CN110937986A - Compound synthesis method and application in field of insulin resistance improving medicines - Google Patents
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Abstract
The invention belongs to the technical field of medicine synthesis, and particularly relates to a compound synthesis method and application thereof in the field of medicines for improving insulin resistance. The invention provides a synthetic method of SN159, after brominating raw material 2, 4-dihydroxy benzaldehyde, protecting para-hydroxyl with methoxymethyl, adopting dimethyl sulfate or methyl iodide to methylate, adopting claisen-Schmidt condensation reaction under alkaline or acidic condition, and increasing the yield of final product from 18.9% in prior art to more than 68%; meanwhile, column chromatography purification is not needed in the preparation process, and the final product with the purity of more than 99 percent can be obtained by recrystallization, so that the method is suitable for large-scale/industrial production. The synthesis method of the compound and the application of the compound in the field of preparation of the medicine for improving insulin resistance solve the technical defects of low synthesis yield and complex purification of SN159 in the prior art.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a compound synthesis method and application thereof in the field of medicines for improving insulin resistance.
Background
The research finds that insulin resistance is the basis of the pathogenesis of obesity, diabetes and cardiovascular diseases and is the main pathophysiological characteristic of type 2 diabetes. The natural product Licocalcone E has the functions of improving blood sugar level, regulating lipid metabolism and improving insulin resistance, and is a derivative after structural modification,
SN159 is a dual partial agonist of PPAR α/gamma, can increase Glucose uptake of C2C12 myoblasts under normal state and insulin resistance condition, promotes insulin-mediated phosphorylation of Insulin Receptors (IR) and Akt, thereby increasing insulin activation of IR-Akt axis and increasing insulin sensitivity, SN159 can promote differentiation of preadipocytes and stem cells to adipocytes, and remarkably increases gene expression level of Glucose transporter 4 (GLUT-4) in 3T3-L1 preadipocytes, thereby increasing insulin sensitivity of adipocytes, and SN159 can increase fatty acid oxidation and Glucose utilization by dual activation of PPAR α/gamma.
In view of the great medical value of the compound SN159, it is necessary to research the synthesis/production process thereof. In the prior art, 2, 4-dihydroxy benzaldehyde is generally used as a raw material for the synthesis process of SN159, and the SN159 is obtained by a multi-step reaction and a separation and purification mode of column chromatography, has the technical defects of low synthesis yield and complex purification, and is difficult to realize large-scale/industrial production.
Therefore, the development of a compound synthesis method and application thereof in the field of drugs for improving insulin resistance is used for solving the technical defects of low synthesis yield and complex purification of SN159 in the prior art, and becomes a problem to be solved by those skilled in the art.
Disclosure of Invention
In view of the above, the invention provides a compound synthesis method and application thereof in the field of drugs for improving insulin resistance, and aims to overcome the technical defects of low synthesis yield and complex purification of SN159 in the prior art.
The invention provides a synthetic method of a compound, wherein the structural formula of the compound is as follows:
preferably, the synthetic route according to claim 1, characterized in that step ii uses chloromethyl methyl ether to protect benzaldehyde para-hydroxy group, and the reaction solvent of step ii is acetone
Preferably, the methylating agent of step iii is dimethyl sulphate and/or methyl iodide.
Preferably, the methylating agent of step iii is dimethyl sulphate and the catalyst of step iii is tetrabutylammonium bromide.
Preferably, the catalyst of step iv is hydrochloric acid solution, the concentration of hydrochloric acid is 4-8mol/L, and the solvent of step iv is methanol and tetrahydrofuran.
Preferably, the catalyst of step v is HCl-EtOH and the reaction solvent of step v is ethanol.
Preferably, the reaction solvent of step v further comprises: 1, 4-dioxane, wherein the volume percentage of the 1, 4-dioxane in the ethanol is 0-500%.
Preferably, the catalyst of step vi is potassium hydroxide; the solvent in the step vi is ethanol-water solution, wherein the volume ratio of ethanol to water is 2: 1.
Preferably, the catalyst in the step vii is hydrochloric acid solution, wherein the concentration of hydrochloric acid is 4-8 mol/L; the solvent in step vii is methanol or a mixed solvent of methanol and 1, 4-dioxane.
