CN114456151A - Method for preserving compound 1 and use thereof - Google Patents
Method for preserving compound 1 and use thereof Download PDFInfo
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- CN114456151A CN114456151A CN202210378674.XA CN202210378674A CN114456151A CN 114456151 A CN114456151 A CN 114456151A CN 202210378674 A CN202210378674 A CN 202210378674A CN 114456151 A CN114456151 A CN 114456151A
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The application provides a preservation method and application of a compound 1, wherein the Chinese cultural name of the compound 1 is as follows: methyl 2- (2- ((1- (3- (((1- (tert-butyl) -5-chloro-6-oxo-1, 6-dihydropyridazin-4-yl) oxy) methyl) benzyl) -1H-1, 2, 3-triazol-4-yl) methoxy) ethoxy) ethyl-4-methylbenzenesulfonate, the structural formula of which is
Description
Technical Field
The application relates to a method for preserving compound 1, in particular to a preserving solvent, concentration and temperature of compound 1.
Background
Compound 1, name of Chinese culture: methyl 2- (2- ((1- (3- (((1- (tert-butyl) -5-chloro-6-oxo-1, 6-dihydropyridazin-4-yl) oxy) methyl) benzyl) -1H-1, 2, 3-triazol-4-yl) methoxy) ethoxy) ethyl-4-methylbenzenesulfonate.
The structural formula is
The molecular formula isC30H36ClN5O7S, molecular weight 646.16, is a colorless or nearly colorless viscous liquid, is very soluble in methanol, ethanol, dichloromethane, acetonitrile, methyl tert-butyl ether and dimethyl sulfoxide, and is insoluble in water.
Reacting furoic acid (MCA) with tert-butylhydrazine hydrochloride to obtain dichloropyridazine, reacting the dichloropyridazine with 1, 3-benzenedimethanol to obtain pyridazine derivative, reacting with TsCl to obtain corresponding sulfonate, and reacting with NaN3The reaction is carried out to obtain the corresponding azide, and finally the azide (TCPB-N3) reacts with PEE-OTs to obtain the compound 1. The preparation method is referred to patents CN103113354A and CN 107964007A.
Disclosure of Invention
So far, no relevant literature data about the stability and the storage condition of the compound 1 is available, and after a great deal of research, the application discovers that the compound 1 generates a great amount of impurities under the condition of being stored at room temperature, and further use of the product is influenced. To this end, the present application provides a method for preserving compound 1.
Specifically, the following technical scheme is adopted in the application:
1. a method for storing Compound 1, which comprises storing Compound 1 dispersed in an organic solvent.
2. The process of item 1, wherein the organic solvent is dimethyl sulfoxide, acetonitrile, methyl tert-butyl ether or dichloromethane.
3. The method of item 2, wherein the organic solvent is dimethyl sulfoxide, acetonitrile.
4. The method according to any one of items 1 to 3, wherein the storage temperature is-70 ℃ to 30 ℃.
5. The method of any one of items 1-3, preserving Compound 1 under a nitrogen atmosphere.
6. The method according to any one of items 1 to 3, wherein the concentration of Compound 1 stored in the organic solvent is less than 250 mg/ml.
7. The method according to item 6, wherein the concentration of Compound 1 stored in the organic solvent is less than 150 mg/ml.
Effects of the invention
In the present application, compound 1 is stored in an organic inert solvent, such as dimethyl sulfoxide, acetonitrile, methyl tert-butyl ether and dichloromethane, and since these solvents can be used as reaction solvents for preparing the drug substance of compound 1, the research of the present application finds that the degradation rate of compound 1 can be reduced by storing compound 1 in a solution of an organic solvent. At the storage temperature provided herein, and at the concentration of compound 1 provided herein, which is stored in an organic solvent solution, compound 1 can be stably stored without significant increase in specific impurity content and total amount of impurities, meeting its quality standards as a radiopharmaceutical precursor.
When the compound 1 is stored in dichloromethane, the compound 1 can be stably stored at the storage temperature and the concentration provided by the application, and the content of specific impurities and the total amount of the impurities are not obviously increased, so that the quality standard of the compound 1 serving as a radiopharmaceutical precursor is met.
The compound 1 is stored in acetonitrile, and under the storage temperature and concentration provided by the application, the compound 1 can be stably stored, the content of specific impurities and the total amount of the impurities are not obviously increased, and the quality standard of the compound 1 serving as a radiopharmaceutical precursor is met. The compound 1 is stored in dimethyl sulfoxide, and the compound 1 can be stably stored at the storage temperature and the concentration provided by the application, the content of specific impurities and the total amount of the impurities are not obviously increased, and the quality standard of the compound 1 serving as a radiopharmaceutical precursor is met.
