Storage method and application of Compound 1

Abstract

The present application provides a preservation method and application of Compound 1. The Chinese chemical name of Compound 1 is 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, and its structural formula is as follows. Through the research of the applicant, it is found that dispersing Compound 1 in an organic solvent can reduce its degradation rate. In the present application, Compound 1 is stored in dimethyl sulfoxide, acetonitrile, methyl tert-butyl ether or dichloromethane. At the storage temperature provided in the present application, the storage temperature is -70°C to 30°C, and at the concentration of Compound 1 stored in the above solution provided in the present application, which is lower than 250 mg / ml, Compound 1 can be stably stored, and the content of specific impurities and the total amount of impurities do not increase significantly, meeting the quality standards as a radiopharmaceutical precursor.

Description

Technical Field

[0001] This application relates to a method for storing Compound 1, specifically to the storage solvent, concentration, and temperature of Compound 1. Background Art

[0002] Compound 1, Chinese chemical name: 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.

[0003] Its structural formula is

[0004]

[0005] The molecular formula is C 30 H 36 ClN5O7S, with a molecular weight of 646.16, is a colorless or almost colorless viscous liquid, highly soluble in methanol, ethanol, dichloromethane, acetonitrile, methyl tert-butyl ether, and dimethyl sulfoxide, and insoluble in water.

[0006] Compound 1 is obtained by reacting mucobromic acid (MCA) with tert-butylhydrazine hydrochloride to obtain dichloropyridazine, which then reacts with 1,3-benzenedimethanol to obtain a pyridazine derivative, followed by reaction with TsCl to obtain the corresponding sulfonate ester, and then reaction with NaN3 to obtain the corresponding azide compound. Finally, the azide compound (TCPB-N3) reacts with PEE-OTs to obtain Compound 1. Its preparation method refers to patents CN103113354A and CN107964007A. Summary of the Invention

[0007] So far, there is no relevant literature on the stability of Compound 1 and its storage conditions. After a large amount of research, this application found that when Compound 1 is stored at room temperature, a large amount of impurities will be generated, affecting the further use of the product. Therefore, this application provides a method for storing Compound 1.

[0008] Specifically, this application adopts the following technical solutions:

[0009] 1. A method for storing Compound 1, wherein the Compound 1 is dispersed in an organic solvent for storage.

[0010] 2. The method according to item 1, wherein the organic solvent is dimethyl sulfoxide, acetonitrile, methyl tert-butyl ether, or dichloromethane.

[0011] 3. The method according to item 2, wherein the organic solvent is dimethyl sulfoxide, acetonitrile.

[0012] 4. According to the method described in any one of Items 1 - 3, the storage temperature is -70°C to 30°C.

[0013] 5. According to the method described in any one of Items 1 - 3, Compound 1 is stored in a nitrogen atmosphere.

[0014] 6. According to the method described in any one of Items 1 - 3, the concentration of Compound 1 in the organic solvent is stored at less than 250 mg / ml.

[0015] 7. According to the method described in Item 6, the concentration of Compound 1 in the organic solvent is stored at less than 150 mg / ml.

[0016] Advantages of the Invention

[0017] In this application, Compound 1 is stored in an organic inert solvent such as dimethyl sulfoxide, acetonitrile, methyl tert - butyl ether, and dichloromethane. Since these solvents can all be used as reaction solvents for preparing the bulk drug of Compound 1, it has been found through the research of this application that storing Compound 1 in a solution of an organic solvent can reduce its degradation rate. At the storage temperature provided in this application and the concentration of Compound 1 in the organic solvent solution provided in this application, Compound 1 can be stored stably, and the content of specific impurities and the total amount of impurities have not increased significantly, meeting the quality standards as a radiopharmaceutical precursor.

[0018] When Compound 1 is stored in dichloromethane, at the storage temperature and concentration provided in this application, Compound 1 can be stored stably, and the content of specific impurities and the total amount of impurities have not increased significantly, meeting the quality standards as a radiopharmaceutical precursor.

