CN115124435A - Opium compound and preparation method and application thereof - Google Patents
Opium compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an opioid compound shown in a formula (I) and a preparation method and application thereof. The compound with high purity is obtained through a series of reactions such as amino protection, bromination, intermolecular coupling, demethylation, deprotection and the like. Through the research on various commercially available opioids, the compound shown in the formula (I) can be detected in the irradiated dezocine injection, and side effects can be caused. Toxicological studies show that the compound disclosed by the invention can be used for the quality research of dezocine and has important significance for the research of adverse reactions of the dezocine.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to an opioid compound, and a preparation method and application thereof.
Background
Opioids, such as fentanyl, morphine, dezocine, oxycodone, and the like, are widely used medically for analgesic treatment, especially in the context of moderate to severe acute and chronic pain. But can produce adverse reactions of different degrees while effectively relieving the pain, and can cause the problems of drug abuse, addiction, even death and the like after long-term use. In the review research of opioid-induced adverse reactions, the humped flyer et al indicate that the adverse reactions caused by the drugs relate to various aspects of gastrointestinal system, nervous system, respiratory system, visual system, muscular system and the like, wherein the adverse reactions caused by morphine and dezocine account for most (journal of epidemiology of drugs, 2019, Vol.28NO.5, 314-318). Moneosone has studied the adverse reactions of the dezocine injection, which are mainly manifested by symptoms of gastrointestinal upset, nausea and vomiting (January 2020, Vol.13, No.1B, 14 and 17). Adverse reactions to a drug may be caused by the influence of the active ingredient of the drug itself on the one hand, and by the fact that the drug contains certain compounds having a structure similar to that of the active ingredient of the drug on the other hand. Therefore, there is a need for further research on structurally similar compounds contained in drugs and effective detection methods for such compounds.
Disclosure of Invention
In order to improve the technical problems, the present invention provides a compound represented by formula (i) or a pharmaceutically acceptable salt thereof:
according to the invention, the chemical name of the compound represented by formula (I) is: (6R,6'R,12S,12' S,15S,15'S) -15,15' -diamino-6, 6 '-dimethyl-7, 7',8,8',9,9',10,10',11,11',12,12',13,13',15,15 '-hexadecahydro-6H, 6' H- [2,2 '-bis (5, 11-methylenebenzocyclodecene) ] -3,3' -diol.
According to an embodiment of the present invention, the pharmaceutically acceptable salt of the compound represented by formula (I) is a pharmaceutically acceptable salt of the compound of formula (I) with an acid known in the art, including but not limited to hydrochloride, hydrobromide, hydroiodide, p-toluenesulfonate, methanesulfonate, maleate or citrate of the compound of formula (I), preferably hydrochloride.
According to an embodiment of the invention, the pharmaceutically acceptable salt may be a mono-or di-salt, i.e. in the pharmaceutically acceptable salt of the compound of formula (i), the molar ratio of the compound of formula (i) to the acid may be 1:1 or 1: 2.