When the compound 1 is stored in methyl tertiary butyl ether, the compound 1 can be stably stored at the storage temperature and the concentration provided by the application, the content of specific impurities and the total amount of the impurities are not obviously increased, and the quality standard of the compound 1 serving as a radiopharmaceutical precursor is met.
Detailed Description
The present application is further described below in conjunction with the following examples, which are intended to be illustrative and explanatory only and are not restrictive of the application.
Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used in experimental or practical applications, the materials and methods are described below. In case of conflict, the present specification, including definitions, will control, and the materials, methods, and examples are illustrative only and not intended to be limiting. The present application is further described with reference to the following specific examples, which should not be construed as limiting the scope of the present application.
The application provides a method for storing the compound 1, wherein the compound 1 is dispersed in an organic solvent for storage, and the stability of the compound 1 can be effectively maintained.
In a preferred embodiment, compound 1 is stored in dimethylsulfoxide, acetonitrile, methyl t-butyl ether, or dichloromethane.
The dimethyl sulfoxide (DMSO) is a sulfur-containing organic compound with a molecular formula of (CH)3)2SO, a colorless, odorless, transparent liquid at room temperature, is a hygroscopic combustible liquid. Has the characteristics of high polarity, high boiling point, good thermal stability, non-proton and water miscibility, can be dissolved in most organic substances such as ethanol, propanol, benzene, chloroform and the like, and is known as an 'universal solvent'.
The acetonitrile is also called methyl cyanide, is colorless liquid, is extremely volatile, has special odor similar to ether, has excellent solvent performance, and can dissolve various organic, inorganic and gaseous substances. Has certain toxicity and is infinitely mutually soluble with water and alcohol.
The methyl tert-butyl ether has low toxicity and danger, is commonly used as an inert organic solvent and can be used instead of low-boiling ether.
The dichloromethane is an organic compound with a chemical formula of CH2Cl2It is colorless transparent liquid, and has pungent odor similar to ether. The gas is slightly soluble in water, is soluble in ethanol and ether, is an incombustible low-boiling-point solvent under common use conditions, can generate a weakly-combusted mixed gas when the vapor of the solvent becomes high-concentration in high-temperature air, and is usually used for replacing inflammable petroleum ether, ether and the like.
In a further preferred embodiment, compound 1 is stored in the above-mentioned solvent.
The solvents are reaction solvents which can be used for preparing the raw material medicine of the compound 1, and the compound 1 is stored in the organic solvents, so that the degradation speed of the compound 1 can be reduced, and other adverse effects caused by introducing other components into the compound 1 can be avoided.
The temperature at which compound 1 is stored in the above organic solvent is not limited, and in certain preferred embodiments of the present application, compound 1 is preferably stored in the organic solvent at-70 ℃ to 30 ℃, for example, at-70 ℃, -65 ℃, -60 ℃, -55 ℃, -50 ℃, -45 ℃, -40 ℃, -30 ℃, -25 ℃, -15 ℃, -10 ℃, -5 ℃, 0 ℃, 5 ℃, 10 ℃, 15 ℃, 25 ℃, 30 ℃.
The storage container of the compound 1 is not limited, and for example, it can be stored in a glass bottle, a plastic bottle, a jar, or a narrow-necked bottle; brown bottle, transparent bottle; ground bottles, non-ground bottles, and various other chemical holding containers commonly found in the art. In some preferred embodiments of the present application, the storage container for compound 1 is an ampoule.
Further, in some preferred embodiments of the present application, compound 1 is stored under an atmosphere containing nitrogen. In other preferred embodiments, compound 1 is maintained under a nitrogen atmosphere.
The concentration of compound 1 stored in the organic solvent is not limited herein, and in certain preferred embodiments, the concentration of compound 1 is less than 250mg/ml, and may be, for example, 250mg/ml, 240 mg/ml, 230 mg/ml, 220 mg/ml, 210 mg/ml, 200 mg/ml, 190 mg/ml, 180 mg/ml, 170 mg/ml, 160mg/ml, 150mg/ml, 140 mg/ml, 130 mg/ml, 120 mg/ml, 110 mg/ml, 100 mg/ml, 90mg/ml, 80mg/ml, 70 mg/ml, 60mg/ml, 50mg/ml, 40 mg/ml, or even lower to 2 mg/ml. More preferably, the concentration of Compound 1 stored in the organic solvent is 150mg/ml or less.
