CN116178276A - Crystal form of chlorpyrifos hydrochloride and preparation method thereof - Google Patents
Crystal form of chlorpyrifos hydrochloride and preparation method thereof Download PDFInfo
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- CN116178276A CN116178276A CN202111425149.0A CN202111425149A CN116178276A CN 116178276 A CN116178276 A CN 116178276A CN 202111425149 A CN202111425149 A CN 202111425149A CN 116178276 A CN116178276 A CN 116178276A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/22—Nitrogen and oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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Abstract
The invention relates to a crystal form of a chlorpyripram hydrochloride and a preparation method thereof, wherein chlorpyripram is a novel PDE4 inhibitor, and the chlorpyripram compound is prepared into salt at the very necessary stage in the early stage of drug development, so that the physicochemical properties of the chlorpyripram compound, such as solubility, crystallinity, hygroscopicity, melting point, solid stability and the like, can be improved. In view of the purpose, the crystal form of the chlorpyrifos hydrochloride is successfully synthesized through a drug salt sieve experiment, compared with the chlorpyrifos, the crystallinity of the chlorpyrifos hydrochloride crystal form is little changed, the polymorphism of salt is not found, the stability temperature is low, the highest stability temperature is between 50 and 115 ℃, and the selection is provided for the final salification of the drug.
Description
Technical Field
The invention relates to the field of chemical medicine, in particular to a crystal form of chlorpyrifos hydrochloride and a preparation method thereof.
Background
The Chinese patent No. CN201611164170.9 discloses a preparation method of PDE4 inhibitor clobiprofen, compared with the prior art, the yield is greatly improved, and experiments prove that the yield is as high as 71Percent of the total weight of the composition. The raw materials are easy to obtain and low in cost, the reaction condition is mild, the requirement on equipment is low, and the industrial production can be realized. The invention provides a high-efficiency and easy-to-implement way for the synthesis method of the chlorbippram. Wherein: the chemical formula of the chlorpyrifos is C 27 H 26 ClN 3 O 4 The structural formula is shown in figure 1.
Drug molecules generally have a variety of arrangements, with different arrangements constituting different crystal forms, i.e. polymorphic phenomena of the drug, which are generally represented by the form in which the drug substance is present in a solid state. A medicine can have multiple crystal forms, and different crystal forms of the same medicine can be dissolved and absorbed differently in vivo, which naturally influences the dissolution and release of the preparation, and further influences the clinical curative effect and safety. Therefore, the problem of the crystal form of the medicine can be directly related to the quality and the curative effect of the medicine, and the research on the crystal form type and the property of the medicine has various meanings and values. The medicine is prepared by selecting the crystal form with medicinal advantages, so that the dissolution rate and bioavailability of the medicine can be improved, and the treatment effect of the medicine is improved, however, the current research on the crystal form of the chlorbippram is less, and the application of the chlorbippram is limited.
Disclosure of Invention
The invention aims to popularize the chlorpyrifos into clinical application and provides a crystal form of the chlorpyrifos and a preparation method thereof.
In order to achieve the above purpose, the present application provides a crystal form of chlorpyrifos hydrochloride, wherein the structural formula of the chlorpyrifos hydrochloride crystal form is as follows:
as a further improvement of the present application, the X-ray powder diffraction pattern of the crystalline form of chlorpyrifos hydrochloride has characteristic peaks at least any five of diffraction angles 2θ of 13.5±0.2°, 13.9±0.2°, 14.4±0.2°, 15.4±0.2°, 16.4±0.2°, 16.8±0.2°, 20.5±0.2°, and 20.9±0.2°.
As a further improvement of the present application, the X-ray powder diffraction pattern of the crystalline form of chlorpyrifos hydrochloride has characteristic peaks at the following diffraction angles 2θ:4.2±0.2°, 6.5±0.2°, 6.9±0.2°, 8.9±0.2°, 12.1±0.2°, 12.9±0.2°, 13.5±0.2°, 13.9±0.2°, 14.4±0.2°, 15.4±0.2°, 15.8±0.2°, 16.4±0.2°, 16.8±0.2°, 17.8±0.2°, 18.7±0.2°, 20.5±0.2°, 20.9±0.2 °, 21.7±0.2°, 24.2±0.2°, 25.8±0.2 °, 27.1±0.2 °, 27.8±0.2°, 28.9±0.2°, 31.0.2 °, 32.9±0.2°, 34.0.2°, and 35.0.2 °.
As a further improvement of the application, the differential scanning calorimeter of the crystalline form of the chlorpyrifos hydrochloride has a first endothermic peak at 100-110 ℃ and a second endothermic peak at 140-146 ℃.
