CN116120305A - Novel compound of formula II, preparation method and application thereof - Google Patents
Novel compound of formula II, preparation method and application thereof Download PDFInfo
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- CN116120305A CN116120305A CN202111346448.5A CN202111346448A CN116120305A CN 116120305 A CN116120305 A CN 116120305A CN 202111346448 A CN202111346448 A CN 202111346448A CN 116120305 A CN116120305 A CN 116120305A
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Abstract
The invention relates to a compound of formula II or pharmaceutically acceptable salt thereof, a preparation method and application thereof. The invention completes the preparation, separation, structure confirmation and application research of the compound of the formula II for the first time, the purity of the purified compound of the formula II is more than or equal to 95 percent, and the purified compound of the formula II is used as a standard or reference for detecting the quality of the pirone or the pharmaceutically acceptable salt thereof or the preparation thereof, thereby being beneficial to realizing the quality control of medicines, improving the quality of medicines and ensuring the safety and effectiveness of clinical medication.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a novel compound shown in a formula II, a preparation method and application thereof.
Background
Pirpirpirone hydrochloride (N- {4- [4- (1, 2-benzisothiazol-3-yl) -1-piperazine]Butyl } cyclohexyl-1, 2-dicarboximide hydrochloride dihydrate, C 23 H 30 N 4 O 2 S·HCl·2H 2 O, molecular weight 499.07)Is an atypical antipsychotic by affecting the dopamine metabolic pathway and blocking dopamine-2, 5-HT 2 The receptor plays a therapeutic role and is effective in the behavior abnormality caused by the dopamine and serotonin systems. Clinical research results show that the pirone is effective for various problematic behaviors caused by the hyperfunction of the dopaminergic nervous system, and remarkably improves negative symptoms, mood disorders and other symptoms which are not effective for traditional antipsychotics, and is widely used for treating schizophrenia clinically. Compared with haloperidol, the parodon hydrochloride has stronger selectivity on striatum parts, less causes extrapyramidal reactions or causes extrapyramidal side reactions, better selectivity and safe and effective clinical medication.
The pirone or its salt is easy to be oxidized and degraded under the conditions of light, oxygen, heat, humidity, etc., and the generated oxidized and degraded impurities affect the quality, stability, effectiveness and safety of the medicine. The preparation of pirpirone or its salts involves a variety of severe reaction conditions including high temperature reaction (temperature not less than 100 ℃), prolonged high temperature drying, etc., thereby leading to the production of oxidation degradation impurities of pirone. In order to improve the quality of the pirone hydrochloride, high-risk process impurities, degradation impurities and key impurities with residual quantity exceeding the control limit of the medicine in the preparation process of the pirone hydrochloride need to be fully researched, and the critical impurities are controlled within the safety limit range, so that the quality control of the medicine is realized, and the effectiveness and safety of the medicine are ensured.
Disclosure of Invention
It is an object of the present invention to provide a compound of formula II or a pharmaceutically acceptable salt thereof,
according to the preferred technical scheme, the pharmaceutically acceptable salt is acid addition salt thereof.
In a preferred embodiment of the present invention, the acid is selected from any one of an organic acid and an inorganic acid.
According to a preferred technical scheme of the invention, the acid is selected from any one or combination of formic acid, acetic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid and hydrobromic acid.
Another object of the present invention is to provide a process for the preparation of a compound of formula II or a pharmaceutically acceptable salt thereof, comprising the steps of: dissolving the pirone in an alcohol solvent under stirring at the temperature of between 10 and 30 ℃, adding the prepared pirone alcohol solution into a periodate solution to perform an oxidation reaction for 10 to 30 hours, and performing post-treatment on the obtained oxidation reaction solution to obtain the product, wherein the molar ratio of the pirone to the periodate is 1:3-5, the concentration of the periodate solution is 0.3-0.5mol/L,
according to the preferred technical scheme, the alcohol solvent is selected from any one or combination of methanol, ethanol and isopropanol.
According to the preferred technical scheme, the mass-volume ratio of the pirone to the alcohol solvent is 1:15-30, preferably 1:19-25.
According to a preferred technical scheme, the periodate is selected from any one or combination of sodium periodate and potassium periodate.
According to the preferred technical scheme, the molar ratio of the parodon to the periodate is 1: 3.5-4.5.
According to the preferred technical scheme, the concentration of the periodate solution is 0.35-0.45mol/L.
According to the preferred technical scheme, the oxidation reaction temperature is 15-25 ℃.
According to the preferred technical scheme, the oxidation reaction time is 15-26 hours.