According to an embodiment of the invention, the pharmaceutically acceptable salt of the compound of formula (i) is a dihydrochloride salt of formula (II):
the invention also provides a preparation method of the compound shown in the formula (I), which comprises the following steps:
step 1: reacting the compound 1 or pharmaceutically acceptable salt thereof with an amino protecting agent to obtain a compound 2, wherein P represents an amino protecting group;
step 2: reacting the compound 2 with a bromization reagent to obtain a compound 3;
and 3, step 3: carrying out coupling reaction on the compound 3 to obtain a compound 4;
and 4, step 4: after the compound 4 reacts with a deamination protective reagent, dissociating to obtain a compound shown in a formula (I);
according to an embodiment of the present invention, P in said compound 2 is preferably an amino protecting group capable of being removed under acidic conditions;
according to an embodiment of the present invention, step 1 is performed in the presence of a first solvent, wherein the first solvent is preferably one or more of alcohol containing 1 to 4 carbon atoms, tetrahydrofuran, dichloromethane, chloroform, acetonitrile and water;
according to an embodiment of the present invention, in step 1, the temperature of the reaction is-10 ℃ to 40 ℃;
according to an embodiment of the invention, the reaction of step 1 is carried out in the presence of a first alkaline reagent or acid-binding agent. Wherein, the first alkaline reagent or acid-binding agent is preferably one or more of sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia water, pyridine, DMAP, DBU, diisopropylethylamine and triethylamine;
according to an embodiment of the present invention, the amino protecting reagent described in step 1 is benzyl chloroformate and/or Boc anhydride;
according to an embodiment of the invention, the molar ratio of the compound 1 to the first alkaline reagent in the step 1 is 1 (0.5-10), or the molar ratio of the compound 1 to the acid-binding agent is 1 (0.5-10);
according to an embodiment of the present invention, the molar ratio of the compound 1 to the amino protecting agent in the step 1) is 1 (0.5-10), and is further preferably 1 (1-10);
according to the embodiment of the invention, the mass-to-volume ratio of the compound 1 to the first solvent in the step 1 is 1g (1-50) mL;
according to an embodiment of the present invention, step 2 is performed in the presence of a second solvent, preferably one or more of carbon tetrachloride, dichloromethane, chloroform, N-dimethylformamide, THF, diethyl ether and DMSO;
according to an embodiment of the invention, the brominating reagent in step 2 is NBS and/or bromine;
according to an embodiment of the present invention, the temperature of the reaction in step 2 is 0 ℃ to 80 ℃;
according to the embodiment of the invention, the molar ratio of the compound 2 to the brominating agent in the step 2 is 1 (0.5-2);
according to the embodiment of the invention, the mass-to-volume ratio of the compound 2 to the second solvent in the step 2 is 1g (5-20) mL;
according to an embodiment of the present invention, step 3 is performed in a third solvent, which is preferably one or more of tetrahydrofuran, N-dimethylformamide, dichloromethane, chloroform and toluene;
according to an embodiment of the present invention, step 3 is carried out in the presence of a second basic agent, preferably one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and potassium phosphate;
according to an embodiment of the invention, step 3 is also carried out in the presence of pinacol boronate and dppf palladium chloride;
according to an embodiment of the present invention, the temperature of the coupling reaction in step 3 is 30 ℃ to 120 ℃;
according to the embodiment of the invention, the mass ratio of the compound 3 to the pinacol borate in the step 3 is 1 (0.2-1);
according to the embodiment of the invention, the molar ratio of the compound 3 to the second basic reagent in the step 3 is 1 (1-5);
according to the embodiment of the invention, the mass-to-volume ratio of the compound 3 to the third solvent in the step 3 is 1g (3-30) mL;
according to an embodiment of the present invention, steps 1, 2 and 3 may further include adding water and ethyl acetate to the reaction system after the reaction is completed, and separating to obtain an organic phase. Further, the organic phase is concentrated and purified.
According to an embodiment of the present invention, step 4 is performed in a fourth solvent, which is preferably one or more of dichloromethane, chloroform, ethanol and acetone;
according to an embodiment of the present invention, the deamination protecting agent in step 4 is boron tribromide, hydroiodic acid, hydrobromic acid or concentrated hydrochloric acid;
according to an embodiment of the present invention, the temperature of the reaction in step 4 is-90 ℃ to 30 ℃.
According to an embodiment of the present invention, after the reaction of step 4 is completed, the reaction product is dissociated in the presence of a third basic reagent, preferably triethylamine, ammonia water, an aqueous solution of sodium bicarbonate, an aqueous solution of sodium carbonate;
according to the embodiment of the invention, a third alkaline reagent is added in the step 4, and the pH value of the system is adjusted to 7-8.
According to the embodiment of the invention, the molar ratio of the compound 4 to the deamination protective agent in the step 4 is 1 (1-10);
according to the embodiment of the invention, the mass-to-volume ratio of the compound 4 to the fourth solvent in the step 4 is 1g (3-50) mL.
The invention also provides a preparation method of the pharmaceutically acceptable salt of the compound shown in the formula (I), which comprises the following steps: reacting the compound shown in the formula (I) with acid to obtain pharmaceutically acceptable salt thereof.
