CN116178277A - Crystal form of chlorpyrifos mesylate and preparation method thereof - Google Patents
Crystal form of chlorpyrifos mesylate and preparation method thereof Download PDFInfo
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- CN116178277A CN116178277A CN202111425157.5A CN202111425157A CN116178277A CN 116178277 A CN116178277 A CN 116178277A CN 202111425157 A CN202111425157 A CN 202111425157A CN 116178277 A CN116178277 A CN 116178277A
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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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Abstract
The invention relates to a crystal form of chlorpyripram mesylate and a preparation method thereof, wherein chlorpyripram is used as 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 mesylate is successfully synthesized through a drug salt screening experiment, 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 mesylate 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 up to 71%. 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 method for synthesizing the chlorbippramA feasible approach. 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, wherein the structural formula of the chlorpyrifos is as follows:
as a further refinement of the present application, the X-ray powder diffraction pattern of the crystalline form of clobiprofilan mesylate has characteristic peaks at least any five of diffraction angles 2θ of 4.9±0.2°, 11.5±0.2°, 13.8±0.2°, 14.7±0.2°, 15.4±0.2°, 16.0±0.2°, 17.3±0.2°, 17.6±0.2°, 19.6±0.2°, 20.4±0.2°, 21.3±0.2°, 22.1±0.2°, 23.1±0.2°, 24.6±0.2°, 29.6±0.2°.
As a further refinement of the present application, the X-ray powder diffraction pattern of the crystalline form of clobippramipexole mesylate has characteristic peaks at the following diffraction angles 2θ: 4.9.+ -. 0.2 °, 9.7.+ -. 0.2 °, 10.2.+ -. 0.2 °, 11.5.+ -. 0.2 °, 13.8.+ -. 0.2 °, 14.7.+ -. 0.2 °, 15.4.+ -. 0.2 °, 16.0.+ -. 0.2 °, 16.6.+ -. 0.2 °, 17.3.+ -. 0.2 °, 17.6.+ -. 0.2 °, 19.1.+ -. 0.2 °, 19.6.+ -. 0.2 °, 20.4.+ -. 0.2 °, 20.7.+ -. 0.2 °, 21.3.+ -. 0.2 °, 21.8.+ -. 0.2 °, 22.1.+ -. 0.2 °, 22.5.+ -. 0.2 °, 23.1.+ -. 0.2 °, 24.1.+ -. 0.2 °, 25.0.+ -. 0.2 °, 19.1.+ -. 0.2 °. 25.6.+ -. 0.2 °, 25.8.+ -. 0.2 °, 26.2.+ -. 0.2 °, 26.8.+ -. 0.2 °, 27.5.+ -. 0.2 °, 27.9.+ -. 0.2 °, 28.2.+ -. 0.2 °, 29.1.+ -. 0.2 °, 29.6.+ -. 0.2 °, 30.6.+ -. 0.2 °, 30.9.+ -. 0.2 °, 31.2.+ -. 0.2 °, 33.0.+ -. 0.2 °, 33.6.+ -. 0.2 °, 33.9.+ -. 0.2 °, 34.7.+ -. 0.2 °, 35.7.+ -. 0.2 °, 36.9.+ -. 0.2 °, 37.4.+ -. 0.2 °, 38.2.+ -. 0.2 °, 39.6.+ -. 0.2 °.
As a further improvement of the present application, the differential scanning calorimeter of the crystalline form of the clobippramipexole mesylate has an endothermic peak at 115 to 120 ℃.
As a further improvement of the application, the thermogravimetric analyzer of the crystal form of the chlorpyrifos mesylate loses weight by 0.35-0.45 percent before 120 ℃, and the decomposition temperature is 193-199 ℃.
As a further improvement of the application, the solubility of the crystal form of the chlorpyrifos mesylate in water at 25 ℃ is less than 0.05mg/ml.