[0019] When Compound 1 is stored in acetonitrile, at the storage temperature and concentration provided in this application, Compound 1 can be stored stably, and the content of specific impurities and the total amount of impurities have not increased significantly, meeting the quality standards as a radiopharmaceutical precursor. When Compound 1 is stored in dimethyl sulfoxide, at the storage temperature and concentration provided in this application, Compound 1 can be stored stably, and the content of specific impurities and the total amount of impurities have not increased significantly, meeting the quality standards as a radiopharmaceutical precursor.

[0020] When Compound 1 is stored in methyl tert - butyl ether, at the storage temperature and concentration provided in this application, Compound 1 can be stored stably, and the content of specific impurities and the total amount of impurities have not increased significantly, meeting the quality standards as a radiopharmaceutical precursor. Detailed Embodiments

[0021] The following further illustrates this application with reference to the embodiments. It should be understood that the embodiments are only used to further illustrate and explain this application and are not used to limit this application.

[0022] Unless otherwise defined, technical and scientific terms used in this specification have the same meanings as commonly understood by those skilled in the art. Although methods and materials similar or equivalent to those described herein can be used in experiments or practical applications, the materials and methods are described below. In case of conflict, the present specification, including its definitions, shall prevail. In addition, the materials, methods, and examples are for illustrative purposes only and not restrictive. The present application will be further described below in conjunction with specific embodiments, but it is not used to limit the scope of the present application.

[0023] The present application provides a method for storing Compound 1. Dispersing Compound 1 in an organic solvent for storage can effectively maintain the stability of Compound 1.

[0024] In a preferred embodiment, Compound 1 is stored in dimethyl sulfoxide, acetonitrile, methyl tert-butyl ether, or dichloromethane.

[0025] The dimethyl sulfoxide (DMSO) is a sulfur-containing organic compound with the molecular formula (CH3)2SO. It is a colorless, odorless, and transparent liquid at room temperature and is a hygroscopic and flammable liquid. It has the characteristics of high polarity, high boiling point, good thermal stability, aproticity, and miscibility with water. It can dissolve in most organic substances such as ethanol, propanol, benzene, and chloroform, and is known as the "universal solvent".

[0026] The acetonitrile, also known as methyl cyanide, is a colorless liquid that is extremely volatile and has a special odor similar to that of ether. It has excellent solvent properties and can dissolve a variety of organic, inorganic, and gaseous substances. It is slightly toxic and is infinitely miscible with water and alcohol.

[0027] The methyl tert-butyl ether has low toxicity and is dangerous. It is commonly used as an inert organic solvent and can replace low-boiling-point ether.

[0028] The dichloromethane is an organic compound with the chemical formula CH2Cl2. It is a colorless, transparent liquid with an irritating odor similar to that of ether. It is slightly soluble in water and soluble in ethanol and ether. Under normal usage conditions, it is a non-flammable low-boiling-point solvent. Its vapor forms a weakly combustible mixture only when it becomes highly concentrated in hot air. It is often used to replace flammable petroleum ether, ether, etc.

[0029] In a further preferred embodiment, Compound 1 is stored in the above solvents.

[0030] The above solvents are also reaction solvents that can be used in the preparation of the active pharmaceutical ingredient of Compound 1. Storing Compound 1 in these organic solvents can not only reduce its degradation rate but also avoid introducing other components into Compound 1 and causing other adverse effects.

[0031] The temperature at which Compound 1 is stored in the above-mentioned organic solvent is not limited. In some preferred embodiments of the present application, the storage temperature of Compound 1 in the organic solvent is preferably -70°C to 30°C. For example, the storage temperature can be -70°C, -65°C, -60°C, -55°C, -50°C, -45°C, -40°C, -30°C, -25°C, -15°C, -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 25°C, 30°C.

[0032] The storage container for Compound 1 is not limited. For example, it can be stored in a glass bottle, plastic bottle, wide-mouth bottle, narrow-mouth bottle; brown bottle, transparent bottle; ground-glass bottle, non-ground-glass bottle, and various other containers for storing chemical reagents commonly used in the art. In some preferred embodiments of the present application, the storage container for Compound 1 is an ampoule bottle.