As a further improvement of the method, the thermogravimetric analyzer of the chlorpyrifos hydrochloride crystal form loses weight by 7.0-8.0% before 110 ℃, and the decomposition temperature is 315-324 ℃.
As a further improvement of the application, the solubility of the chlorpyrifos hydrochloride crystal form in water at 25 ℃ is less than 0.05mg/ml.
In order to achieve the above purpose, the present application provides a preparation method of a crystalline form of clobiproflumilast hydrochloride, comprising the following steps: respectively forming a solution system of the chlorpyrifos and the hydrochloric acid in a soluble solvent, mixing the two systems to form a mixed solution containing flocculent precipitate, and crystallizing at the temperature of between 10 ℃ below zero and 50 ℃ to form a chlorpyrifos hydrochloride crystal form.
As a further improvement of the present application, the soluble solvent is acetone.
As a further improvement of the application, the mass molar ratio of the chlorpyrifos to the hydrochloric acid is 1:1.
As a further improvement of the present application, the crystallization temperature is room temperature.
The method has the beneficial effects that the crystal form of the chlorpyrifos hydrochloride is successfully synthesized through a drug salt sieve experiment, the physicochemical properties of the chlorpyrifos compound, such as solubility, crystallinity, hygroscopicity, melting point, solid stability and the like, are improved, the stability temperature of the chlorpyrifos hydrochloride crystal form is low, the highest stability temperature is between 50 and 115 ℃, and the selection is provided for the final salification of the drug.
Drawings
FIG. 1 is a structural formula of chlorpyrifos in example 1;
FIG. 2 is an XRPD pattern for clomiphene in example 1;
FIG. 3 is a TGA plot of the clomiphene of example 1;
FIG. 4 is a DSC of the clomipramine of example 1;
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of chlorbippram in example 1;
FIG. 6 is an XRPD pattern for the crystalline form of chlorobippram hydrochloride in example 2;
FIG. 7 is a heat block XRPD pattern for the crystalline form of chlorobippram hydrochloride in example 2;
FIG. 8 is a TGA graph of crystalline forms of clobippram hydrochloride in example 2;
FIG. 9 is a DSC chart of the crystalline form of clobippraml hydrochloride in example 2.
Detailed Description
The present invention will be described in detail below with reference to the drawings and the specific embodiments, which are not described in detail herein, but the embodiments of the present invention are not limited to the following embodiments.
1. Test instrument for experiments
X-ray powder diffractometer (XRPD)
The instrument model and test parameters of the XRPD are shown in table 1.
Table 1: XRPD instrument model and test parameters
2. Thermogravimetric analyzer (TGA) and Differential Scanning Calorimeter (DSC)
The instrument model and test parameters of TGA and DSC are shown in table 2.
Table 2: instrument model and test parameters of TGA and DSC
3. Ion chromatograph
Specific instruments and test parameters of the ion chromatograph are shown in table 3.
Table 3: instrument model and test parameters of ion chromatograph
4. Nuclear magnetic instrument (NMR)
The specific instrumentation and test parameters for Nuclear Magnetic Resonance (NMR) are shown in table 4.
Table 4: instrument model and test parameters of nuclear magnetic instrument
5. Analytical balance
The specific instruments and test parameters of the analytical balance are shown in Table 5.
Table 5: instrument model and test parameters of analytical balance
6. Counter ion used in salt sieve experiments and related information thereof
Table 6: counter ion used in salt sieve experiments and related information thereof
| Ion pair name | Molecular weight |
| Hydrochloric acid | 36.46 |
The application also provides a preparation method of the crystal form of the chlorpyrifos hydrochloride, which comprises the following steps: respectively forming a solution system of the chlorpyrifos and the hydrochloric acid in a soluble solvent, mixing the two systems to form a mixed solution containing flocculent precipitate, and crystallizing at the temperature of between 10 ℃ below zero and 50 ℃ to form a chlorpyrifos hydrochloride crystal form.
In some embodiments, the soluble solvent is preferably acetone. The crystallization temperature is preferably room temperature. The crystallization time is preferably 1 to 60 hours, and more preferably 48 hours. The mass mol ratio of the chlorpyrifos to the hydrochloric acid is 1:1.