In order to achieve the above purpose, the present application further provides a preparation method of the crystal form of the chlorpyrifos mesylate, which comprises the following steps: respectively forming a solution system of the chlorpyrifos and the methanesulfonic 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 mesylate 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 methanesulfonic 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 mesylate is successfully synthesized through a drug salt screening experiment, the physicochemical properties of the chlorpyrifos compound, such as solubility, crystallinity, hygroscopicity, melting point, solid stability and the like, are improved, 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 clobippramipexole mesylate in example 2;
FIG. 7 is a TGA profile of the crystalline form of clobippramipexole mesylate of example 2;
FIG. 8 is a DSC of the crystalline form of clobiprole mesylate of example 2;
FIG. 9 is a nuclear magnetic resonance spectrum of the crystalline form of chlorpyrifos mesylate of 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 diffraction spectrum (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 |
| Methanesulfonic acid | 96.11 |
The application also provides a preparation method of the crystal form of the chlorpyrifos mesylate, which comprises the following steps: respectively forming a solution system of the chlorpyrifos and the methanesulfonic 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 mesylate crystal form.
In a specific embodiment, the soluble solvent is preferably acetone and the crystallization temperature is preferably room temperature. Preferably, the mass molar ratio of the chlorpyrifos to the methanesulfonic acid is 1:1. The crystallization time is preferably 1 to 60 hours, and more preferably 48 hours.
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) Calculating the pKa (acid dissociation constant) value of the flurbiprofen (ZX-101) according to the ACD/LABS software 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: solubility data of chlorbippram in different solvents
| 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 39mg of methanesulfonic acid (1.1 equivalent) is dissolved in 0.2mL of acetone, the solution is added dropwise into the above clarification system at room temperature without precipitation, the solution is stirred overnight, white solid is precipitated, the solution is filtered under reduced pressure, and the solution is dried under vacuum at room temperature for 24 hours, thus 82mg of chlorpyrifos mesylate crystal form is obtained.
The XRPD diffractogram is shown in figure 6. And (3) displaying: crystalline form of clobiproflumilast mesylate.
The TGA profile is shown in figure 7. And (3) displaying: the crystal form of the chlorpyrifos mesylate loses weight by 0.4 percent before 120 ℃ and is anhydrous, and the decomposition temperature is about 196 ℃.
The DSC pattern is shown in FIG. 8. And (3) displaying: the crystalline form of clobippramipexole mesylate has a melting point of about 118 ℃.
The nuclear magnetic resonance hydrogen spectrum is shown in figure 9, and the chlorobippram compound and methanesulfonic acid form a 1:1 salt.
The detection results of the prepared samples show that: the solubility of the crystal form of the chlorpyrifos mesylate in water at 25 ℃ is less than 0.05mg/ml, and the crystal form of the chlorpyrifos mesylate is stable at high temperature and is not easy to absorb moisture.
The table 10 shows the peaks from XRPD diffraction analysis of the crystalline form of clorplan mesylate.
Table 10: XRPD diffraction analysis peak list of crystal form of chlorpyrifos mesylate
Table 11 summarizes experimental data for the salt screen in the experiment described above in example 2 with isopropanol as the solvent.
Table 11: salt sieve experimental data summarization
In conclusion, the crystal form of the chlorpyrifos mesylate is successfully synthesized through a drug salt screening experiment, physical and chemical properties of the chlorpyrifos compound, such as solubility, crystallinity, hygroscopicity, melting point and solid stability, are improved, compared with the chlorpyrifos, the crystal form of the chlorpyrifos mesylate has little change in crystallinity after salifying, no salt polymorphism is found, the melting point is slightly improved, moisture absorption is not easy, obvious change is not observed in solubility, and a choice is provided for the final salifying 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 mesylate is characterized by comprising the following structural formula:
2. the crystalline form of clobiprofilan mesylate according to claim 1, wherein the X-ray powder diffraction pattern of the crystalline form of clobiprofilan mesylate has characteristic peaks at least any five of diffraction angles 2Θ of 4.9±0.2°, 11.5±0.2°, 13.8±0.2°, 14.7±0.2°, 15.4±0.2°, 16.0±0.2°, 17.3±0.2°, 17.6±0.2°, 19.6±0.2°, 20.4±0.2°, 21.3±0.2°, 22.1±0.2°, 23.1±0.2°, 24.6±0.2°, 29.6±0.2°.