Example 1 detection apparatus and method
1. Instrument and reagent
Octadecylsilane bonded silica gel as filler (Waters Tnature C18, 250mm × 4.6mm, 5 μm), electronic balance (Sartorius, CPA225D), HPLC (shimadzu LC-2030).
Acetonitrile (Honeywell, HPLC grade), sodium acetate (Fisher, LC-MS grade)
2. Chromatographic conditions
Mobile phase: acetonitrile-sodium acetate buffer (20: 80) as mobile phase A;
acetonitrile-sodium acetate buffer (90: 10) as mobile phase B;
flow rate: 1.0 ml/min;
detection wavelength: 240 nm;
sample introduction amount: 20 μ l.
And calculating the content of each substance according to an area normalization method.
The applicant researches and researches show that the compound 1 generates a main impurity with a relative retention time RRT of 0.70-0.81 and other unknown impurities under the normal storage condition, and the embodiment of the application mainly researches the content of the impurity with the RRT of 0.70-0.81 (called as specific impurity in the application) and the total impurity content, so as to judge the stability of the compound 1 solution.
In the mass standard of the compound 1, the content of the specific impurity must not exceed 0.5% in general; the total amount of impurities should not exceed 5.0%.
EXAMPLE 2 Compound 1 acetonitrile solution stability study
Firstly, examining the stability of the acetonitrile solution of the compound 1, and examining the stability of the compound 1 when the concentration of the compound 1 in the acetonitrile is respectively 20mg/ml, 150mg/ml, 250mg/ml, 350mg/ml and 550 mg/ml; the examination conditions were 5 ℃ C. + -. 3 ℃ C., 25 ℃ C. + -. 2 ℃ C./RH 60% + -. 5%.
The information for 5 samples examined for compound 1 is shown in table 1 and the experimental conditions are shown in example 1.
TABLE 1 information relating to stability test samples
The results of the initial impurity level measurements at day 0 for each sample are detailed in table 2 below. It can be seen from table 2 that the initial impurity content of each sample, before investigation, increased with increasing concentration, with increasing amounts of specific impurities and total impurities: the specific impurities in the samples of 20mg/ml, 150mg/ml and 250mg/ml do not exceed 2.0 percent; the specific impurities in the samples of 350mg/ml and 550mg/ml are close to or exceed 2.0 percent.
According to the detection data in Table 2, the acetonitrile solution of the compound 1 is at 5 ℃ +/-3 ℃, and three concentrations of 20mg/ml, 150mg/ml and 250mg/ml are taken as the key concentration to be examined.
TABLE 2 stability study results (5 ℃. + -. 3 ℃)0 day test results
The samples with various concentrations are placed at 5 +/-3 ℃ for 2 months, detected according to stability investigation items, and the results are compared with the results of 0 month, and the results are shown in Table 3. As can be seen from the experimental data in Table 3, each sample is placed at 5 +/-3 ℃ for 2 months, and the detection result of 2 months is not obviously changed from the detection result of 0 month under the concentration of 150mg/ml and 20mg/ml compared with the detection result of 0 month; the detection result of the concentration unknown single impurity which is more than 250mg/ml is obviously increased within 2 months and 0 day, and the stable storage concentration of the acetonitrile solution of the compound 1 is below 250 mg/ml.
TABLE 3 summary of stability studies (5 ℃. + -. 3 ℃)
Samples of each concentration were allowed to stand at 25 ℃. + -. 2 ℃/RH 60%. + -. 5% for 2 months, test for related substances was conducted, and the results were compared with those of 0 month, and the results are shown in Table 4. As can be seen from the test data in Table 4, under the condition of 25 ℃. + -. 2 ℃/RH60% + -5%, the total amount of specific impurities and impurities is significantly increased between the concentration of 20mg/ml and 550mg/ml, so that the compound 1 acetonitrile solution cannot be stably stored under the condition of 25 ℃. + -. 2 ℃/RH60% + -5%.
TABLE 4 summary of stability studies (25 ℃. + -. 2 ℃/RH 60%. + -. 5%)
Secondly, the stability of samples with different concentrations below 250mg/ml of the acetonitrile solution of the compound 1 is further examined, and the concentrations of the samples are respectively examined to be 2mg/ml, 90mg/ml, 160mg/ml and concentrates (obtained by purification and reduced pressure concentration); the examination conditions were 25 ℃, 5 ℃ and-40 ℃.
The information of the 4 samples examined is shown in table 5, and the experimental conditions are shown in example 1.