According to an embodiment of the invention, the acid may be selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, p-toluenesulphonic acid, methanesulphonic acid, maleic acid or citric acid.
According to an embodiment of the present invention, the compound represented by formula (I) may be obtained by the above-mentioned preparation method of the compound represented by formula (I).
The invention also provides application of the compound shown in the formula (I) or pharmaceutically acceptable salt thereof in controlling the quality of dezocine bulk drugs or dezocine injection.
The invention also provides application of the compound shown in the formula (I) or pharmaceutically acceptable salt thereof as a standard substance or a reference substance, preferably application as a drug standard substance or a reference substance, and more preferably application as a quality research standard substance or a reference substance of a dezocine bulk drug or a dezocine injection.
The invention also provides a quality control method of the dezocine bulk drug or the dezocine injection, which comprises the step of taking the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof as a standard substance or a reference substance, preferably as a drug standard substance or a reference substance.
The invention also provides a quality control method of the dezocine bulk drug or the dezocine injection, which comprises the step of detecting the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof.
The invention also provides a quality control method of the dezocine bulk drug or the dezocine injection, which comprises the step of storing the dezocine bulk drug or the dezocine injection in a dark place.
The present invention also provides a method for detecting a compound represented by the above formula (i) or a pharmaceutically acceptable salt thereof, which comprises detecting the compound represented by the formula (i) or a pharmaceutically acceptable salt thereof in a test sample solution by liquid chromatography, for example, high performance liquid chromatography.
According to an embodiment of the invention, the stationary phase of the column in the liquid chromatography, such as high performance liquid chromatography, is silica gel, e.g. C18-bonded silica gel, preferably reversed phase C18-bonded silica gel. As an example, the chromatography column may be selected from silica gel chromatography columns, preferably C18-bonded silica gel chromatography columns, such as reverse phase C18-bonded silica gel chromatography columns.
According to an embodiment of the present invention, the mobile phase of the high performance liquid chromatography is a mixture of an ion-pair reagent, water and an organic solvent.
According to an embodiment of the invention, the ion pairing agent is preferably an anion pairing agent, such as C 4-14 Sodium alkylsulfonates, e.g. C 5-12 Sodium alkylsulfonates, examples of which may be selected from one, two or more of sodium pentane sulfonates, sodium hexane sulfonates, sodium heptane sulfonates, sodium octane sulfonates, and sodium dodecyl sulfonates.
According to an embodiment of the present invention, the organic solvent may be selected from methanol, acetonitrile or a mixture thereof, preferably acetonitrile.
According to an embodiment of the present invention, the mobile phase of the high performance liquid chromatography may be a mixture of an aqueous solution of an ion-pair reagent and an organic solvent. As an example, the mobile phase may be a mixed solution of sodium heptanesulfonate, water and acetonitrile, for example, a mixed solution obtained by mixing an aqueous solution of sodium heptanesulfonate and acetonitrile.
According to an embodiment of the invention, the ratio of the sum of the volumes of ion pairing reagent and water to the volume of acetonitrile in the mobile phase may be from 1:9 to 9:1, for example from 2:8 to 8: 2.
According to an embodiment of the invention, the concentration of the ion-pairing reagent in the mobile phase is 1-10mmol/L, such as 4-6mmol/L, e.g. 1mmol/L, 2mmol/L, 3mmol/L, 4mmol/L, 5mmol/L, 6mmol/L, 7mmol/L, 8mmol/L, 9mmol/L or 10mmol/L based on the total volume of the ion-pairing reagent and water.
It will be understood by those skilled in the art that numerical ranges in the context of this specification include not only the particular values (e.g., integer values) recited by the text, but also values (e.g., non-integer values) that are possible between adjacent particular values.
