CN111909159A - Epipiprazole related substance and preparation method thereof - Google Patents
Epipiprazole related substance and preparation method thereof Download PDFInfo
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Abstract
The invention provides a novel compound and a preparation method thereof, wherein the compound is an impurity for degrading brexpiprazole. In addition, the invention also provides a detection method of the compound and application of the compound as an impurity reference substance in the detection of related substances in the bulk drug or preparation of the brexpiprazole, and provides a new direction for improving the quality standard of the brexpiprazole bulk drug and the preparation thereof and obtaining the brexpiprazole with higher safety, reliability and definite curative effect.
Description
Technical Field
The invention provides an brexpiprazole related substance and a preparation method thereof, wherein the related substance can be used for the mass analysis of brexpiprazole bulk drugs and preparations thereof, and belongs to the field of pharmaceutical analytical chemistry.
Background
Epipezole was first developed by Otsuka Denshi pharmaceutical company and the first dopamine, partial 5-HT1A receptor agonist and 5-HT2A receptor antagonist compound, which was later co-developed with Denmark North pharmaceuticals, was considered to be a heavy breed following aripiprazole, a popular drug developed by this company. Compared with aripiprazole, the product shows higher affinity with dopamine D2 receptor, 5-HT2A receptor and 5-HT1A receptor, and relatively lower affinity with H1 and M1 receptor. The product submits a new drug application to the FDA in 7-month and 14-2014, is sold on the market in 10-7-month and 2015, and is used for the auxiliary treatment of major depression and the treatment of schizophrenia. The chemical name of the brexpiprazole is 7- (4- (4 benzo [ b ] thiophene-4-yl piperazine-1-yl) butoxy-1H-quinoline-2-ketone, and the chemical structural formula is as follows:
the molecular formula is as follows: C8H10S, molecular weight: 138.23.
the quality of the raw material medicine is the key and source of the medicine quality control. Among them, the research on impurities and the control of clinical safety of the drugs of concern are one of the key links for quality control of raw material drugs, because adverse reactions generated in clinical use of the drugs are not only related to the physicochemical activity of the drugs, but also have a great relationship with impurities existing in the drugs. By selecting a proper analysis method, the content of impurities is accurately distinguished and determined, proper impurity limit is determined by combining the results of pharmacy, toxicology and clinical research, and then the impurities are controlled in a safe and reasonable range by controlling the source of the initial raw and auxiliary materials, controlling the process of the preparation process and the like, which is the final purpose of impurity research. The impurities can be classified into organic impurities, inorganic impurities and residual solvents. The organic impurities mainly refer to process impurities such as intermediates and byproducts, and organic matters generated by degradation, association or reaction between medicines, which may be known or unknown and volatile or nonvolatile, and are also called related substances because of similar structures or source relationships with active ingredients. The research on related substances in the research on impurities has become more and more important and extensive. Such as: CN106645494A discloses related substances A1-A4 of 4 starting materials A of brexpiprazole and an analysis method thereof:
CN106892909A discloses 4 related processes of brexpiprazole and degradation of impurities I-IV.
Disclosure of Invention
In one aspect, the invention provides a compound having the structure:
the chemical name is: 8-benzo [ b ] thiophen-4-yl-8-aza-5-azoniaspiro [4.5] decane hydroxide dihydrate.
The inventors have unexpectedly found that the above impurities can be detected in both the self-made and original formulations, and that the impurities are growing in size through accelerated or high temperature tests. Through destructive tests, the inventor accurately identifies the structure of the impurity, which is a product after the degradation of the bulk drug.
In another aspect, the present invention also provides a method for preparing the above compound, comprising the steps of: adding the brexpiprazole into a mixed solvent of N, N-dimethylformamide and water, heating for reaction, then carrying out reduced pressure distillation to obtain an oily substance, and carrying out column chromatography to obtain a target product.
In the preparation method, the volume ratio of the N, N-dimethylformamide to the water is 1: 1-5: 1, preferably 3: 1-5: 1.
In the preparation method, the reaction temperature is 100-150 ℃, preferably 120-135 ℃; the reaction time is 4 to 24 hours, preferably 4 to 10 hours, more preferably 4 to 6 hours.