3. The crystalline form of clobippramipexole mesylate according to claim 1, wherein the X-ray powder diffraction pattern of the crystalline form of clobippramipexole mesylate has characteristic peaks at the following diffraction angles 2Θ: 4.9.+ -. 0.2 °, 9.7.+ -. 0.2 °, 10.2.+ -. 0.2 °, 11.5.+ -. 0.2 °, 13.8.+ -. 0.2 °, 14.7.+ -. 0.2 °, 15.4.+ -. 0.2 °, 16.0.+ -. 0.2 °, 16.6.+ -. 0.2 °, 17.3.+ -. 0.2 °, 17.6.+ -. 0.2 °, 19.1.+ -. 0.2 °, 19.6.+ -. 0.2 °, 20.4.+ -. 0.2 °, 20.7.+ -. 0.2 °, 21.3.+ -. 0.2 °, 21.8.+ -. 0.2 °, 22.1.+ -. 0.2 °, 22.5.+ -. 0.2 °, 23.1.+ -. 0.2 °, 24.1.+ -. 0.2 °, 25.0.+ -. 0.2 °, 19.1.+ -. 0.2 °. 25.6.+ -. 0.2 °, 25.8.+ -. 0.2 °, 26.2.+ -. 0.2 °, 26.8.+ -. 0.2 °, 27.5.+ -. 0.2 °, 27.9.+ -. 0.2 °, 28.2.+ -. 0.2 °, 29.1.+ -. 0.2 °, 29.6.+ -. 0.2 °, 30.6.+ -. 0.2 °, 30.9.+ -. 0.2 °, 31.2.+ -. 0.2 °, 33.0.+ -. 0.2 °, 33.6.+ -. 0.2 °, 33.9.+ -. 0.2 °, 34.7.+ -. 0.2 °, 35.7.+ -. 0.2 °, 36.9.+ -. 0.2 °, 37.4.+ -. 0.2 °, 38.2.+ -. 0.2 °, 39.6.+ -. 0.2 °.
4. The crystalline form of clobippramipexole mesylate according to claim 1, wherein the differential scanning calorimeter of the crystalline form of clobippramipexole mesylate has an endothermic peak at 115-120 ℃.
5. The crystalline form of clobippramipexole mesylate according to claim 1, wherein the thermogravimetric analyzer of the crystalline form of clobippramipexole mesylate loses weight 0.35 to 0.45% before 120 ℃ and has a decomposition temperature of 193 to 199 ℃.
6. The crystalline form of clobippram mesylate according to claim 1, wherein the solubility of the crystalline form of clobippram mesylate in water at 25 ℃ is < 0.05mg/ml.
7. The process for the preparation of the crystalline form of clobipplace mesylate according to any one of claims 1 to 6, comprising the steps of:
respectively forming a solution system of the chlorpyrifos and the methanesulfonic 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 mesylate crystal form.
8. The process for the preparation of crystalline form of clobippramipexole mesylate according to claim 7, wherein the soluble solvent is acetone.
9. The method for preparing the crystal form of the chlorpyrifos mesylate according to claim 8, wherein the mass molar ratio of the chlorpyrifos to the methanesulfonic acid is 1:1.
10. The process for the preparation of the crystalline form of clobipplace mesylate according to claim 9, wherein the crystallization temperature is room temperature.
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| CN202111425157.5A CN116178277A (en) | 2021-11-27 | 2021-11-27 | Crystal form of chlorpyrifos mesylate and preparation method thereof |
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