CN-121717736-B - Guanidine dipeptide compound and synthetic method and application thereof

CN121717736BCN 121717736 BCN121717736 BCN 121717736BCN-121717736-B

Abstract

The invention discloses a guanidine dipeptide compound and a synthesis method and application thereof, belonging to the technical field of chemical synthesis, wherein the compound has the following chemical structural formula: The synthesis method of the guanidine dipeptide compound comprises the following steps of heating L-ornithine hydrochloride and 1, 2-dimethyl-2-isothiourea hydroiodidate in an alkaline solution for reaction overnight, adjusting the pH value of the solution to be neutral, purifying, adding water for dissolution and adjusting to be acidic, passing through ion exchange resin to obtain an intermediate 1, adding pure water and isopropanol into the intermediate 1 and adjusting to be alkaline, adding isovaleryl chloride into the solution and adjusting to be alkaline, stirring at room temperature for reaction, keeping the solution to be alkaline, heating to 45-55 ℃, adjusting to be weak acid, cooling to 5-15 ℃, collecting precipitate, preparing a crude product, adding a methanol-water mixed solution into the crude product for dissolution, eluting through a liquid chromatography gradient, and drying to prepare the guanidine dipeptide compound. The guanidine dipeptide compound synthesized by the method has high purity, simple synthesis process and convenient operation.

Inventors

GENG ZHAO
GAO BIXING
LIANG MINGJIN
Gou yan
Jiang Ercheng
TAN LING
HE CHENGJUN
ZHANG CHAO
ZHANG ZHICHUN
LI QIAN
ZHONG LIAN

Assignees

四川省药品检验研究院(四川省医疗器械检测中心、四川养麝研究所)
四川新荷花中药饮片股份有限公司

Dates

Publication Date: 20260508
Application Date: 20260213

Claims (10)