According to a preferred technical scheme of the invention, the post-treatment comprises the following steps: concentrating the prepared oxidation reaction liquid under reduced pressure to remove alcohol solvent, regulating pH of the reaction liquid to 9.5-10, adding organic solvent to extract for 2-3 times, collecting and combining extracted organic phases, drying by anhydrous sulfate, filtering, collecting filtrate, concentrating under reduced pressure to dryness, wherein the organic solvent is selected from any one of dichloromethane, dichloroethane, chloroform, ethyl acetate, methyl acetate and butyl acetate or a combination thereof.
According to a preferred technical scheme of the invention, the substance for regulating the pH is selected from any one or combination of sodium hydroxide, potassium carbonate and sodium carbonate.
According to the preferable technical scheme, the substance for regulating the pH is an aqueous solution thereof.
According to a preferred technical scheme of the invention, the concentration of the pH adjusting solution is 3-8mol/L, preferably 4-7.5mol/L.
According to the preferred technical scheme, the anhydrous sulfate is any one or combination of anhydrous magnesium sulfate and anhydrous sodium sulfate.
In a preferred embodiment of the present invention, the stirring speed is 80-160r/min, preferably 100-120r/min.
According to the preferred technical scheme, the prepared compound of the formula II is separated and purified by preparative liquid chromatography to prepare a purified product of the compound of the formula II.
According to the preferred technical scheme, octadecylsilane chemically bonded silica is used as a filler for a chromatographic column stationary phase in the preparation liquid chromatography, the detection wavelength is 230nm, the flow rate is 15mL/min, and the mobile phase is an acetonitrile aqueous solution with the concentration of 53-95% for gradient elution.
According to the preferred technical scheme, the chromatographic column is
5-120 C18 Polar (21.2×250mm，5μm)。
According to the preferred technical scheme, the gradient elution program comprises the following steps:
| time (min) | Acetonitrile (%) | Water (%) |
| 0 | 95 | 5 |
| 7 | 73 | 27 |
| 20 | 53 | 47 |
| 21 | 95 | 5 |
| 26 | 95 | 5 |
According to the preferred technical scheme, the purity of the prepared compound of the formula II is more than or equal to 95%, preferably more than or equal to 96%.
Another object of the present invention is to provide a highly safe pharmaceutical composition of pirone hydrochloride containing the compound of formula II or a pharmaceutically acceptable salt thereof in an amount of 0.1% or less.
According to the preferred technical scheme, the content of the compound of the formula II or pharmaceutically acceptable salt thereof in the pharmaceutical composition is less than or equal to 0.05%, preferably less than or equal to 0.01%.
It is another object of the present invention to provide a compound of formula II or a pharmaceutically acceptable salt thereof for use as a standard or control for detecting the quality of pirpirone or a pharmaceutically acceptable salt thereof or a formulation thereof.
The invention also aims to provide a high performance liquid chromatography for efficiently separating and detecting a compound of formula II of pirone hydrochloride or pharmaceutically acceptable salt thereof, wherein the chromatographic column stationary phase takes octadecylsilane chemically bonded silica as a filler, and a mobile phase consists of a mobile phase A and a mobile phase B, and gradient elution is carried out, wherein the mobile phase A is a triethylamine aqueous solution with the concentration of 0.05-0.3%, the mobile phase B is acetonitrile, and the mobile phase A is: the volume ratio of the mobile phase B is 70:30-20:80, the detection wavelength is 210-240nm, the flow rate is 0.7-0.9mL/min, the column temperature is 28-32 ℃, and the sample injection amount is 10-20 mu L.
In a preferred embodiment of the invention, the detector is selected from a diode array detector or an ultraviolet detector.
According to the preferred technical scheme, the mobile phase A is a triethylamine aqueous solution with the concentration of 0.1-0.2%.
According to a preferred embodiment of the present invention, the mobile phase A is a 0.1% aqueous triethylamine solution, and the pH is adjusted to 7.5 with phosphoric acid.
According to the preferred technical scheme, the diameter of the chromatographic column is 3-5mm, the length of the chromatographic column is 100-300mm, and the particle size of the filler in the chromatographic column is 3-5 mu m.
According to a preferred embodiment of the present invention, the chromatographic column is Waters Symmetry C (3.9X105 mm,5 μm).