According to an embodiment of the present invention, the test conditions of the high performance liquid chromatography are as follows:
a chromatographic column: a Sunfire C18 chromatography column, preferably 250mm x 4.6mm, with a particle size of 5 μm;
a mobile phase A: a mixed solution of sodium heptanesulfonate aqueous solution and acetonitrile, preferably a mixed solution of 5mmol/L sodium heptanesulfonate aqueous solution and acetonitrile, wherein the volume ratio of the sodium heptanesulfonate aqueous solution to the acetonitrile is 80: 20;
mobile phase B: a mixed solution of sodium heptanesulfonate aqueous solution and acetonitrile, preferably a mixed solution of 5mmol/L sodium heptanesulfonate aqueous solution and acetonitrile, wherein the volume ratio of the sodium heptanesulfonate aqueous solution to the acetonitrile is 20: 80;
gradient elution.
According to an embodiment of the invention, the gradient elution may be performed using the following gradient:
according to an embodiment of the present invention, the test conditions of the high performance liquid chromatography further include:
flow rate: 0.9mL/min, column temperature: 40 ℃, detection wavelength: 281 nm.
The invention also provides a composition comprising silica gel and a compound of formula (I) or a salt thereof.
According to an embodiment of the present invention, the silica gel is selected from C18-bonded silica gels, preferably reversed phase C18-bonded silica gels.
According to an embodiment of the present invention, in the composition, the salt of the compound represented by formula (i) may be selected from pharmaceutically acceptable salts of the compound represented by formula (i) described above or salts of the compound represented by formula (i) with other acids known to those skilled in the art.
According to an embodiment of the invention, the composition comprises a chromatography column, wherein the chromatography column contains silica gel as described above. Preferably, the silica gel is a stationary phase of the chromatography column.
According to an embodiment of the present invention, the composition may further comprise one, two or three selected from the group consisting of the above-mentioned anion-pairing agent, water and organic solvent.
Advantageous effects
The compound shown in the formula (I) or the pharmaceutically acceptable salt thereof provided by the invention is similar to dezocine in chemical structure, and is detected in trace amount in dezocine injection (especially under the condition of illumination). The research on the adverse reactions of the compound and the dezocine injection shows that the compound can cause the malformation of zebra fish embryo development, and has higher lethality under the condition of high dose, so that the strict control of the relative content of the compound in the dezocine is necessary.
The invention defines the material basis of the impurity compound shown in the formula (I) or the salt thereof, finds the reason and the preparation method of the impurity compound (a high-purity compound can be obtained through a series of reactions such as amino protection, bromination, intermolecular coupling, demethylation, deprotection and the like), finds the possible adverse reaction, is favorable for improving the quality of a dezocine product through reasonable quality control, reduces the occurrence probability of the adverse reaction, and has profound significance for researching the adverse reaction of the dezocine.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of compound (II) prepared in example 2;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of Compound (II) prepared in example 2;
FIG. 3 is an HPLC-ESI (+) mass spectrum of Compound (II) prepared in example 2;
FIG. 4 is an HPLC chromatogram (a) of compound (II) in example 3 and a 7-day-light HPLC chromatogram (b) of dezocine injection;
FIG. 5 shows the result of the zebrafish embryotoxicity test, wherein different doses of compound (II) were injected, compared with the zebrafish embryonal development of the control group and the test group; wherein WT is a blank control group, DMSO is a solvent control group, YYY-00411 is a dezocine 45ng group, and the rest are experimental groups of compound (II) with different injection doses (9, 45, 90, 270, 450 and 720 ng).
FIG. 6 is a statistic of the results of zebrafish embryotoxicity experiments.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the techniques realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
EXAMPLE 1 preparation of Compound (I)
Step 1: adding 120.0 g of the compound into 200mL of THF at 0-5 ℃, adding 20.3g of triethylamine, dropwise adding 16.0g of Boc anhydride, heating to room temperature after adding, reacting for 0.5h, adding 200mL of water and 50mL of ethyl acetate into the reaction system, stirring, standing, separating liquid, and collecting an organic phase. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to give 16.5g of Compound 2.
And 2, step: 7.56g of Compound 2 was added to 80mL of DMF, followed by addition of 3.72g of NBS in portions, reaction was carried out for 0.5h, 240mL of water and 100mL of ethyl acetate were added to the reaction system, followed by stirring, standing for liquid separation, and collection of the organic phase. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 9.0g of Compound 3.