The invention also aims to provide a detection method of the brexpiprazole bulk drug or the preparation containing the related substances, which comprises the following parameters:
a chromatographic column: bonding of silica gel with octadecylsilane (3 μm, 150X 4.6mm or equivalent performance column)
Mobile phase: acetonitrile solution containing 0.1% formic acid is used as mobile phase A, and 0.1% formic acid-0.04 mol/L ammonium chloride solution is used as mobile phase B
Gradient elution procedure:
flow rate of mobile phase: 1ml/min
Column temperature: 35 deg.C
Detection wavelength: 254nm
Sample introduction amount: 20 μ L.
The invention also aims to provide the application of the related substance as an impurity reference substance in the detection of the related substance in the bulk drug or preparation of the brexpiprazole.
The invention has the advantages that: the inventor of the invention unexpectedly discovers the compound in the research on related substances of crude drugs and preparations of the brexpiprazole, provides a method for preparing the related substances with simple synthetic route and higher purity and yield, provides an impurity reference substance for better controlling the quality of the brexpiprazole, provides a detection and analysis method of the related substances, and provides more comprehensive information for the qualitative research on the brexpiprazole impurities. The invention is beneficial to the further research of the quality research control of the bulk drug of the brexpiprazole and the preparation thereof, such as long-term stability research and toxicology research, so as to improve the quality standard of the bulk drug of the brexpiprazole and the preparation thereof and provide a new direction for obtaining the brexpiprazole which is safer and more reliable and has exact curative effect.
Drawings
FIG. 1 is a LC-MS diagram of 8-benzo [ b ] thiophen-4-yl-8-aza-5-azoniaspiro [4.5] decane hydroxide dihydrate of example 6;
FIG. 2 is the 8-benzo [ b ] ring of example 7]Thien-4-yl-8-aza-5-azanium-spiro [4.5]Decane hydroxide dihydrate1H-NMR chart;
FIG. 3A is an HPLC chart of a mixture of brexpiprazole and its impurity control sample of example 9 for 0-75 min;
FIG. 3B is a partially enlarged HPLC chart of a 5-35min mixture of brexpiprazole and its impurity control of example 9;
FIG. 4A is an HPLC chart of a sample solution of brexpiprazole tablet of example 10 for 0-75 min;
FIG. 4B is a partially enlarged HPLC chart of a sample solution of brexpiprazole tablet in example 10 for 5-35 min;
FIG. 5 is an HPLC chart of a sample solution of the brexpiprazole tablet in example 11.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
EXAMPLE 18 preparation of benzo [ b ] thiophen-4-yl-8-aza-5-azoniaspiro [4.5] decane hydroxide dihydrate
Adding 10g of ipiprazole into a mixed system of 150ml of N, N-dimethylformamide and 50ml of water, heating to 120 ℃, stirring for 6h, cooling to below 25 ℃, separating out a solid, filtering the solid, concentrating the filtrate to dryness, and purifying by silica gel column chromatography to obtain 8-benzo [ b ] thiophene-4-yl-8-aza-5-azoniaspiro [4.5] decane hydroxide dihydrate solid with HPLC purity: 98.17%, yield: 84.35 percent.
EXAMPLE 28 preparation of benzo [ b ] thiophen-4-yl-8-aza-5-azoniaspiro [4.5] decane hydroxide dihydrate
Adding 10g of ipiprazole into a mixed system of 100ml of N, N-dimethylformamide and 100ml of water, heating to 110 ℃, stirring for 8h, cooling to below 25 ℃, separating out a solid, filtering the solid, concentrating the filtrate to dryness, and purifying by silica gel column chromatography to obtain 8-benzo [ b ] thiophene-4-yl-8-aza-5-azonia-spiro [4.5] decane hydroxide dihydrate solid with HPLC purity: 98.45%, yield: 77.5 percent.