1. A guanidine dipeptide compound characterized by the following chemical structural formula: 。
2. The method for synthesizing a guanidine dipeptide compound of claim 1, comprising the steps of: (1) Dissolving L-ornithine hydrochloride and 1, 2-dimethyl-2-isothiouronium hydroiodide in an alkaline solution, and heating and reacting at 70-110 ℃ overnight; (2) Adjusting the pH value of the solution to be neutral, purifying, then adding water for dissolving, adjusting the pH value of the solution to be acidic, passing through ion exchange resin, firstly flushing with pure water, eluting with ammonia water, and freeze-drying to obtain an intermediate 1; (3) Adding pure water and isopropanol into the intermediate 1, and adding alkali liquor to adjust the pH value of the solution to be alkaline; (4) Adding isovaleryl chloride into the solution, and stirring at room temperature for reaction for 2-4h; (5) Keeping the pH value of the solution to be alkaline, heating to 45-55 ℃, then adjusting the pH value of the solution to be weak acid, cooling to 5-15 ℃, and collecting the separated precipitate to obtain a crude compound; (6) Adding methanol-water mixed solution into the crude compound to dissolve, then carrying out gradient elution by liquid chromatography, and drying to obtain the compound.
3. The method for synthesizing a guanidine dipeptide compound of claim 2, wherein the molar ratio of L-ornithine hydrochloride to 1, 2-dimethyl-2-isothiouronium hydroiodide in step (1) is 1:3-5, and the alkaline solution is a sodium hydroxide solution with a concentration of 1M.
4. The method for synthesizing the guanidine dipeptide compound according to claim 2, wherein the step (2) is characterized in that dilute hydrochloric acid is used for adjusting the pH of the solution, the purification process is that methanol is added into the solution after the solvent is evaporated to dryness for dissolution, the solution is filtered for removing impurities, the methanol solvent is recovered, the pH value of the solution is adjusted to 3-5, and the concentration of ammonia water is 0.2M.
5. The method for synthesizing a guanidine dipeptide compound as claimed in claim 2, wherein the intermediate 1, pure water and isopropyl alcohol are used in the step (3) in a ratio of 9-11mmol:7-9ml:24-26ml, and a sodium hydroxide solution is added to adjust the pH of the solution to 10-12.
6. The method for synthesizing a guanidine dipeptide compound of claim 2, wherein in the step (4), the molar ratio of isovaleryl chloride to intermediate 1 is 14-16:1.
7. The method for synthesizing a guanidine dipeptide compound according to claim 2, wherein in the step (5), the pH of the solution is adjusted to 5-6 by using concentrated hydrochloric acid after heating, and the volume ratio of methanol to water in the methanol-water mixed solution in the step (6) is 1-2:1-2.
8. The method for synthesizing a guanidine dipeptide compound of claim 2, wherein the chromatographic column is Waters Xbridge 19x250mm 10 μm, mobile phase a is purified water, mobile phase B is acetonitrile, and the flow rate is 25ml/min when eluting in step (6); The gradient elution conditions were 0min, 95% of A phase, 5% of B phase, 1.5min, 95% of A phase, 5% of B phase, 9.5min, 80% of A phase, 20% of B phase, 9.7min, 5% of A phase, 95% of B phase, 12.7min, 5% of A phase, 95% of B phase, 13min, 95% of A phase, 5% of B phase, 16min, 95% of A phase and 5% of B phase.
9. The use of the guanidine dipeptide compound of claim 1 as a reference substance for identifying rhizoma Pinelliae adulterated rhizoma Pinelliae Cordatae and decoction pieces.
10. The use of the guanidine dipeptide compound of claim 9 as a reference substance for identifying rhizoma Pinelliae adulterated with rhizoma Pinelliae Cordatae and decoction pieces, characterized in that the specific detection method is as follows: (1) Preparing a reference substance solution by taking a guanidine dipeptide compound as a reference substance and a water-soluble organic solvent mixed system as a solvent; (2) Pulverizing rhizoma Pinelliae or decoction pieces, sieving, adding water-water soluble organic solvent mixed system solution, ultrasonic extracting, and filtering to obtain rhizoma Pinelliae extractive solution; (3) Performing chromatographic-mass spectrometry detection on the reference substance solution in the step (1) and the pinellia ternate extract in the step (2) respectively, wherein the high performance liquid chromatography condition comprises a chromatographic column Thermo Hypersil GOLD aQ C 18 , a sample injection volume of 1 mul, a flow rate of 0.3 ml/min, a column temperature of 35 ℃, acetonitrile as a mobile phase A, ammonium formate-10% methanol system solution as a mobile phase B, 5% as a mobile phase B, 95% as a mobile phase B, 2min as a mobile phase A, 5% as a mobile phase B, 95% as a mobile phase 8min as a mobile phase B, 22% as a mobile phase A and 78% as a mobile phase B; The mass spectrum conditions comprise a triple quadrupole mass spectrometer, an electrospray positive ion mode, multi-reaction monitoring, static spray voltage, a positive ion mode, an ion transmission tube temperature of 3500V, an atomizer temperature of 280 ℃, a sheath gas of 40 Arb, a purge gas of 1 Arb, and a guanidine dipeptide mass spectrum acquisition parameter: (4) Comparing the chromatograms of the reference substance solution and the pinellia tuber medicinal material or decoction piece extracting solution, if the chromatogram of the pinellia tuber medicinal material or decoction piece shows chromatographic peaks with the same retention time as the chromatogram of the reference substance, judging that the pinellia tuber medicinal material or decoction piece has the rhizoma Pinelliae water blending effect, otherwise, judging that the pinellia tuber is anhydrous; wherein, the peak area of the biguanide dipeptide increases with the doping proportion of the rhizoma Pinelliae, and has good linear relation, R 2 is not less than 0.99.