And 3, step 3: 6.0g of compound 3, 2.1g of pinacol borate, 13.9g of potassium phosphate heptahydrate and 0.56g of dppf palladium chloride are sequentially added to 90mL of DMF, the mixture is heated to 90 ℃ to react for 3 hours, the temperature is reduced to room temperature, 400mL of water and 250mL of ethyl acetate are added to the reaction system, and the organic phase is collected after liquid separation. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography to give 7.5g of Compound 4.
And 4, step 4: adding 4.7g of compound 4 into 100mL of dichloromethane, cooling to-78 ℃, dropwise adding 26mL of boron tribromide dichloromethane solution of 1mol/L into the system, heating to room temperature after adding, reacting for 1H, cooling to-20 ℃, adjusting the pH to 7-8 with ammonia water, filtering, collecting a filter cake, and performing vacuum drying to obtain 3.1g of crude (6R,6'R,12S,12' S,15S,15'S) -15,15' -diamino-6, 6 '-dimethyl-7, 7',8,8',9,9',10,10',11,11',12,12',13,13',15,15 '-hexadecahydro-6H, 6' H- [2,2 '-bis (5, 11-methylene benzocyclodecene) ] -3,3' -diol (namely compound (I)), and 2.5g of refined compound (I) is obtained after column chromatography purification.
Example 2: preparation of Compound (II)
Adding 2.5g of refined compound (I) into 200mL of ethyl acetate, controlling the temperature to be 0-10 ℃, dropwise adding 30mL of 4mol/L HCl solution, heating to room temperature after dropwise adding, reacting for 3h, concentrating the reaction solution to dryness, adding 30mL of methanol, heating to 60 ℃, preserving the temperature for 1h, cooling to room temperature, stirring for 1h, filtering, collecting a filter cake, and drying in vacuum to obtain 1.8g of a product, namely compound (II), which is dihydrochloride of compound (I).
Example 3: structure validation
The structure of the compound (II) prepared in example 2 was confirmed by hydrogen, carbon and mass nmr spectroscopy, and the test results were as follows:
NMR spectroscopy (BRUKER model AV-400 NMR instrument, solvent DMSO)
The hydrogen spectrum of nuclear magnetic resonance is shown in FIG. 1, and the total number of 46 hydrogen atoms and the chemical shifts are as follows: 9.08(2H, s), 8.29(6H, s), 6.94(2H, s), 6.76(2H, s), 3.50(2H, m), 3.07-3.13(2H, m), 2.62-2.66(2H, m), 2.47-2.50(2H, m), 1.69-1.86(8H, m), 1.30-1.50(14H, m), 0.77-0.80(4H, m). Where 9.08(2H, s) is the phenolic hydroxyl hydrogen, 8.29(6H, s) is the hydrogen of the amino hydrochloride, 6.94(2H, s) and 6.76(2H, s) are the hydrogens of the aromatic rings.
The nuclear magnetic resonance carbon spectrum is shown in fig. 2, and has 16 peaks, which are specifically as follows: 152.29, 140.61, 130.87, 125.05, 124.28, 114.00, 58.73, 37.71, 35.89, 34.10, 32.95, 32.28, 28.72, 28.07, 25.93, 22.15.
The mass spectrum (Agilent 1200-] + The peak mass to charge ratio was 489.1.
Example 4: detection of related impurities in dezocine injection
In this example, the dezocine injection after 7 days of natural illumination is subjected to HPLC detection, and the HPLC detection and analysis method is as follows:
a Sunfire C18 chromatographic column with the specification of 250 multiplied by 4.6mm and the particle size of 5 μm;
mobile phase A: a mixed solution of 5mmol/L sodium heptanesulfonate water solution and acetonitrile, wherein the volume ratio of the 5mmol/L sodium heptanesulfonate water solution to the acetonitrile is 80: 20;
mobile phase B: a mixed solution of 5mmol/L sodium heptanesulfonate water solution and acetonitrile, wherein the volume ratio of the 5mmol/L sodium heptanesulfonate water solution to the acetonitrile is 20: 80;
elution was performed according to the following gradient:
flow rate: 0.9mL/min, column temperature: 40 ℃, detection wavelength: 220nm and 281 nm.