EXAMPLE 38 preparation of benzo [ b ] thiophen-4-yl-8-aza-5-azoniaspiro [4.5] decane hydroxide dihydrate
Adding 10g of ipiprazole into a mixed system of 150ml of N, N-dimethylformamide and 50ml of water, heating to 120 ℃, stirring for 6h, cooling to below 25 ℃, separating out a solid, filtering the solid, concentrating the filtrate to dryness, and purifying by silica gel column chromatography to obtain 8-benzo [ b ] thiophene-4-yl-8-aza-5-azoniaspiro [4.5] decane hydroxide dihydrate solid with HPLC purity: 98.17%, yield: 84.35 percent.
EXAMPLE 48 preparation of benzo [ b ] thiophen-4-yl-8-aza-5-azoniaspiro [4.5] decane hydroxide dihydrate
Adding 10g of ipiprazole into a mixed system of 200ml of N, N-dimethylformamide and 50ml of water, heating to 130 ℃, stirring for 4h, cooling to below 25 ℃, adding 50ml of water, separating out a solid, filtering the solid, concentrating the filtrate to dryness, and purifying by silica gel column chromatography to obtain 8-benzo [ b ] thiophene-4-yl-8-aza-5-aza-onium-spiro [4.5] decane hydroxide dihydrate solid with HPLC purity: 98.03%, yield: 80.74 percent.
EXAMPLE 58 preparation of benzo [ b ] thiophen-4-yl-8-aza-5-azoniaspiro [4.5] decane hydroxide dihydrate
Adding 10g of ipiprazole into a mixed system of 250ml of N, N-dimethylformamide and 50ml of water, heating to 135 ℃, stirring for 4h, cooling to below 25 ℃, supplementing 100ml of water, separating out a solid, filtering the solid, concentrating the filtrate to dryness, and purifying by silica gel column chromatography to obtain 8-benzo [ b ] thiophene-4-yl-8-aza-5-aza-onium-spiro [4.5] decane hydroxide dihydrate solid with HPLC purity: 98.49%, yield: 82.32 percent.
EXAMPLE 68 LC-MS detection of benzo [ b ] thiophen-4-yl-8-aza-5-azoniaspiro [4.5] decane hydroxide dihydrate
1. Sample preparation: an appropriate amount of the product prepared in example 1 was weighed, dissolved in methanol to prepare a sample with a concentration of about 100. mu.g/mL, and injected into an instrument for detection.
2. Testing an instrument: HPLC Agilent 1260 MS Thermo LTQ
3. Conditions of liquid chromatography
A chromatographic column: inertsil ODS-3C 18 chromatography column (4.6X 150mm, 3 μm)
Mobile phase A: acetonitrile
Mobile phase B: 0.1% formic acid
Flow rate: 1ml/min
Column temperature: 35 deg.C
Detection wavelength: 254nm
Sample introduction amount: 20 μ L
Gradient elution procedure:
4. conditions of Mass Spectrometry
The solution from the ultraviolet detector is shunted, the flow rate of the solution entering a mass spectrometer is 0.2ml/min, electrospray ionization and positive ion mode detection are carried out, and nitrogen is used as sheath gas, an auxiliary device and purge gas. The spraying voltage is 4.5kV, the sheath gas is 20arb, the auxiliary gas is 5arb, the purge gas is 0arb, the capillary temperature is 275 ℃, the capillary voltage is 29V, and the scanning range is 150 amu and 500 amu.
5. And (3) detection results:
the results are shown in FIG. 1. The molecular ion peak of the compound is m/z 273.19 by LC-MS detection.
Example 78 benzo [ b ]]Thien-4-yl-8-aza-5-azanium-spiro [4.5]Nuclear magnetic resonance hydrogen spectrum of decane hydroxide dihydrate: (1H-NMR) spectrum
1. Sample preparation: an appropriate amount of the product prepared in example 1 was weighed out and dissolved in MeOD to prepare a sample having a concentration of about 1 mg/mL.