According to the preferred technical scheme, the gradient program comprises the following steps:
| time (min) | Mobile phase a (%) | Mobile phase B (%) |
| 0 | 70 | 30 |
| 10 | 20 | 80 |
| 20 | 20 | 80 |
| 25 | 70 | 30 |
Unless otherwise indicated, when the invention relates to a percentage between liquids, the percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentage between solids and liquids, the percentage being weight/volume percentage; the balance being weight/weight percent.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention completes the preparation, separation, structure confirmation and application research of the compound of the formula II for the first time, the purity of the purified compound of the formula II is more than or equal to 95 percent, and the purified compound of the formula II is used as a standard or reference for detecting the quality of the pirone or the pharmaceutically acceptable salt thereof or the preparation thereof, thereby being beneficial to realizing the quality control of medicines, improving the quality of medicines and ensuring the safety and effectiveness of clinical medication.
2. The invention researches and screens the chromatographic conditions and elution conditions of the high performance liquid chromatography to obtain the high performance liquid chromatography for efficiently separating and detecting the compound of formula II in the pirpirone hydrochloride. The method has the advantages of good specificity, high separation degree, excellent sensitivity and the like, can realize the quantitative detection of the compound of the formula II of the pirone hydrochloride, better control the quality of the pirone hydrochloride and the preparation thereof, and ensure the safety and the effectiveness of clinical medication.
Drawings
FIG. 1 is a LC-MS spectrum of the compound of formula II prepared in example 2;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of the compound of formula II prepared in example 2;
FIG. 3 is a nuclear magnetic resonance carbon spectrum of the compound of formula II prepared in example 2;
FIG. 4 is a high performance liquid chromatography detection result of the compound of formula II used as a control to detect the quality of the pimento Luo Pi hydrochloride.
Detailed Description
The foregoing is further elaborated by the following specific embodiments, which are not to be construed as limiting the claimed subject matter. All technical schemes realized based on the above content of the invention belong to the scope of the invention.
Example 1Preparation of Compounds of formula II
The preparation of the compound of formula II comprises the following steps:
1) 13.00g of pirpirone is dissolved in 250mL of methanol under stirring at 120r/min to prepare a methanol solution of pirone;
2) Under the stirring condition of 120r/min, 25.27g of sodium periodate is dissolved in 300mL of water to prepare a sodium periodate solution;
3) Adding the pirone methanol solution prepared in the step 1) into the sodium periodate solution prepared in the step 2) under the conditions of stirring at 120r/min and 25 ℃ to perform an oxidation reaction for 26 hours. And (3) placing the prepared oxidation reaction liquid at 45+/-5 ℃ for decompression concentration to remove methanol, then adjusting the pH value to 10 by using 7.5mol/L sodium hydroxide aqueous solution, extracting with 200mL of dichloromethane each time for 3 times, collecting and combining three dichloromethane extracts, drying by using anhydrous sodium sulfate, filtering, and decompressing and concentrating the filtrate at 45+/-5 ℃ until the filtrate is dried.
Example 2Purification of the Compound of formula II
The compound of formula II prepared in example 1 was isolated and purified by preparative liquid chromatography:
chromatographic column:
5-120 C18 Polar，21.2×250mm，5μm
detection wavelength: 230nm
Flow rate: 15mL/min
Mobile phase: acetonitrile aqueous solution with concentration of 53-95% (v/v)
Elution mode: gradient elution
| Time (min) | Acetonitrile (%) | Water (%) |
| 0 | 95 | 5 |
| 7 | 73 | 27 |
| 20 | 53 | 47 |
| 21 | 95 | 5 |
| 26 | 95 | 5 |
Separating and purifying by preparative liquid chromatography to obtain 5.20g of purified compound of formula II.
Analyzing the structure of the compound of the formula II by using an ion chromatography-mass spectrometry system (LC-MS) to obtain an excimer ion peak m/z:459[ M+H ]] + (see fig. 1) and nuclear magnetic resonance hydrogen (fig. 2) and carbon (fig. 3) spectra:
1 H NMR(400MHz，CDCl 3 )，δ＝7.867-8.028(d，2H)；7.620-7.692(m， 2H)；4.392-4.588(t，4H)；3.528-3.562(t，2H)；3.300-3.451(t，6H)；2.843-2.885(m，2H)；1.664-2.020(m，8H)；1.385-1.496(m，4H)。
13 C NMR(100MHz，CDCl 3 )，δ＝179.861、165.350、131.687、 130.287、125.994、125.302、71.125、63.602、42.506-42.781、39.732、 37.421、25.099、23.785、21.621、19.108。
example 3Purity detection of Compounds of formula II
The purity of the compound of formula II prepared in example 2 was checked by high performance liquid chromatography.