[0033] Furthermore, in some preferred embodiments of the present application, Compound 1 is stored in an atmosphere containing nitrogen. In some other preferred embodiments, Compound 1 is stored in a nitrogen atmosphere.

[0034] In the present application, the concentration of Compound 1 stored in the organic solvent is not limited. In some preferred embodiments, the concentration of Compound 1 is less than 250 mg / ml. For example, it can be 250 mg / 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, 160 mg / ml, 150 mg / ml, 140 mg / ml, 130 mg / ml, 120 mg / ml, 110 mg / ml, 100 mg / ml, 90 mg / ml, 80 mg / ml, 70 mg / ml, 60 mg / ml, 50 mg / ml, 40 mg / ml, or even as low as 2 mg / ml. More preferably, the concentration of Compound 1 stored in the organic solvent is below 150 mg / ml.

[0035] Example 1 Detection Instruments and Methods

[0036] 1. Instruments and Reagents

[0037] Octadecylsilane-bonded silica gel as the filler (Waters Tnature C18, 250 mm × 4.6 mm, 5 µm), electronic balance (Sartorius, CPA225D), HPLC (Shimadzu LC-2030).

[0038] Acetonitrile (Honeywell, HPLC grade), sodium acetate (Fisher, LC-MS grade)

[0039] 2. Chromatographic Conditions

[0040] Mobile phase: Acetonitrile - sodium acetate buffer solution (20:80) was used as mobile phase A;

[0041] Acetonitrile - sodium acetate buffer solution (90:10) was used as mobile phase B;

[0042] Flow rate: 1.0 ml / min;

[0043] Detection wavelength: 240 nm;

[0044] Injection volume: 20 μl.

[0045] The contents of the measured substances were calculated by the area normalization method.

[0046] Through the research of the applicant, it was found that when Compound 1 was stored under normal conditions, a main impurity would be produced, with a relative retention time (RRT) of 0.70 - 0.81, and other unknown impurities. In the examples of this application, the content of the impurity with an RRT of 0.70 - 0.81 (referred to as the specific impurity in this application) and the total impurity content were mainly studied to judge the stability of the Compound 1 solution.

[0047] In the quality standard of Compound 1, generally, the content of the specific impurity shall not exceed 0.5%; the total impurity content shall not exceed 5.0%.

[0048] Example 2 Investigation on the Stability of Compound 1 Acetonitrile Solution

[0049] I. The stability of the Compound 1 acetonitrile solution was investigated, and the stability of Compound 1 at concentrations of 20 mg / ml, 150 mg / ml, 250 mg / ml, 350 mg / ml, and 550 mg / ml in acetonitrile was investigated; the investigation conditions were 5°C ± 3°C, 25°C ± 2°C / RH 60% ± 5%.

[0050] The information of 5 samples of Compound 1 is shown in Table 1, and the experimental conditions are as shown in Example 1.

[0051] Table 1 Relevant Information of Samples for Stability Test

[0052]

[0053] The initial impurity content detection results of each sample on the 0th day are shown in the following Table 2. It can be seen from Table 2 that before the investigation, the initial impurity content of each sample gradually increased with the increase in concentration: the specific impurity in the samples of 20 mg / ml, 150 mg / ml, and 250 mg / ml did not exceed 2.0%; the specific impurity in the samples of 350 mg / ml and 550 mg / ml was close to or exceeded 2.0%.

[0054] According to the detection data in Table 2, for the acetonitrile solution of Compound 1, at the condition of 5°C ± 3°C, the three concentrations of 20 mg / ml, 150 mg / ml, and 250 mg / ml are the key concentrations to be investigated.

[0055] Table 2 Stability study results (5°C ± 3°C), detection results at day 0

[0056]

[0057] Samples at each concentration were placed at 5°C ± 3°C for 2 months, detected according to the stability investigation items, and the results were compared with the results at month 0. The results are shown in Table 3. It can be seen from the experimental data in Table 3 that for each sample placed at 5°C ± 3°C for 2 months, when comparing the detection results at month 2 with those at day 0, there were no obvious changes in the detection results at month 2 and day 0 at the concentrations of 150 mg / ml and 20 mg / ml; for the detection results of the unknown single impurity at concentrations above 250 mg / ml, there was an obvious increase in the detection results at month 2 compared with those at day 0. The stable storage concentration of the acetonitrile solution of Compound 1 should be below 250 mg / ml.