TABLE 5 relevant information for test samples
The samples at each concentration were allowed to stand at 25 ℃ for 32 days, tested according to stability evaluation items, and the results were compared with the results of 0 day, and are shown in Table 6. It can be seen that, when each sample is placed at 25 ℃ for 32 days, the purity of the sample is reduced, and the reduction rate of the purity of the sample is slower along with the reduction of the concentration of the sample; the content of specific impurities in a sample with the concentration of 2mg/ml is not more than 0.5 percent in 32 days, the purity of the sample is more than 98 percent, and the total amount of the impurities is not more than 2 percent; the content of specific impurities in a sample with the concentration of 90mg/ml is 0.25 percent in the detection result in 15 days, is only 0.6 percent in 32 days, the purity of the sample is more than 98 percent in 32 days, and the total amount of the impurities is not more than 2 percent; the content of the specific impurities in the sample with the concentration of 160mg/ml is 0.68 percent in the detection result in 15 days, is only 1.06 percent in the 32 days, the purity of the sample is more than 97 percent in the 32 days, and the total amount of the impurities is not more than 3 percent. The samples at concentrations of 2mg/ml, 90mg/ml and 160mg/ml had good stability. The impurity content of the concentrate reaches 1.01% on the first day, the specific impurity content reaches 18.02% on the 32 th day, and the purity of the sample is only 72.7%, which is obviously unstable.
TABLE 6 summary of stability studies (25 deg.C)
The samples at each concentration were allowed to stand at 5 ℃ for 55 days, tested according to stability evaluation items, and the results were compared with the results obtained at 0 day, and are shown in Table 7. As can be seen, when the samples were stored at 5 ℃ for 55 days, the purity of the samples with the concentrations of 2mg/ml, 90mg/ml and 160mg/ml was reduced to different degrees, but the purity was 98% or more, the total impurity content was not more than 2%, the specific impurity content was not more than 0.3%, and the total impurity content of 160mg/ml and 90mg/ml was reduced from 0.1% to 0.2% after 55 days, indicating that the samples with the concentrations of 2mg/ml, 90mg/ml and 160mg/ml were stable well at 5 ℃. The concentrate was significantly unstable on storage, and after 55 days, it decreased from 98.84% to 93.18%.
TABLE 7 summary of stability studies (5 ℃ C.)
The samples at each concentration were allowed to stand at-40 ℃ for 55 days, tested according to stability evaluation items, and the results were compared with the results obtained at 0 day, and are shown in Table 8. It can be seen that, when the samples are stored at-40 ℃ for 55 days, the purity of the samples with the concentration of 2mg/ml, 90mg/ml and 160mg/ml is more than 98.5%, the total impurity content is not more than 1.5%, and the specific impurity content is not more than 0.11%, which indicates that the stability of the samples with the concentration of 2mg/ml, 90mg/ml and 160mg/ml is good under the condition of-40 ℃. The specific impurity content in the concentrate is increased by less than 0.11%.
TABLE 8 summary of stability studies (-40 ℃ C.)
EXAMPLE 3 Compound 1 dimethyl sulfoxide solution stability study
Stability of the dimethylsulfoxide solution of Compound 1 was examined at 25 ℃, 5 ℃ and-40 ℃ for the stability of Compound 1 at a concentration of 40 mg/ml in dimethylsulfoxide.
The sample number is 10, the batch number is XTR004-20210619-10, and the batch number of the raw material medicine is: LXT004-210428, the packaging material is ampoule bottle, and nitrogen is filled. .
The samples were kept at 25 deg.C, 5 deg.C, and-40 deg.C for 55 days, tested according to stability test items, and the results were compared with the results obtained at 0 day, and are shown in Table 9. As can be seen from the table, compound 1 was stable at the storage temperatures and concentrations provided herein, with no significant increase in specific impurities and total impurity levels, meeting its quality standards as a radiopharmaceutical precursor.
TABLE 9 stability of Compound 1 in dimethylsulfoxide solution
EXAMPLE 4 stability study of Compound 1 in methylene chloride solution
Stability of the dichloromethane solution of Compound 1 was examined at a concentration of 80mg/ml of Compound 1 in dichloromethane at 25 ℃, 5 ℃ and-40 ℃.
The sample number is 11, the batch number is XTR004-20210619-11, the batch number of the raw material medicine is LXT004-210428, the packaging material is an ampoule bottle, and nitrogen is filled in the ampoule bottle.
The samples were kept at 25 deg.C, 5 deg.C, and-40 deg.C for 55 days, tested according to stability test items, and the results were compared with the results obtained at 0 day, and are shown in Table 10. As can be seen from the table, compound 1 was stable at the storage temperatures and concentrations provided herein, with no significant increase in specific impurity levels and total impurities, meeting its quality standards as a radiopharmaceutical precursor.