As a result, as shown in fig. 4(a) and fig. 4(b), when the dezocine injection is irradiated for 7 days, a chromatographic peak with a retention time of 22.546 can be detected, which is within an error range from the chromatographic peak with a retention time of 22.542 in the HPLC chromatogram of compound (II), thus confirming the presence of compound (I) in the irradiated dezocine injection.
Example 5: toxicity test of Zebra fish
The chinese food and drug testing institute was entrusted with the study on the embryotoxicity test of zebrafish of compound (II).
The test method is as follows:
1. sample preparation:
preparing samples with different concentrations by taking DMSO as a solvent;
2. experimental animals:
the zebra fish AB strain is wild type, and is fed by institute of medical and biotechnology of Chinese academy of medical sciences.
3. Experimental procedure:
test group: YYY-00411 chemical reference substances (namely dezocine, DZX for short) and the compound (II) with different concentrations are respectively given by microinjection;
control group: the same non-injected wild zebra fish batch was used as a normal control (WT); zebrafish microinjected with DMSO were used as solvent control (DMSO);
4. experimental procedure for embryo development toxicity:
microinjection is carried out on early (6hpf) embryos, and 25 or 35 embryos are taken; placing the mixture in a standard environment for development; when the embryos developed to the third day, they were changed to the feeding solution and observed continuously for the third day. Embryonic development, such as brain, eye, heart, blood flow, trunk (spinal cord/nerve, somites), speed of growth of the embryo, ability of the larva to swim and respond to stimuli, etc. (including statistics of malformations and number of deaths/number of survivals on the third day of development) were recorded (photographed as necessary) by daily observation until the end of the experiment. Each concentration test solution was tested in parallel at least three times.
5. The experimental results are as follows:
FIG. 5 shows the result of the zebrafish embryotoxicity test, wherein different doses of compound (II) were injected, compared with the control and test groups for the development of zebrafish embryos.
Statistical analysis, shown in FIG. 6, shows that compound (II) at certain concentrations can cause malformation of embryonic development with a dose-dependent increase in mortality rate of 60% at 270 ng. Half-lethal dose (LD50) and half-abnormal dose (AD50) of compound (II) were estimated to be 182ng and 89 ng. The half lethal dose (LD50) of dezocine injection is 900ng, and the half abnormal dose (AD50) is 533 ng. The above results indicate that compound (II) is highly lethal to embryos. Therefore, the content of the compound (I) or the pharmaceutically acceptable salt thereof in the irradiated dezocine injection is reduced through quality control, and the side effect caused by the compound (I) or the pharmaceutically acceptable salt thereof can be effectively avoided or reduced.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made without departing from the spirit and principle of the present invention shall fall within the protection scope of the present invention.