Description

Guanidine dipeptide compound and synthetic method and application thereof Technical Field The invention belongs to the technical field of chemical synthesis, and particularly relates to a guanidine dipeptide compound, a synthesis method and application thereof. Background Pinellia ternate is a dry tuber of pinellia ternate PINELLIA TERNATE (thunder.) Breit of Araceae, is a traditional and common Chinese medicinal material in China, and mainly contains chemical components such as alkaloid, organic acid, amino acid, polysaccharide, protein, volatile oil, sterol, flavone and the like, and the research is focused on the aspects of organic acid, alkaloid and the like at present. The rhizoma pinellinae praeparata is a dry tuber of a Blume tip Typhonium flagelliforme (Lodd.) of a plant of the genus Coptis of the family Araceae, and the rhizoma pinellinae praeparata are both traditional Chinese medicines of the same family and capable of drying dampness, resolving phlegm, relieving cough and relieving asthma, and the like, and can be widely applied to the aspects of treating cough and excessive phlegm in clinic in traditional Chinese medicine, but researches show that the rhizoma pinellinae praeparata has stronger toxicity than the rhizoma pinellinae praeparata, and the pharmacological effects of relieving cough and vomiting are weaker than those of the rhizoma pinellinae praeparata, so that certain potential safety hazards of medicine can be brought if the rhizoma pinellinae praeparata is used blindly instead of the rhizoma pinellinae praeparata. On the other hand, compared with the planting condition of the pinellia ternate, the requirements of the pinellia ternate on the planting condition are relatively lower, the harvesting is relatively time-saving and labor-saving, the yield is high, the price interval of the pinellia ternate in recent years is generally 10-20 yuan, the price fluctuation interval of the pinellia ternate is 70-120 yuan, and the price difference of the pinellia ternate and the pinellia ternate is close to 5 times, so that a considerable part of illegal merchants can impersonate the banked pinellia ternate by carrying out plastic surgery on the pinellia ternate. The chemical components in the rhizoma Pinelliae Cordatae and the rhizoma Pinelliae Cordatae are detected and compared, so that the two are distinguished by detecting the content of the distinguishing compound in the rhizoma Pinelliae Cordatae and the rhizoma Pinelliae Cordatae. However, the purification process of the present distinguishing compound is relatively complex, the amount of the purified product obtained after purification is small, and the use requirement cannot be met, so that the development of a synthetic method of the compound is particularly important for preparing the purified product in a large quantity. Disclosure of Invention Aiming at the defects in the prior art, the application provides the guanidine dipeptide compound and the synthesis method thereof, and the synthesized guanidine dipeptide compound has high purity, simple synthesis process and convenient operation. In order to achieve the above purpose, the technical scheme adopted by the invention for solving the technical problems is as follows: A guanidine dipeptide compound having the chemical formula: the synthesis method of the guanidine dipeptide compound comprises the following steps: (1) Dissolving L-ornithine hydrochloride and 1, 2-dimethyl-2-isothiouronium hydroiodide in an alkaline solution, and heating and reacting at 70-110 ℃ overnight; (2) Adjusting the pH value of the solution to be neutral, purifying, then adding water for dissolving, adjusting the pH value of the solution to be acidic, passing through ion exchange resin, firstly flushing with pure water, eluting with ammonia water, and freeze-drying to obtain an intermediate 1; (3) Adding pure water and isopropanol into the intermediate 1, and adding alkali liquor to adjust the pH value of the solution to be alkaline; (4) Adding isovaleryl chloride into the solution, adding alkali liquor to adjust the pH value of the solution to be alkaline, and stirring at room temperature for reaction for 2-4h; (5) Keeping the pH value of the solution to be alkaline, heating to 45-55 ℃, then adjusting the pH value of the solution to be weak acid, cooling to 5-15 ℃, and collecting the separated precipitate to obtain a crude compound; (6) Adding methanol-water mixed solution into the crude compound to dissolve, then carrying out gradient elution by liquid chromatography, and drying to obtain the compound. Further, in the step (1), the molar ratio of L-ornithine hydrochloride to 1, 2-dimethyl-2-isothiouronium hydroiodide is 1:3-5, and the alkaline solution is sodium hydroxide solution with the concentration of 1M. Further, in the step (2), dilute hydrochloric acid is used for regulating the pH value of the solution, the purification process comprises the steps of evaporating the solvent, adding methanol into t