(1) Chromatographic conditions
Instrument: high performance liquid chromatograph Agilent 1260
A detector: ultraviolet detector
Chromatographic column: octadecylsilane chemically bonded silica (Waters Symmetry C, 3.9X105 mm,5 μm)
Mobile phase a:0.1% aqueous triethylamine solution, pH was adjusted to 7.5 with phosphoric acid
Mobile phase B: acetonitrile
Detection wavelength: 230nm
Column temperature: 30 DEG C
Flow rate: 0.8mL/min
Sample injection amount: 10 mu L
Blank solution: mobile phase a: mobile phase b=65:35
Gradient elution:
| time (min) | Mobile phase a (%) | Mobile phase B (%) |
| 0 | 70 | 30 |
| 10 | 20 | 80 |
| 20 | 20 | 80 |
| 25 | 70 | 30 |
(2) Solution preparation
A diluent: mobile phase a: mobile phase b=65:35.
Test solution: and dissolving and diluting a proper amount of the compound of the formula II with a diluent to prepare a solution with the concentration of 0.5 mg/mL.
(3) Measurement
Precisely measuring a blank solution and a sample solution, measuring according to the chromatographic conditions, and recording a chromatogram.
The purity of the purified product of the compound of formula II, as measured according to the method of the present invention, was 96.87%.
Example 4Preparation of Compounds of formula II
The preparation of the compound of formula II comprises the following steps:
1) 13.00g of pirpirone is dissolved in 250mL of ethanol under the stirring condition of 120r/min to prepare a pirone ethanol solution;
2) 24.53g of potassium periodate is dissolved in 300mL of water under the stirring condition of 120r/min to prepare a potassium periodate solution;
3) And (2) adding the pirone ethanol solution prepared in the step (1) into the potassium periodate solution prepared in the step (2) under the conditions of stirring at 120r/min and 15 ℃ to perform an oxidation reaction for 26 hours. And (3) placing the prepared oxidation reaction liquid at 45+/-5 ℃ for decompression concentration to remove ethanol, then adjusting the pH value to 10 by using a potassium hydroxide aqueous solution with the concentration of 7.0mol/L, extracting with 200mL of dichloromethane each time for 3 times, collecting and combining three dichloromethane extracts, drying by using anhydrous sodium sulfate, filtering, and decompressing and concentrating the filtrate at 45+/-5 ℃ to be dry.
Example 5Purification of the Compound of formula II
The compound of formula II obtained in example 4 was purified by preparative liquid chromatography according to example 2 to obtain 5.05g of a purified compound of formula II.
The purity of the purified product of the compound of formula II obtained was 96.50% as measured according to the method of the present invention.
Example 6Compound of formula II as reference substance for detecting quality of piperonyl hydrochloride Luo Pi
The purified product of the compound of formula II prepared in example 2 was used as a control for detecting the quality of the pimento Luo Pi hydrochloride.
(1) Chromatographic conditions
Instrument: high performance liquid chromatograph Agilent 1260
A detector: ultraviolet detector
Chromatographic column: octadecylsilane chemically bonded silica (Waters Symmetry C, 3.9X105 mm,5 μm)
Mobile phase a:0.1% aqueous triethylamine solution, pH7.5 was adjusted with phosphoric acid
Mobile phase B: acetonitrile
Detection wavelength: 230nm
Column temperature: 30 DEG C
Flow rate: 0.8mL/min
Sample injection amount: 10 mu L
Blank solution: mobile phase a: mobile phase b=65:35
Gradient elution:
| time (min) | Mobile phase a (%) | Mobile phase B (%) |
| 0 | 70 | 30 |
| 10 | 20 | 80 |
| 20 | 20 | 80 |
| 25 | 70 | 30 |
(2) Solution preparation
A diluent: mobile phase a: mobile phase b=65:35.
Control solution: precisely weighing a proper amount of the purified product of the compound of the formula II prepared in the example 2, dissolving the purified product with a diluent and diluting the dissolved product into a solution with the concentration of 10 mug/mL to obtain the compound.
Test solution: precisely weighing 100mg of the pirone hydrochloride sample, placing in a 10mL volumetric flask, adding a diluent to dilute to a scale, and shaking uniformly to obtain the product.
(3) Measurement
Precisely measuring a blank solution, a control solution and a test solution, measuring according to the chromatographic conditions, and recording a chromatogram. The chromatogram of the test solution has the peak of the compound of formula II, and is calculated by an area normalization method.
The results of the assay are shown in FIG. 4, with a retention time of 2.079min for the compound of formula II. The pirpirpirone hydrochloride sample contained 0.1893% of the compound of formula II, calculated by area normalization.