Claims (10)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
preferably, the pharmaceutically acceptable salt of the compound represented by formula (I) is a pharmaceutically acceptable salt of the compound of formula (I) with an acid known in the art, including, but not limited to, hydrochloride, hydrobromide, hydroiodide, p-toluenesulfonate, methanesulfonate, maleate or citrate of the compound of formula (I);
preferably, the pharmaceutically acceptable salt is a mono-or di-salt;
preferably, the pharmaceutically acceptable salt of the compound of formula (i) is a dihydrochloride salt of formula (II):
2. a process for the preparation of a compound of formula (i) or a pharmaceutically acceptable salt thereof as claimed in claim 1, which comprises the steps of:
step 1: reacting the compound 1 or pharmaceutically acceptable salt thereof with an amino protecting agent to obtain a compound 2, wherein P represents an amino protecting group;
and 2, step: reacting the compound 2 with a bromization reagent to obtain a compound 3;
and step 3: carrying out coupling reaction on the compound 3 to obtain a compound 4;
and 4, step 4: after the compound 4 reacts with a deamination protective reagent, dissociating to obtain a compound shown in a formula (I);
3. the process according to claim 2, wherein P in the compound 2 is an amino-protecting group which can be removed under acidic conditions;
preferably, the step 1 is carried out in the presence of a first solvent, wherein the first solvent is one or more of alcohol containing 1-4 carbon atoms, tetrahydrofuran, dichloromethane, trichloromethane, acetonitrile and water;
preferably, in the step 1, the temperature of the reaction is-10 ℃ to 40 ℃;
preferably, the reaction of step 1 is carried out in the presence of a first alkaline or acid-binding agent; wherein, the first alkaline reagent or acid-binding agent is preferably one or more of sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia water, pyridine, DMAP, DBU, diisopropylethylamine and triethylamine;
preferably, the amino protecting reagent in step 1 is benzyl chloroformate and/or Boc anhydride;
preferably, the molar ratio of the compound 1 to the first alkaline reagent in the step 1 is 1 (0.5-10), or the molar ratio of the compound 1 to the acid-binding agent is 1 (0.5-10);
preferably, the molar ratio of the compound 1 to the amino protecting agent in the step 1) is 1 (0.5-10), preferably 1 (1-10);
preferably, the mass-to-volume ratio of the compound 1 to the first solvent in the step 1 is 1g (1-50) mL;
preferably, step 2 is performed in the presence of a second solvent, which is preferably one or more of carbon tetrachloride, dichloromethane, chloroform, N-dimethylformamide, THF, diethyl ether and DMSO;
preferably, the brominating reagent in step 2 is NBS and/or bromine;
preferably, the temperature of the reaction in the step 2 is 0-80 ℃;
preferably, the molar ratio of the compound 2 to the brominating agent in the step 2 is 1 (0.5-2);
preferably, the mass-to-volume ratio of the compound 2 to the second solvent in the step 2 is 1g (5-20) mL;
preferably, step 3 is performed in a third solvent, wherein the third solvent is preferably one or more of tetrahydrofuran, N-dimethylformamide, dichloromethane, chloroform and toluene;
preferably, step 3 is carried out in the presence of a second basic agent, preferably one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and potassium phosphate;
preferably, step 3 is also carried out in the presence of pinacol boronate and dppf palladium chloride;
preferably, the temperature of the coupling reaction in the step 3 is 30-120 ℃;
preferably, the mass ratio of the compound 3 to the pinacol borate in the step 3 is 1 (0.2-1);
preferably, the molar ratio of the compound 3 to the second basic reagent in the step 3 is 1 (1-5);
preferably, the mass-to-volume ratio of the compound 3 to the third solvent in the step 3 is 1g (3-30) mL;
preferably, the steps 1, 2 and 3 further comprise adding water and ethyl acetate into the reaction system after the reaction is finished, and separating to obtain an organic phase;
preferably, step 4 is performed in a fourth solvent, wherein the fourth solvent is preferably one or more of dichloromethane, chloroform, ethanol and acetone;
preferably, the deamination protecting agent in step 4 is boron tribromide, hydroiodic acid, hydrobromic acid or concentrated hydrochloric acid;
preferably, the temperature of the reaction in the step 4 is-90 ℃ to 30 ℃;
preferably, after the reaction in step 4 is finished, the reaction product is dissociated in the presence of a third basic reagent, wherein the third basic reagent is preferably triethylamine, ammonia water, an aqueous solution of sodium bicarbonate or an aqueous solution of sodium carbonate;
preferably, adding a third alkaline reagent in the step 4, and adjusting the pH value of the system to 7-8;
preferably, the molar ratio of the compound 4 to the deamination protective agent in the step 4 is 1 (1-10);
preferably, the mass-to-volume ratio of the compound 4 to the fourth solvent in the step 4 is 1g (3-50) mL.
4. The method according to claim 2 or 3, characterized in that it comprises the steps of: reacting a compound of formula (I) according to claim 1 with an acid to obtain a pharmaceutically acceptable salt thereof;
preferably, the acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, p-toluenesulfonic acid, methanesulfonic acid, maleic acid or citric acid.