Specific examples are provided below for illustration:
example 1
The preparation method of the PDE4 inhibitor clobiprofen prepared by Shanghai Meidixi biological medicine Co., ltd is referred to in China patent with the application number of CN201611164170.9, and is not described in detail herein. In the early stage of drug development, the preparation of the chlorpyrifos compound into salt is an important means for improving the physicochemical properties of the chlorpyrifos compound, such as solubility, crystallinity, hygroscopicity, melting point, solid state stability and the like. The screening of the salt forms of the medicaments is firstly started from the selection of the counter ions, then the crystallization conditions are selected to prepare the corresponding salt forms, and finally the final salt forms of the medicaments are determined according to the factors such as crystallinity, melting point, hygroscopicity, physicochemical stability, crystal forms and the like. To investigate the salt form of a fluroxypyr-meptyl compound, a sample of fluroxypyr-meptyl was first characterized in this example, and the characterization results are shown in table 7:
table 7: sample characterization results of chlorbippram
In the characterization results of table 7: 1) The characterization result of XRPD is shown in figure 2, and the chlorbippram is a crystalline substance and named as Form A; the peak list for the chlorpyrifos XRPD diffraction analysis is shown in table 8; 2) The characterization result of TGA is shown in figure 3, the chlorbippram is anhydrous, and the decomposition temperature is 319+/-3 ℃; the DSC characterization result is shown in the attached figure 4, and the melting point of the chlorpyrifos is 110+/-3 ℃; 3) The base ACD/LABS software calculated pKa (acid dissociation constant) values for chlorbippram (ZX-101) to be about 0.67; 4) The nuclear magnetic hydrogen profile in fig. 5 is shown as the chlorine bippram to be treated.
Table 8: list of XRPD diffraction analysis peaks for clobipland
The solubility of chlorpyrifos in various soluble solvents was also tested in this application and the test data are shown in table 9.
Table 9: solvent solubility data
| Solvent(s) | Solubility (mg/mL) |
| |
5～12.5 |
| Water and its preparation method | <1 |
| Acetone (acetone) | 25～50 |
Example 2
100mg of chlorpyrifos is taken, 1.8mL of acetone is added, the solution is stirred at room temperature, about 41mg of hydrochloric acid (1.1 equivalent) is dissolved in 0.2mL of acetone, the solution is dropwise added into the clarification system at room temperature, a large amount of flocculent precipitate starts to appear immediately, 3mL of acetone is added, the mixture is stirred overnight, the mixture is filtered under reduced pressure and filtered under suction, and the mixture is dried at room temperature for 24 hours under vacuum, so as to obtain 77mg of chlorpyrifos hydrochloride crystal form.
The XRPD diffractogram is shown in figure 6. And (3) displaying: crystalline form of clobiproflumilast hydrochloride.
The heat table XRPD diffractogram is shown in figure 7. And (3) displaying: the crystal form of the chlorpyrifos hydrochloride is heated to 50 ℃ to be unchanged, the sample is partially melted and decomposed when the temperature is raised to 115 ℃, the crystal state is obviously deteriorated, and the sample is completely melted when the temperature is raised to 150 ℃.
The TGA profile is shown in figure 8. And (3) displaying: the crystalline form of clobippram hydrochloride lost weight about 7.5% before 110 ℃ and had a decomposition temperature of 319 ℃.
The DSC pattern is shown in FIG. 9. And (3) displaying: the crystalline form of chlorpyrifos hydrochloride had a broad desolvation peak before 100 c, the melting point of the sample was about 105 c and 143 c, with melting accompanied by molecular desolvation of the hydrochloric acid.
Ion chromatographic signs show that the chloride ratio of the chlorpram compound and the hydrochloric acid form salts in a ratio of 1:1. The IC detection result has chloride ions of 1 hydrochloric acid molecule, and the sample obtained at this time is judged to be the crystal form of the chlorbippram hydrochloride.
The detection result shows that: the crystal form of the chlorpyrifos hydrochloride has lower stability temperature and the highest stability temperature is between 50 and 115 ℃.
The table 10 shows the peaks of XRPD diffraction analysis of the crystalline form of clorplan hydrochloride and the table 11-13 shows the peaks of XRPD diffraction analysis of the crystalline form of clorplan hydrochloride.