2. Chemical structural formula and hydrogen atom numbering
3. Test apparatus and conditions
Testing an instrument: BrukeraVIII-400 MHz nuclear magnetic resonance instrument
And (3) testing conditions are as follows: TMS internal standard, MeOD is testing solvent
4. As a result: the NMR data are shown in Table 1 and FIG. 2.
TABLE 11H-NMR data and attribution
EXAMPLE 8 determination of Water of crystallization
The method comprises the following steps: 0.1g of the product prepared in example 1 was weighed out and precisely weighed. The measurement is carried out according to the first method of 0832 moisture measurement method of the general rules of the four parts of the pharmacopoeia 2015 edition. Methanol is used as a solvent, and the end point is reached by titration with Karl-Fischer titration solution.
As a result: contains 11.4% of water, and the compound contains 2 crystal waters.
Example 9 Epipiprazole impurity detection
1. Detection instrument and detection conditions
A detection instrument: high performance liquid chromatograph (LC-2010CHT, Shimadzu Japan)
Chromatographic conditions and system: a chromatographic column: inertsil ODS-3C 18 chromatographic column (4.6X 150mm, 3 μm), acetonitrile solution containing 0.1% formic acid as mobile phase A, 0.1% formic acid-ammonium chloride solution (0.04mol/L ammonium chloride solution, adding 0.1% formic acid, shaking to obtain) as mobile phase B, flow rate per minute 1ml, column temperature 35 deg.C, sample loading: 20 μ L, photodiode array detector (DAD), detection wavelength 254nm, gradient elution according to the following table:
2. reference substance
Epipiprazole impurity BPZ-8 (batch number: PCL- # -BC080, source: Chengdu Mei Si Ke pharmaceutical science and technology Co., Ltd.)
Epipiprazole impurity BPZ-9 (batch number: PCL- # -BC090, source: Chengdu Mei Si Ke pharmaceutical science and technology Co., Ltd.)
Epipiprazole impurity BPZ-16 (batch number: PCL- # -BC0160, source: Chengdu Mei Si Ke pharmaceutical science and technology Co., Ltd.)
Brexpiprazole impurity BPZ-14 lot No.: 161101, source: fuzhou Qizhi medicine science and technology Co., Ltd
Brexpiprazole impurity BPZ-17 batch No.: PCL- # -BC0170, source: chengdumask medicine science and technology limited
The brexpiprazole BPZ is synthesized according to the method of patent "example 1 in CN 101155804B"; the brexpiprazole impurity BPZ-20 is synthesized according to the method in the patent "CN 101155804B reference example 1"; the brexpiprazole impurity BPZ-23 is synthesized by referring to the new synthesis method of the prior art' Zhouweijun.7-hydroxy-3, 4-dihydro-2 (1H) -quinolinone [ J ]. Guangzhou chemical engineering, 2012, 40(10):89-89 ].
Brexpiprazole impurity BPZ-29 batch No.: 170818, purity: 98.17%, the preparation method is the same as example 3
3. Sample preparation
Precisely weighing appropriate amounts of brexpiprazole reference substance and impurities BPZ-23, BPZ-17, BPZ-29, BPZ-16, BPZ-9, BPZ-14, BPZ-20 and BPZ-8 reference substance, and diluting with diluent [0.02mol/LNa ]2SO4-acetonitrile-methanol-glacial acetic acid (56:33:11:1)]Dissolving and quantitatively diluting to prepare a mixed solution containing about 0.4mg of ipiprazole and 0.8 mu g of BPZ impurity respectively per 1ml as a system applicability solution, precisely measuring 20 mu l of the mixed solution, injecting the mixed solution into a liquid chromatograph, recording a chromatogram, wherein the separation degree of the ipiprazole and adjacent impurities is not lower than 2.0, and the separation degree of the impurities is not lower than 1.0.
4. The result of the detection
The detection results are shown in FIG. 3A and FIG. 3B, and the specific data are shown in Table 2.
TABLE 2 data for each substance in HPLC chromatogram
Example 10 accelerated test of Epipprazole tablets (temperature 40 ℃ C. + -. 2 ℃ C., relative humidity 75%. + -. 5%) sample detection analysis
1. The detection apparatus and detection conditions were the same as in example 9
2. Samples and controls
Epipiprazole tablets: from Tsukamur Japan pharmaceutical Co Ltd
Referring to the 2015 version of Chinese pharmacopoeia (guiding principle of drug stability test) to perform accelerated test at the temperature of 40 +/-2 ℃ and the relative humidity of 75 +/-5%, obtaining the ipiprazole tablet subjected to accelerated test as a sample.