The invention also provides application of the synthesis method in the field of preparation of medicines for improving insulin resistance.
In summary, the present invention provides a synthesis method of SN159, and the present invention also provides the above synthesis route. In the technical scheme provided by the invention, after 2, 4-dihydroxy benzaldehyde is brominated as a raw material, methoxy methyl is used for protecting para-hydroxyl; performing o-hydroxyl methylation by using tetrabutylammonium bromide as a phase transfer catalyst and dimethyl sulfate as a methyl source; the claisen-Schmidt condensation reaction under the alkaline or acidic condition is adopted, so that the yield of the final product can be improved to more than 68 percent from 18.9 percent in the prior art; meanwhile, in the preparation process, the final product with the purity of over 99 percent can be obtained only by recrystallization without column chromatography purification, and the method is suitable for large-scale/industrial production. The synthesis method of the compound and the application of the compound in the field of preparation of the medicine for improving insulin resistance solve the technical defects of low synthesis yield and complex purification of SN159 in the prior art.
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 a graph showing the effect of SN159 on glucose uptake by myoblasts of C2C12 under normal conditions in example 3;
FIG. 2 is a graph of the effect of Compound SN159 on glucose uptake by C2C12 myoblasts under insulin resistant conditions in example 3;
FIG. 3 is a hydrogen spectrum of intermediate 2;
FIG. 4 is a carbon spectrum of intermediate 2;
FIG. 5 is a hydrogen spectrum of intermediate 3;
FIG. 6 is a carbon spectrum of intermediate 3;
FIG. 7 is a hydrogen spectrum of intermediate 4;
FIG. 8 is a carbon spectrum of intermediate 4;
FIG. 9 is a hydrogen spectrum of intermediate 6;
FIG. 10 is a carbon spectrum of intermediate 6;
FIG. 11 is a hydrogen spectrum of Compound SN 159;
fig. 12 is a carbon spectrum of compound SN 159.
Detailed Description
The invention provides a compound synthesis method and application thereof in the field of medicines for improving insulin resistance, and aims to overcome the technical defects of low synthesis yield and complex purification of SN159 in the prior art.
The technical solutions in the embodiments of the present invention will be 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.
In order to illustrate the invention in more detail, the following examples are provided to describe the synthesis method of a compound and the application of the compound in the preparation field of antidiabetic drugs for improving insulin resistance.
Example 1
This embodiment is one specific example of synthesizing SN 158.
1.1 step i-preparation of intermediate 1 (5-bromo-2, 4-hydroxybenzaldehyde)
2, 4-dihydroxybenzaldehyde (10g, 72.4mmol) was dissolved in acetic acid and the reaction was placed under an ice bath. Liquid bromine (3.78ml, 72.4mmol) was slowly added dropwise with stirring, and the reaction temperature was slowly raised to room temperature. After reacting for 3 hours, the reaction mixture was poured into 100mL of cold water, filtered, washed with 100mL of cold water, dried, and recrystallized from 1:1 acetonitrile/toluene to obtain 13.09g of intermediate 1 crystal (yield: 83%).
Structural characterization of intermediate 1:
melting point: 165-168 ℃.
1.2 step ii-preparation of intermediate 2 (5-bromo-2-hydroxy-4- (methoxymethyl) benzaldehyde)
Intermediate 1(10.9g, 50mmol) and potassium carbonate (20.8g, 150.3mmol) were mixed in 100mL of acetone and chloromethyl methyl ether (3.8mL, 50mmol) was added dropwise with constant stirring. The mixture was stirred at room temperature for 30 minutes, filtered and the solvent was evaporated. The residue was dissolved in ethyl acetate, dispersed with water and extracted 3 times with 50mL portions of ethyl acetate. The combined organic layers were washed with 50mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and recrystallized from 50:1 n-hexane/ethyl acetate to obtain 12.3g of intermediate 2 (yield: 92%).