Table 10: XRPD diffraction analysis peak list of chlorpyrifos hydrochloride crystal form
Table 11: peak list of XRPD diffraction analysis of crystal form of clobiplan hydrochloride at room temperature with heat table
Table 12: peak list of XRPD diffraction analysis of 50 ℃ hot stage for crystalline form of flurbiproflumin hydrochloride
| 2-Theta | d | Height | I％ | Area | I％ |
| 6.822 | 12.9457 | 115 | 4.9 | 950 | 3.8 |
| 7.282 | 12.1301 | 69 | 2.9 | 1060 | 4.2 |
| 8.86 | 9.9721 | 74 | 3.1 | 2501 | 10 |
| 10.08 | 8.7678 | 64 | 2.7 | 151 | 0.6 |
| 10.859 | 8.1406 | 87 | 3.7 | 244 | 1 |
| 12.049 | 7.3392 | 69 | 2.9 | 798 | 3.2 |
| 13.443 | 6.5811 | 1254 | 53.2 | 12927 | 51.5 |
| 13.838 | 6.3939 | 140 | 5.9 | 3737 | 14.9 |
| 14.36 | 6.1627 | 2355 | 100 | 25110 | 100 |
| 15.379 | 5.7566 | 777 | 33 | 8398 | 33.4 |
| 16.324 | 5.4256 | 233 | 9.9 | 3118 | 12.4 |
| 16.778 | 5.2799 | 206 | 8.7 | 2189 | 8.7 |
| 20.443 | 4.3408 | 424 | 18 | 9055 | 36.1 |
| 20.821 | 4.2627 | 495 | 21 | 8691 | 34.6 |
| 22.261 | 3.9902 | 68 | 2.9 | 1154 | 4.6 |
| 23.397 | 3.7989 | 67 | 2.8 | 466 | 1.9 |
| 27.116 | 3.2858 | 136 | 5.8 | 1725 | 6.9 |
| 27.823 | 3.2039 | 84 | 3.6 | 1202 | 4.8 |
Table 13: peak list of 115 ℃ hot stage XRPD diffraction analysis of crystalline form of flurbiproflumin hydrochloride
Table 14 summarizes experimental data for the salt screen in the experiment described above for example 2 and using isopropyl alcohol solvent.
Table 14: salt sieve experimental data summarization
In conclusion, the crystal form of the chlorpyrifos hydrochloride is successfully synthesized through a drug salt screening experiment, physical and chemical properties of the chlorpyrifos compound, such as solubility, crystallinity, hygroscopicity, melting point, solid stability and the like, are improved, compared with the chlorpyrifos, the crystallinity of the chlorpyrifos hydrochloride crystal form is not greatly changed, salt polymorphism is not found, the stability temperature is low, and the highest stability temperature is between 50 and 115 ℃, so that the selection is provided for the final salification of the drug.
The above description is only one embodiment of the present invention, and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. The crystal form of the chlorpyrifos hydrochloride is characterized by having the structural formula:
2. the crystalline form of clobiproflumilast hydrochloride according to claim 1, wherein the X-ray powder diffraction pattern of the crystalline form of clobiproflumilast hydrochloride has characteristic peaks at least any five of diffraction angles 2Θ of 13.5 ± 0.2 °, 13.9 ± 0.2 °, 14.4 ± 0.2 °, 15.4 ± 0.2 °, 16.4 ± 0.2 °, 16.8 ± 0.2 °, 20.5 ± 0.2 °, 20.9 ± 0.2 °.
3. The crystalline form of clorplan hydrochloride according to claim 1, characterized by an X-ray powder diffraction pattern having characteristic peaks at the following diffraction angles 2Θ:4.2±0.2°, 6.5±0.2°, 6.9±0.2°, 8.9±0.2°, 12.1±0.2°, 12.9±0.2°, 13.5±0.2°, 13.9±0.2°, 14.4±0.2°, 15.4±0.2°, 15.8±0.2°, 16.4±0.2°, 16.8±0.2°, 17.8±0.2°, 18.7±0.2°, 20.5±0.2°, 20.9±0.2 °, 21.7±0.2°, 24.2±0.2°, 25.8±0.2 °, 27.1±0.2 °, 27.8±0.2°, 28.9±0.2°, 31.0.2 °, 32.9±0.2°, 34.0.2°, and 35.0.2 °.
4. The crystalline form of clobippram hydrochloride according to claim 1, wherein the differential scanning calorimeter of the crystalline form of clobippram hydrochloride has a first endothermic peak at 100-110 ℃ and a second endothermic peak at 140-146 ℃.
5. The crystalline form of clobippram hydrochloride according to claim 1, wherein the thermogravimetric analyzer of the crystalline form of clobippram hydrochloride loses weight 7.0 to 8.0% before 110 ℃ and has a decomposition temperature of 315 to 324 ℃.
6. The crystalline form of clobippram hydrochloride according to claim 1, wherein the solubility of the crystalline form of clobippram hydrochloride in water at 25 ℃ is < 0.05mg/ml.
7. The process for the preparation of crystalline forms of clobippram hydrochloride according to any one of claims 1 to 6, comprising the steps of:
respectively forming a solution system of the chlorpyrifos and the hydrochloric acid in a soluble solvent, mixing the two systems to form a mixture containing flocculent precipitate, and crystallizing at the temperature of between-10 and 50 ℃ to form a chlorpyrifos hydrochloride crystal form.
8. The process for the preparation of crystalline form of clobippram hydrochloride according to claim 7, wherein the soluble solvent is acetone.
9. The process for the preparation of crystalline forms of flurbiproflumilast hydrochloride according to claim 7, wherein the mass molar ratio of flurbiproflumilast to hydrochloric acid is 1:1.
10. The process for the preparation of crystalline form of clobippram hydrochloride according to claim 7, wherein the crystallization temperature is room temperature.
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