Example 7Preparation of pirpirone hydrochloride
The preparation of pirpirone hydrochloride comprises the following steps:
1) 23mL of N, N-dimethylformamide was added to a 50mL reaction flask, 2.45g of potassium carbonate, 2.60g of cis-hexahydrophthalimide and 5.73g of 8- (benzisothiazol-3-yl) -5, 8-diazaspiro [4.5] decane 5-ammonium bromide were sequentially added, the temperature was raised to 100.+ -. 5 ℃ and stirred until the reaction was complete, and filtration was performed. Adding 23mL of sodium hydroxide solution with the concentration of 0.035mmol/mL into the reaction solution, reacting for 3h at 20+ -5 ℃, filtering, and washing the filter cake with purified water; the filter cake was dried under reduced pressure at 40.+ -. 5 ℃ for 4 h.+ -. 10min to give 5.70g of paromomine.
2) Adding the prepared pirone into 28.5mL of isopropanol, dropwise adding concentrated hydrochloric acid to pH 1-2 at room temperature under stirring, stirring at room temperature for 1h with a large amount of solid generated, filtering, and collecting a filter cake to obtain a crude product of the pirone hydrochloride.
3) The crude product of pirone hydrochloride thus obtained was recrystallized from 80% isopropyl alcohol, filtered, the cake was collected, washed and dried to obtain 5.90g of pirone hydrochloride.
The purity of the pirpirone hydrochloride is 99.97% by detection, and the compound of formula II is not detected.
The above description of the embodiments is only for aiding in the understanding of the method of the present invention and its core ideas. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the invention can be made without departing from the principles of the invention and these modifications and adaptations are intended to be within the scope of the invention as defined in the following claims.
Claims (10)
1. A compound of formula II or a pharmaceutically acceptable salt thereof,
2. a process for the preparation of a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, comprising the steps of: dissolving the pirone in an alcohol solvent under stirring at the temperature of between 10 and 30 ℃, adding the prepared pirone alcohol solution into a periodate solution to perform an oxidation reaction for 10 to 30 hours, and performing post-treatment on the obtained oxidation reaction solution to obtain the product, wherein the molar ratio of the pirone to the periodate is 1:3-5, the concentration of the periodate solution is 0.3-0.5mol/L,
3. the method of claim 2, wherein the alcoholic solvent is selected from any one of methanol, ethanol, isopropanol, or a combination thereof.
4. A process according to any one of claims 2 to 3, wherein the mass to volume ratio of the pirpirone to the alcoholic solvent is 1:15 to 30, preferably 1:19 to 25.
5. The method according to any of claims 2-4, wherein the post-treatment comprises the steps of: concentrating the prepared oxidation reaction liquid under reduced pressure to remove alcohol solvent, regulating pH of the reaction liquid to 9.5-10, adding organic solvent to extract for 2-3 times, collecting and combining extracted organic phases, drying by anhydrous sulfate, filtering, collecting filtrate, concentrating under reduced pressure to dryness, wherein the organic solvent is selected from any one of dichloromethane, dichloroethane, chloroform, ethyl acetate, methyl acetate and butyl acetate or a combination thereof.
6. The method of any one of claims 2-5, wherein the resulting compound of formula II is purified by preparative liquid chromatography to produce a purified product of the compound of formula II.
7. The process according to any of claims 2 to 6, wherein the purified product of the compound of formula II is produced with a purity of 95% or more, preferably 96% or more.
8. A highly safe pirone hydrochloride pharmaceutical composition, wherein the content of the compound of formula II or a pharmaceutically acceptable salt thereof as defined in claim 1 or the compound of formula II or a pharmaceutically acceptable salt thereof prepared by the method as defined in any one of claims 2 to 7 is less than or equal to 0.1%.
9. The compound of formula II as defined in claim 1 or a pharmaceutically acceptable salt thereof or the compound of formula II as defined in any one of claims 2 to 7 or a pharmaceutically acceptable salt thereof, as a standard or control for detecting the quality of pirpirone or a pharmaceutically acceptable salt thereof or a formulation thereof.
10. A high performance liquid chromatography for efficiently separating and detecting a compound of formula II as defined in claim 1 or a pharmaceutically acceptable salt thereof or a compound of formula II as defined in any one of claims 2 to 7 in pirone hydrochloride, wherein the chromatographic column stationary phase uses octadecylsilane chemically bonded silica as a filler, and a mobile phase is composed of a mobile phase a and a mobile phase B, and the mobile phase a is 0.05 to 0.3% triethylamine aqueous solution, the mobile phase B is acetonitrile, and the mobile phase a: the volume ratio of the mobile phase B is 70:30-20:80, the detection wavelength is 210-240nm, the flow rate is 0.7-0.9mL/min, the column temperature is 28-32 ℃, and the sample injection amount is 10-20 mu L.
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