[0058] Table 3 Summary of stability study results (5°C ± 3°C)

[0059]

[0060] Samples at each concentration were placed at 25°C ± 2°C / RH60% ± 5% for 2 months, and the related substances were detected, and the results were compared with the results at month 0. The results are shown in Table 4. It can be seen from the test data in Table 4 that under the condition of 25°C ± 2°C / RH60% ± 5%, between the concentrations of 20 mg / ml and 550 mg / ml, there was an obvious increase in the specific impurity and the total amount of impurities. Therefore, the acetonitrile solution of Compound 1 cannot be stably stored under the condition of 25°C ± 2°C / RH60% ± 5%.

[0061] Table 4 Summary of stability study results (25°C ± 2°C / RH60% ± 5%)

[0062]

[0063] II. The present application further conducts stability investigations on samples of the acetonitrile solution of Compound 1 at different concentrations below 250 mg / ml, and investigates the concentrations of 2 mg / ml, 90 mg / ml, 160 mg / ml, and the concentrate (obtained by purification and reduced pressure concentration); the investigation conditions are 25°C, 5°C, and -40°C.

[0064] The information of the 4 samples investigated is shown in Table 5, and the experimental conditions are as shown in Example 1.

[0065] Table 5 Relevant information of the test samples

[0066]

[0067] Samples of each concentration were placed at 25°C for 32 days, tested according to the stability investigation items, and the results were compared with those at day 0. The results are shown in Table 6. It can be seen from the table that when the samples were placed at 25°C for 32 days, the purity of each sample decreased to some extent. With the decrease of the sample concentration, the rate of decrease in sample purity became slower. The content of specific impurities in the sample with a concentration of 2 mg / ml did not exceed 0.5% in the 32-day test, the sample purity was above 98%, and the total impurity content did not exceed 2%. The content of specific impurities in the sample with a concentration of 90 mg / ml was 0.25% on the 15th day and only 0.6% on the 32nd day. The sample purity was above 98% within 32 days, and the total impurity content did not exceed 2%. The content of specific impurities in the sample with a concentration of 160 mg / ml was 0.68% on the 15th day and only 1.06% on the 32nd day. The sample purity was above 97% within 32 days, and the total impurity content did not exceed 3%. The samples with concentrations of 2 mg / ml, 90 mg / ml, and 160 mg / ml had good stability. However, for the concentrate, the content of impurities reached 1.01% on the first day, and 18.02% on the 32nd day, and the sample purity was only 72.7%, indicating obvious instability.

[0068] Table 6 Summary of Stability Study Results (25°C)

[0069]

[0070] Samples of each concentration were placed at 5°C for 55 days, tested according to the stability investigation items, and the results were compared with those at day 0. The results are shown in Table 7. It can be seen from the table that when the samples were stored at 5°C for 55 days, the purity of the samples with concentrations of 2 mg / ml, 90 mg / ml, and 160 mg / ml decreased to varying degrees, but all were above 98%. The total impurity content did not exceed 2%, and the content of specific impurities did not exceed 0.3%. The decrease in the content of 160 mg / ml and 90 mg / ml decreased from 0.1% to 0.2% after 55 days, indicating that under the condition of 5°C, the samples with concentrations of 2 mg / ml, 90 mg / ml, and 160 mg / ml had good stability. However, the storage of the concentrate was significantly unstable, decreasing from 98.84% to 93.18% after 55 days.

[0071] Table 7 Summary of Stability Study Results (5°C)

[0072]

[0073] Samples of each concentration were stored at -40°C for 55 days, tested according to the stability study items, and the results were compared with those at day 0. The results are shown in Table 8. It can be seen that when stored at -40°C for 55 days, the purity of the samples with concentrations of 2 mg / ml, 90 mg / ml, and 160 mg / ml is above 98.5%, the total impurity content does not exceed 1.5%, and the content of specific impurities does not exceed 0.11%. This indicates that the samples with concentrations of 2 mg / ml, 90 mg / ml, and 160 mg / ml have good stability at -40°C. The increase in the content of specific impurities in the concentrate is all below 0.11%.