Control information the same as in example 9
3. Procedure for the preparation of the
Taking a proper amount of tablets after accelerated test (about equivalent to the tablet10mg of ipiprazole), precisely weighing, placing in a 25ml measuring bottle, adding a proper amount of diluent, shaking to disperse the mixture, ultrasonically treating for 30min, cooling, diluting to a scale with the diluent, and taking a subsequent filtrate as a test solution; precisely weighing appropriate amount of reference substances of impurities BPZ-23, BPZ-17, BPZ-29, BPZ-16, BPZ-9, BPZ-14, BPZ-20 and BPZ-8, and diluting with diluent [0.02mol/LNa ]2SO4-acetonitrile-methanol-glacial acetic acid (56:33:11:1)]Dissolving and diluting to prepare solutions with 0.8 mu g of BPZ impurities respectively as reference solutions, precisely measuring 20 mu l of the test solution and the impurity reference solution, injecting into a liquid chromatograph, and recording the chromatogram.
4. And (3) detection results:
the test results of the test solution are shown in FIG. 4, and the specific data are shown in Table 3.
TABLE 3 data for each substance in HPLC chromatogram
Example 11 Epipiprazole tablet (60 ℃ C. high temperature 10 days) sample detection analysis
1. The detection apparatus and detection conditions were the same as in example 10
2. Samples and controls
Epipiprazole tablets: from Tsukamur Japan pharmaceutical Co Ltd
Referring to the 2015 version of Chinese pharmacopoeia (guiding principle for drug stability test) to perform an influence factor test at the temperature of 60 ℃ for 10 days, the obtained ipiprazole tablet is used as a sample.
Control information the same as in example 9
3. Procedure for the preparation of the
Taking a proper amount of tablets (about equivalent to 10mg of ipiprazole) subjected to the influence factor test, precisely weighing, placing in a 25ml measuring bottle, adding a proper amount of diluent, shaking to disperse the tablets, ultrasonically treating for 30min, cooling, diluting to a scale with the diluent, and taking a subsequent filtrate as a test sample solution; the preparation of the reference solution was performed in the same manner as in example 10, and 20. mu.l of the test solution and 20. mu.l of the impurity reference solution were precisely measured and injected into a liquid chromatograph, and the chromatogram was recorded.
4. The test results of the test solution are shown in FIG. 5, and the specific data are shown in Table 4.
TABLE 4 data for each substance in HPLC chromatogram
Claims (10)
1. A compound characterized by the structure:
2. the method for preparing the compound according to claim 1, wherein the brexpiprazole is added into a mixed solvent of N, N-dimethylformamide and water, the mixture is heated and reacted, then the oily substance is obtained by reduced pressure distillation, and the target product is obtained after column chromatography.
3. The method according to claim 2, wherein the volume ratio of N, N-dimethylformamide to water is 1:1 to 5: 1.
4. The method according to claim 3, wherein the volume ratio of N, N-dimethylformamide to water is 3:1 to 5: 1.
5. The method as claimed in claim 2, wherein the reaction temperature is 100-150 ℃.
6. The method as claimed in claim 5, wherein the reaction temperature is 120-135 ℃.
7. The process according to claim 2, wherein the reaction time is 4 to 24 hours.
8. The process according to claim 7, wherein the reaction time is 4 to 6 hours.
9. A method for detecting an ipiprazole drug substance or formulation comprising the compound of claim 1, comprising the following parameters:
a chromatographic column: bonding silica gel with octadecylsilane;
mobile phase: taking an acetonitrile solution containing 0.1% formic acid as a mobile phase A, and taking a 0.1% formic acid-0.04 mol/L ammonium chloride solution as a mobile phase B;
gradient elution procedure:
flow rate of mobile phase: 1 ml/min;
the column temperature is 35 ℃;
detection wavelength: 254nm
Sample introduction amount: 20 μ L.
10. The use of the compound of claim 1 as an impurity control in the detection of related substances in an epipiprazole drug substance or formulation.
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