TABLE 10 stability of Compound 1 in dichloromethane solution
EXAMPLE 5 Compound 1 methyl tert-butyl ether solution stability study
Stability of the methyl tert-butyl ether solution of Compound 1 was examined to determine the concentration of Compound 1 in methyl tert-butyl ether at 8 mg/ml, at 25 deg.C, 5 deg.C and-40 deg.C.
The sample number is 12, the batch number is XTR 004-20210619-12, and the batch number of the raw material medicine is: LXT004-210428, the packaging material is ampoule bottle, and nitrogen is filled.
The samples were kept at 25 deg.C, 5 deg.C, and-40 deg.C for 55 days, tested according to stability test items, and the results were compared with the results of 0 day, and are shown in Table 11. As can be seen from the table, compound 1 was stable at the storage temperatures and concentrations provided herein, with no significant increase in specific impurity levels and total impurities, meeting its quality standards as a radiopharmaceutical precursor.
TABLE 11 stability of Compound 1 in methyl tert-butyl ether solution
Claims (6)
1. A method for preserving a compound 1, characterized by dispersing the compound 1 in an organic solvent for preservation, the organic solvent being dimethyl sulfoxide, acetonitrile, methyl tert-butyl ether or dichloromethane,
the Chinese cultural name of the compound 1: methyl 2- (2- ((1- (3- (((1- (tert-butyl) -5-chloro-6-oxo-1, 6-dihydropyridazin-4-yl) oxy) methyl) benzyl) -1H-1, 2, 3-triazol-4-yl) methoxy) ethoxy) ethyl-4-methylbenzenesulfonate,
the structural formula is
2. The method of claim 1, wherein the organic solvent is dimethyl sulfoxide or acetonitrile.
3. The method according to claim 1 or 2, characterized in that the preservation temperature is-70 ℃ to 30 ℃.
4. The method according to claim 1 or 2, characterized in that compound 1 is preserved under nitrogen atmosphere.
5. The method according to claim 1 or 2, wherein the concentration of compound 1 stored in the organic solvent is less than 250 mg/ml.
6. The method according to claim 5, wherein the concentration of Compound 1 stored in the organic solvent is less than 150 mg/ml.
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| CN202210378674.XA CN114456151A (en) | 2022-04-12 | 2022-04-12 | Method for preserving compound 1 and use thereof |
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| CN202210378674.XA CN114456151A (en) | 2022-04-12 | 2022-04-12 | Method for preserving compound 1 and use thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024008075A1 (en) * | 2022-07-04 | 2024-01-11 | 北京先通国际医药科技股份有限公司 | Preparation method for liquid composition containing compound i and use in myocardial perfusion pet imaging |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103113354A (en) * | 2012-11-01 | 2013-05-22 | 张现忠 | PEGylated benzyltriazolyl pyridazinone compounds, and preparation method and application thereof |
| CN112807276A (en) * | 2021-01-26 | 2021-05-18 | 北京先通国际医药科技股份有限公司 | Preparation method and application of pyridazinone myocardial perfusion PET radiopharmaceutical |
-
2022
- 2022-04-12 CN CN202210378674.XA patent/CN114456151A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103113354A (en) * | 2012-11-01 | 2013-05-22 | 张现忠 | PEGylated benzyltriazolyl pyridazinone compounds, and preparation method and application thereof |
| CN112807276A (en) * | 2021-01-26 | 2021-05-18 | 北京先通国际医药科技股份有限公司 | Preparation method and application of pyridazinone myocardial perfusion PET radiopharmaceutical |
Non-Patent Citations (2)
| Title |
|---|
| TIANTIAN MOU等: "Synthesis and bioevaluation of 4-chloro-2-tert-butyl-5-[2-[[1-[2-[18F]fluroethyl]-1H-1,2,3-triazol-4-yl]methyl]phenylmethoxy]-3(2H)-pyridazinone as potential myocardial perfusion imaging agent with PET", 《J. LABEL COMPD. RADIOPHARM》 * |
| TIANTIAN MOU等: "Synthesis and Bio-Evaluation of New 18F-Labeled Pyridaben Analogs with Improved Stability for Myocardial Perfusion Imaging in Mice", 《CHEM BIOL DRUG DES》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024008075A1 (en) * | 2022-07-04 | 2024-01-11 | 北京先通国际医药科技股份有限公司 | Preparation method for liquid composition containing compound i and use in myocardial perfusion pet imaging |
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