Structural characterization of intermediate 2:
the melting point is 59-62 ℃;
1H-NMR(300MHz，CDCl3):δ9.70(s，1H)，7.69(s，2H)，6.74(s，1H)，5.30(s，2H)，3.51(s，3H)，2.60(s，3H)；
13C-NMR(75MHz，CDCl3):δ193.8，163.1，160.2，137.4，116.5，103.4，102.7，94.8，56.7；
ESI-MS:m/z261[M-H]+。
1.3 step iii-preparation of intermediate 3 (5-bromo-2-methoxy-4-methoxymethylbenzaldehyde)
Intermediate 2(5.8g, 22.56mmol) was dissolved in 75mL of a methylene chloride/water complex solvent (volume ratio: 3:2), NaOH (1.35g, 33.84mmol) and tetrabutylammonium bromide (0.73g, 2.26mmol) were added under constant stirring, dimethyl sulfate was added, and the reaction was continued with stirring at room temperature for 2 hours. The solvent was recovered under reduced pressure, dispersed in water, and extracted with ethyl acetate 3 times with 45mL each time. The organic layers were combined, washed with 50mL of saturated brine to remove excess tetrabutylammonium bromide, dried over anhydrous sodium sulfate, filtered, and the solvent was recovered under reduced pressure and dried to obtain 6.14g of intermediate 3 as white crystals (yield: 99%).
Structural characterization of intermediate 3:
the melting point is 70-73 ℃;
1H-NMR(300MHz，CDCl3):δ10.26(s，1H)，8.01(s，1H)，6.79(s，1H)，5.33(s，2H)，3.92(s，3H)，3.54(s，3H)；
13C-NMR(75MHz，CDCl3):δ187.2，162.2，159.6，132.8，120.2，104.1，99.0，95.0，56.6，55.9；
ESI-MS:m/z275[M-H]+。
1.4 step iv-preparation of intermediate 4 (5-bromo-2-methoxy-4-hydroxybenzaldehyde)
Intermediate 3(1g, 3.7mmol) was dissolved in 20mL of methanol, 20mL of 6M HCl was slowly added dropwise with constant stirring in an ice bath, the reaction temperature was gradually raised to room temperature, and the reaction was carried out for 24 hours. The reaction was quenched with ice-water, extracted 3 times with 25mL of ethyl acetate, and the combined organic layers were washed with 50mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was recovered under reduced pressure and dried to obtain 0.82g of intermediate 4 (yield: 98%) as white crystals.
Structural characterization of intermediate 4:
the melting point is 203.5-206.5 ℃;
1H-NMR(300MHz，DMSO-d6):δ11.57(s，1H)，10.05(s，1H)，7.74(s，1H)，6.67(s，1H)，3.85(s，3H)；
13C-NMR(300MHz，DMSO-d6):δ186.10，162.45，161.04，132.21，118.08，101.52，99.92，55.94。
1.5 step v-preparation of SN159((E) -1- (3-aminophenyl) -3- (5-bromo-4-hydroxy-2-methoxyphenyl) prop-2-en-1-one)
Meta-aminoacetophenone (0.28g, 2.06mmol) was dissolved in 10mL of 1, 4-dioxane, 12mL of 2.2M HCl-EtOH was added under stirring at a constant speed, and after 30 minutes of reaction, intermediate 4(0.5g, 2.16mmol) was added. The reaction solution reacts at 0 ℃ under the protection of argon, and the thin-layer chromatography detects whether the reaction is complete. After the reaction was complete, 100mL of ice water was added to quench the reaction. After filtration and washing with ice water, the mixture was dried to obtain 0.66g of compound SN159 (yield: 92%) which was yellow in color.
Structural characterization of SN 159:
the melting point is 152-155 ℃;
1H-NMR(300MHz，DMSO-d6):δ8.10(s，1H)，7.85(d，J＝15.7Hz，1H)，7.66(d，J＝15.7Hz，1H)，7.36–7.28(m，1H)，7.21(dt，J＝15.5，4.8Hz，2H)，6.81(ddd，J＝7.9，2.3，0.9Hz，1H)，6.65(s，1H)，5.33(s，2H)，3.84(s，3H)；
13C-NMR(75MHz，DMSO-d6):δ189.38，158.95，157.47，149.06，138.75，136.79，132.15，129.08，119.75，118.34，116.28，112.95，101.06，99.92，55.83；
ESI-MS:m/z349[M+H]+。
example 2
This embodiment is another specific example of synthesizing SN 158.