5. Use of a compound of formula (i) or a pharmaceutically acceptable salt thereof as claimed in claim 1 for controlling the quality of a dezocine bulk drug or a dezocine injection; or
Use of the compound of formula (i) or a pharmaceutically acceptable salt thereof according to claim 1 as a standard or reference substance, preferably as a pharmaceutical standard or reference substance, more preferably as a quality research standard or reference substance for a dezocine bulk drug or a dezocine injection.
6. A method for controlling the quality of dezocine bulk drugs or dezocine injection is characterized in that the method comprises the steps of using the compound shown in the formula (I) in claim 1 or pharmaceutically acceptable salt thereof as a standard or reference substance, preferably as a drug standard or reference substance; and/or
The method of controlling comprising detecting a compound of formula (i) or a pharmaceutically acceptable salt thereof as claimed in claim 1.
7. A quality control method of dezocine bulk drug or dezocine injection is characterized by comprising the step of storing the dezocine bulk drug or the dezocine injection in a dark place.
8. A method for detecting a compound represented by the formula (i) or a pharmaceutically acceptable salt thereof as claimed in claim 1, which comprises detecting the compound represented by the formula (i) or a pharmaceutically acceptable salt thereof in a test sample solution by liquid chromatography, for example, by high performance liquid chromatography;
preferably, the stationary phase of the column in liquid chromatography, such as high performance liquid chromatography, is silica gel, e.g. C18-bonded silica gel, preferably reversed phase C18-bonded silica gel;
preferably, the mobile phase of the high performance liquid chromatography is a mixture of an ion pair reagent, water and an organic solvent; wherein, the instituteThe ion-pairing reagent is preferably an anion-pairing reagent, e.g. C 4-14 Sodium alkyl sulfonates, for example, one or more selected from sodium pentane sulfonate, sodium hexane sulfonate, sodium heptane sulfonate, sodium octane sulfonate and sodium dodecyl sulfonate;
preferably, the organic solvent may be selected from methanol, acetonitrile or mixtures thereof, preferably acetonitrile;
preferably, the ratio of the sum of the volumes of ion pair reagent and water to the volume of acetonitrile in the mobile phase may be from 1:9 to 9:1, for example from 2:8 to 8: 2;
preferably, the concentration of the ion-pairing reagent in the mobile phase is in the range of from 1 to 10mmol/L, for example from 4 to 6mmol/L, based on the total volume of the ion-pairing reagent and water.
9. The detection method according to claim 8, wherein the test conditions of the high performance liquid chromatography are as follows:
a chromatographic column: a Sunfire C18 chromatography column, preferably 250mm x 4.6mm, with a particle size of 5 μm;
mobile phase A: a mixed solution of sodium heptanesulfonate aqueous solution and acetonitrile, preferably a mixed solution of 5mmol/L sodium heptanesulfonate aqueous solution and acetonitrile, wherein the volume ratio of the sodium heptanesulfonate aqueous solution to the acetonitrile is 80: 20;
and (3) mobile phase B: a mixed solution of sodium heptanesulfonate aqueous solution and acetonitrile, preferably a mixed solution of 5mmol/L sodium heptanesulfonate aqueous solution and acetonitrile, wherein the volume ratio of the sodium heptanesulfonate aqueous solution to the acetonitrile is 20: 80;
gradient elution;
preferably, the gradient elution is performed as follows:
preferably, the test conditions of the high performance liquid chromatography further include:
flow rate: 0.9mL/min, column temperature: 40 ℃, detection wavelength: 281 nm.
10. A composition comprising silica gel and a compound of formula (i) or a salt thereof;
preferably, the silica gel is selected from C18-bonded silica gels, preferably reversed phase C18-bonded silica gels;
for example, the composition further comprises a chromatography column, wherein the chromatography column contains a silica gel as described above; preferably, the silica gel is a stationary phase of the chromatographic column;
for example, the composition further comprises one, two or three selected from the group consisting of an anion-pairing agent, water and an organic solvent, wherein the anion-pairing agent and the organic solvent independently of each other have the definitions in claim 8.
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