[0074] Table 8 Summary of Stability Study Results (-40°C)

[0075]

[0076] Example 3 Stability Study of Compound 1 in Dimethyl Sulfoxide Solution

[0077] The stability of Compound 1 in dimethyl sulfoxide solution was studied. The stability of Compound 1 at a concentration of 40 mg / ml in dimethyl sulfoxide was investigated at temperatures of 25°C, 5°C, and -40°C.

[0078] The sample number was 10, the batch number was XTR004-20210619-10, the batch number of the active pharmaceutical ingredient was LXT004-210428, the packaging material was an ampoule bottle, and nitrogen was filled.

[0079] The samples were stored at 25°C, 5°C, and -40°C for 55 days, tested according to the stability study items, and the results were compared with those at day 0. The results are shown in Table 9. It can be seen from the table that at the storage temperatures and concentrations provided in this application, Compound 1 can be stably stored, and the content of specific impurities and total impurities has not increased significantly, meeting the quality standards as a radiopharmaceutical precursor.

[0080] Table 9 Stability of Compound 1 in Dimethyl Sulfoxide Solution

[0081]

[0082] Example 4 Stability Study of Compound 1 in Dichloromethane Solution

[0083] The stability of Compound 1 in dichloromethane solution was studied. The stability of Compound 1 at a concentration of 80 mg / ml in dichloromethane was investigated at temperatures of 25°C, 5°C, and -40°C.

[0084] The sample number was 11, the batch number was XTR004-20210619-11, the batch number of the active pharmaceutical ingredient was LXT004-210428, the packaging material was an ampoule bottle, and nitrogen was filled.

[0085] The samples were placed at 25 °C, 5 °C, and -40 °C for 55 days respectively, detected according to the stability investigation items, and the results were compared with the results on day 0. The results are shown in Table 10. It can be seen from the table that under the storage temperature and concentration provided in this application, Compound 1 can be stably stored, and the content of specific impurities and the total amount of impurities have not increased significantly, meeting the quality standards for its use as a radiopharmaceutical precursor.

[0086] Table 10 Stability of Compound 1 in Dichloromethane Solution

[0087]

[0088] Example 5 Investigation on the Stability of Compound 1 in Methyl tert-Butyl Ether Solution

[0089] The stability of the methyl tert-butyl ether solution of Compound 1 was investigated. The concentration of Compound 1 in methyl tert-butyl ether was 8 mg / ml, and the investigation temperatures were 25 °C, 5 °C, and -40 °C.

[0090] The sample number was 12, the batch number was XTR004 - 20210619 - 12, the batch number of the active pharmaceutical ingredient was LXT004 - 210428, the packaging material was an ampoule bottle, and nitrogen was filled.

[0091] The samples were placed at 25 °C, 5 °C, and -40 °C for 55 days respectively, detected according to the stability investigation items, and the results were compared with the results on day 0. The results are shown in Table 11. It can be seen from the table that under the storage temperature and concentration provided in this application, Compound 1 can be stably stored, and the content of specific impurities and the total amount of impurities have not increased significantly, meeting the quality standards for its use as a radiopharmaceutical precursor.

[0092] Table 11 Stability of Compound 1 in Methyl tert-Butyl Ether Solution

[0093]

Claims

1. Method for storing Compound 1, characterized in that, The compound 1 is dispersed in an organic solvent for storage; the storage temperature is -25°C to 15°C; the concentration of compound 1 in the organic solvent is lower than 250 mg / ml and not less than 40 mg / ml; the organic solvent is acetonitrile, The Chinese chemical 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, Its structural formula is 2. The method according to claim 1, wherein Compound 1 is stored under a nitrogen atmosphere.

3. The method according to claim 1, characterized in that The concentration of compound 1 stored in the organic solvent is lower than 150 mg / ml.

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