2.1 step i-preparation of intermediate 1 (5-bromo-2, 4-hydroxybenzaldehyde)
2, 4-dihydroxybenzaldehyde (10g, 72.4mmol) was dissolved in acetic acid and the reaction was placed under an ice bath. Liquid bromine (3.78ml, 72.4mmol) was slowly added dropwise with stirring, and the reaction temperature was slowly raised to room temperature. After reacting for 3 hours, the reaction mixture was poured into 100mL of cold water, filtered, washed with 100mL of cold water, dried, and recrystallized from 1:1 acetonitrile/toluene to obtain 13.09g of intermediate 1 crystal (yield: 83%).
Structural characterization of intermediate 1:
melting point: 165-168 ℃.
2.2 step ii-preparation of intermediate 2 (5-bromo-2-hydroxy-4- (methoxymethyl) benzaldehyde)
Intermediate 1(10.9g, 50mmol) and potassium carbonate (20.8g, 150.3mmol) were mixed in 100mL of acetone and chloromethyl methyl ether (3.8mL, 50mmol) was added dropwise with constant stirring. The mixture was stirred at room temperature for 30 minutes, filtered and the solvent was evaporated. The residue was dissolved in ethyl acetate, dispersed with water and extracted 3 times with 50mL portions of ethyl acetate. The combined organic layers were washed with 50mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and recrystallized from 50:1 n-hexane/ethyl acetate to obtain 12.3g of intermediate 2 (yield: 92%).
Structural characterization of intermediate 2:
the melting point is 59-62 ℃;
1H-NMR(300MHz，CDCl3):δ9.70(s，1H)，7.69(s，2H)，6.74(s，1H)，5.30(s，2H)，3.51(s，3H)，2.60(s，3H)；
13C-NMR(75MHz，CDCl3):δ193.8，163.1，160.2，137.4，116.5，103.4，102.7，94.8，56.7；
ESI-MS:m/z261[M-H]+。
2.3 step iii-preparation of intermediate 3 (5-bromo-2-methoxy-4-methoxymethylbenzaldehyde)
Intermediate 2(5.8g, 22.56mmol) was dissolved in 75mL of a methylene chloride/water complex solvent (volume ratio: 3:2), NaOH (1.35g, 33.84mmol) and tetrabutylammonium bromide (0.73g, 2.26mmol) were added under constant stirring, dimethyl sulfate was added, and the reaction was continued with stirring at room temperature for 2 hours. The solvent was recovered under reduced pressure, dispersed in water, and extracted with ethyl acetate 3 times with 45mL each time. The organic layers were combined, washed with 50mL of saturated brine to remove excess tetrabutylammonium bromide, dried over anhydrous sodium sulfate, filtered, and the solvent was recovered under reduced pressure and dried to obtain 6.14g of intermediate 3 as white crystals (yield: 99%).
Structural characterization of intermediate 3:
the melting point is 70-73 ℃;
1H-NMR(300MHz，CDCl3):δ10.26(s，1H)，8.01(s，1H)，6.79(s，1H)，5.33(s，2H)，3.92(s，3H)，3.54(s，3H)；
13C-NMR(75MHz，CDCl3):δ187.2，162.2，159.6，132.8，120.2，104.1，99.0，95.0，56.6，55.9；
ESI-MS:m/z275[M-H]+。
2.4 step vi-preparation of intermediate 6((E) -1- (3-aminophenyl) -3- (5-bromo-2-methoxy-4-methoxymethylphenyl) prop-2-en-1-one)
M-aminoacetophenone (0.74g, 5.5mmol) was dissolved in 10mL of ethanol/water (volume ratio 1:1), and 1.22g of potassium carbonate powder (21.8mmol) was added. An ethanol solution (5mL) of intermediate 3(1.5g, 5.5mmol) was slowly added dropwise to the reaction solution under ice bath conditions, and the reaction was gradually warmed to room temperature for 24 hours. After the reaction was completed, 90mL of ice water was added to quench, filtered, washed with ice water, and dried. Recrystallization from methylene chloride gave 1.92g of intermediate 6 as a yellow solid (yield: 90%).
