185A (en) * | 2011-04-15 | 2011-10-05 | 吉林大学 | Process for refining bendazac lysine and analogs thereof |
| CN103641784A (en) * | 2013-12-03 | 2014-03-19 | 杭州民生药业有限公司 | Bendazac lysine synthesis process |
Non-Patent Citations (3)
| Title |
|---|
| 1-苄基-1H-吲唑-3-氧乙酸的合成;金初瑢等;《化学药学杂志》;19901231;第5卷(第1期);第32-33页 * |
| Development of separation fluoroimmunoassays for bendazac and 5-hydroxy bendazac;Kristina staley，et al.;《therapeutic drug monitoring》;19881231;第321-326页 * |
| RADICAL SCAVENGER ACTIVITY OF BENDAZAC, AN ANTICATARACT NON-STEROIDAL ANTI-INFLAMMATORY AGENT;A. GUGLIELMOTTI，et al.;《Pharmacological Research》;19951231;第32卷(第6期);第369-373页 * |
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