Structural characterization of intermediate 6:
the melting point is 130-131 ℃;
1H-NMR(300MHz，CDCl3):δ7.99(d，J＝16.1Hz，1H)，7.80(s，1H)，7.46(d，J＝15.8Hz，1H)，7.38(dd，J＝5.3，3.8Hz，1H)，7.31(dd，J＝4.4，2.6Hz，1H)，7.29–7.23(m，2H)，6.92–6.85(m，1H)，6.78(s，1H)，5.30(s，2H)，3.90(s，3H)，3.54(s，3H)；
13C-NMR(75MHz，CDCl3):δ190.66，159.18，156.27，146.73，139.51，138.11，132.46，129.32，121.61，119.31，119.19，118.78，114.39，103.39，99.64，95.08，56.52，55.88。
2.5 step vii-preparation of SN159((E) -1- (3-aminophenyl) -3- (5-bromo-4-hydroxy-2-methoxyphenyl) prop-2-en-1-one)
Intermediate 6(0.46g, 1.18mmol) was dissolved in 15mL of methanol and 10mL of 1, 4-dioxane, 6 mL of HCl was added dropwise under ice bath conditions, the reaction was carried out at room temperature for 12 hours, 150mL of ice water was added to quench the reaction, and 350mg of the yellow compound SN159 (yield: 86%) was obtained by filtration, washing with ice water and drying.
Structural characterization of SN 159:
the melting point is 152-155 ℃;
1H-NMR(300MHz，DMSO-d6):δ8.10(s，1H)，7.85(d，J＝15.7Hz，1H)，7.66(d，J＝15.7Hz，1H)，7.36–7.28(m，1H)，7.21(dt，J＝15.5，4.8Hz，2H)，6.81(ddd，J＝7.9，2.3，0.9Hz，1H)，6.65(s，1H)，5.33(s，2H)，3.84(s，3H)；
13C-NMR(75MHz，DMSO-d6):δ189.38，158.95，157.47，149.06，138.75，136.79，132.15，129.08，119.75，118.34，116.28，112.95，101.06，99.92，55.83；
ESI-MS:m/z349[M+H]+。
comparative example 1
This comparative example is a comparative example of a synthetic route to step iii, i.e. preparation of intermediate 3.
In this comparative example, intermediate 3 was obtained by recrystallization after the reaction under the basic condition of potassium carbonate with methyl iodide as a methyl source and acetone as a reaction solvent (yield: 73%).
Comparative example 2
This comparative example is a step iv synthetic route, a comparative example to prepare intermediate 4.
In this comparative example, the solvent used was tetrahydrofuran, which was identical to example 1 except for the reaction conditions specified, to give intermediate 4 (yield: 89%).
Comparative example 3
This comparative example is a synthetic route to step vi, a comparative example to prepare intermediate 6.
In this comparative example, the procedure was as in example 2 except for the reaction conditions specified; in the hydrolysis, a 6M HCl solution was used, and methanol was used as a solvent, to obtain intermediate 6 (yield: 54%).
Comparative example 4
This comparative example is the synthetic route to step v, a comparative example to prepare SN 159.
In this comparative example, the procedure was as in example 1 except for the reaction conditions specified.
Intermediate 5 is used as a raw material, Aldol condensation reaction is carried out under alkaline conditions, however, a high-purity compound SN159 cannot be obtained under the conditions, and the use requirement cannot be met.
Example 3
This example is a specific example of verifying that the prepared SN159 improves insulin resistance.
C2C12 myoblasts were differentiated into myotubes over 4 days in DMEM medium with 2% horse serum. Then cultured in DMEM containing 2% BSA and 10% FBS for 16 hours, and whether normal or insulin resistant conditions were controlled by the addition and non-addition of 0.75mM palmitate.
After 1 hour stimulation with insulin, myotubes were incubated with 2-NBDG (purchased from Invitrogen) at 50. mu.M for 15 minutes, washed 3 times with PBS, and free 2-NBDG was removed. In an Infinite M1000 microplate reader (TECKAN,
switzerland) was measured for the fluorescence intensity of 2-NBDG entering the cell, with an excitation wavelength of 485nm and an emission wavelength of 535 nm.
The results of the experiment are shown in fig. 1 and fig. 2, wherein fig. 1 shows the effect of compound SN159 on glucose uptake of C2C12 myoblasts under normal conditions, wherein insulin-is the baseline state and insulin + is the insulin stimulated state; FIG. 2 is a graph of the effect of Compound SN159 on glucose uptake by C2C12 myoblasts under insulin resistant conditions, where insulin-is the baseline state and insulin + is the insulin stimulated state.
As can be derived from fig. 1 and 2, compound SN159 was able to significantly increase glucose uptake in insulin activated or baseline states in C2C12 cells under normal conditions; SN159 also significantly increased glucose uptake at insulin baseline or activated state for C2C12 cells under palmitic acid-induced insulin resistance conditions. The above results indicate that SN159 increases glucose uptake and increases insulin sensitivity through insulin activation of the IR-Akt signaling axis.
In summary, the present invention provides a synthesis method of SN159, and the present invention also provides the above synthesis route. In the technical scheme provided by the invention, after 2, 4-dihydroxy benzaldehyde is brominated as a raw material, methoxy methyl is used for protecting para-hydroxyl; performing o-hydroxyl methylation by using tetrabutylammonium bromide as a phase transfer catalyst and dimethyl sulfate as a methyl source; the claisen-Schmidt condensation reaction under the alkaline or acidic condition is adopted, so that the yield of the final product can be improved to more than 68 percent from 18.9 percent in the prior art; meanwhile, in the preparation process, the final product with the purity of over 99 percent can be obtained only by recrystallization without column chromatography purification, and the method is suitable for large-scale/industrial production. The invention provides a compound synthesis method and application thereof in the field of medicines for improving insulin resistance, and solves the technical defects of low synthesis yield and complex purification of SN159 in the prior art.
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 (10)
1. A method of synthesizing a compound having the formula:
the method is characterized by comprising the following steps:
2. the synthetic route according to claim 1, characterized in that step ii uses chloromethyl methyl ether to protect the p-hydroxy group of benzaldehyde and the reaction solvent of step ii is acetone.
3. The synthesis process according to claim 1, wherein the methylating agent of step iii is dimethyl sulfate and/or methyl iodide.
4. A synthesis process according to claim 3, characterised in that the methylating agent of step iii is dimethyl sulphate and the catalyst of step iii is tetrabutylammonium bromide.
5. The synthesis method according to claim 1, wherein the catalyst of step iv is hydrochloric acid solution, the concentration of hydrochloric acid is 4-8mol/L, and the solvent of step iv is methanol and tetrahydrofuran.
6. The synthesis method according to claim 1, wherein the catalyst of step v is HCl-EtOH, and the reaction solvent of step v is ethanol.
7. The synthesis method according to claim 6, wherein the reaction solvent of step v further comprises: 1, 4-dioxane, wherein the volume percentage of the 1, 4-dioxane in the ethanol is 0-500%.
8. The synthesis method according to claim 1, wherein the catalyst of step vi is potassium hydroxide; the solvent in the step vi is ethanol-water solution, wherein the volume ratio of ethanol to water is 2: 1.
9. The synthesis method of claim 1, wherein the catalyst in step vii is hydrochloric acid solution, wherein the concentration of hydrochloric acid is 4-8 mol/L;
the solvent in step vii is methanol or a mixed solvent of methanol and 1, 4-dioxane.
10. Use of a synthetic method according to any one of claims 1 to 9 in the manufacture of a medicament for improving insulin resistance.
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| CN113402437A (en) * | 2021-06-29 | 2021-09-17 | 河北维达康生物科技有限公司 | Novel method for synthesizing dietary supplement melatonin |
| CN113735693A (en) * | 2021-10-20 | 2021-12-03 | 河北维达康生物科技有限公司 | Synthesis method of resveratrol monomethyl ether |
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| ZENGTAOWANG ET AL.: ""design,synthesis and docking study of 5-(substituted benzylidene)thiazolidine-2,4-dione derivatives as inhibitors of protein tyrosine phosphatase 1B", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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| CN113402437A (en) * | 2021-06-29 | 2021-09-17 | 河北维达康生物科技有限公司 | Novel method for synthesizing dietary supplement melatonin |
| CN113735693A (en) * | 2021-10-20 | 2021-12-03 | 河北维达康生物科技有限公司 | Synthesis method of resveratrol monomethyl ether |
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