CN112480165A - A crystal form of polysubstituted diphenylethane phosphate sodium salt EBTP and preparation method thereof - Google Patents
A crystal form of polysubstituted diphenylethane phosphate sodium salt EBTP and preparation method thereof Download PDFInfo
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- -1 polysubstituted diphenylethane phosphate sodium salt Chemical class 0.000 title claims abstract description 52
- 239000013078 crystal Substances 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 44
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 238000001035 drying Methods 0.000 claims description 16
- 238000001914 filtration Methods 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- 229910001868 water Inorganic materials 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000012535 impurity Substances 0.000 claims description 5
- 238000001291 vacuum drying Methods 0.000 claims description 5
- 238000000862 absorption spectrum Methods 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 3
- 238000001228 spectrum Methods 0.000 claims description 3
- 238000010521 absorption reaction Methods 0.000 claims description 2
- 238000004537 pulping Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 abstract description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- ZTDFJUJEHIVCQF-UHFFFAOYSA-L CCOC(C=CC(CCC(C=C1OC)=CC(OC)=C1OC)=C1)=C1OP([O-])([O-])=O.[Na+].[Na+] Chemical compound CCOC(C=CC(CCC(C=C1OC)=CC(OC)=C1OC)=C1)=C1OP([O-])([O-])=O.[Na+].[Na+] ZTDFJUJEHIVCQF-UHFFFAOYSA-L 0.000 description 12
- 235000019441 ethanol Nutrition 0.000 description 12
- 239000000843 powder Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- 238000002329 infrared spectrum Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- UXDFUVFNIAJEGM-UHFFFAOYSA-N 2-methoxy-5-[2-(3,4,5-trimethoxyphenyl)ethyl]phenol Chemical compound C1=C(O)C(OC)=CC=C1CCC1=CC(OC)=C(OC)C(OC)=C1 UXDFUVFNIAJEGM-UHFFFAOYSA-N 0.000 description 3
- LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2r)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 description 3
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 description 3
- LGZKGOGODCLQHG-UHFFFAOYSA-N combretastatin Natural products C1=C(O)C(OC)=CC=C1CC(O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-UHFFFAOYSA-N 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 150000002989 phenols Chemical class 0.000 description 3
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical compound C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 description 3
- 235000021286 stilbenes Nutrition 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 3
- BSZXAFXFTLXUFV-UHFFFAOYSA-N 1-phenylethylbenzene Chemical class C=1C=CC=CC=1C(C)C1=CC=CC=C1 BSZXAFXFTLXUFV-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- XXMFJKNOJSDQBM-UHFFFAOYSA-N 2,2,2-trifluoroacetic acid;hydrate Chemical compound [OH3+].[O-]C(=O)C(F)(F)F XXMFJKNOJSDQBM-UHFFFAOYSA-N 0.000 description 1
- 229910017488 Cu K Inorganic materials 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- PMZXXNPJQYDFJX-UHFFFAOYSA-N acetonitrile;2,2,2-trifluoroacetic acid Chemical compound CC#N.OC(=O)C(F)(F)F PMZXXNPJQYDFJX-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229960005527 combretastatin A-4 phosphate Drugs 0.000 description 1
- WDOGQTQEKVLZIJ-WAYWQWQTSA-N combretastatin a-4 phosphate Chemical compound C1=C(OP(O)(O)=O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 WDOGQTQEKVLZIJ-WAYWQWQTSA-N 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000012844 infrared spectroscopy analysis Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
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- Molecular Biology (AREA)
Abstract
The invention relates to a crystal form A of polysubstituted diphenylethane phosphate sodium salt EBTP and a preparation method thereof, and the crystal form A has the following structure:
the X-ray powder diffraction pattern expressed in terms of 2 θ angle has characteristic peaks at 2.94 °, 5.94 °, 7.78 °, 8.32 °, 11.94 °, 15.00 °, 15.96 °, 18.02 °, 21.08 °, 22.48 °, and 23.63 °, with an error of ± 2 °. Compared with the prior art, the invention has the advantages of good crystallinity, strong chemical stability, simple preparation method and the like.
Description
Technical Field
The invention relates to the technical field of crystal form medicaments, in particular to a crystal form A of polysubstituted diphenylethane phosphate sodium salt and a preparation method thereof.
Background
Compared with combretastatin (CA4) and vanillin, the stilbene or diphenylethane fluoro derivative has obviously enhanced antitumor activity (CN107365248A, US2012/0046492A1, CN 103539642). Although these polysubstituted phenol (stilbene and diphenylethane) compounds have stronger antitumor activity, the polysubstituted phenol (stilbene and diphenylethane) compounds have the defects of poor water solubility, poor pharmacokinetics and low bioavailability as the drug development, phosphate groups are introduced on phenolic hydroxyl groups of the polysubstituted phenol compounds to prepare water-soluble phosphate salt prodrugs which have better drug forming properties, the phosphate sodium salt (CA4P) of CA4 has entered clinical three-phase research at present, and the development report of the erianin phosphate sodium salt is provided in China. 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate sodium salt (code number EBTP) is phosphate sodium salt of erianin structure modifier, and the phosphate group is introduced to prepare a water-soluble phosphate prodrug with better drug forming property; however, in the prior art, EBTP has poor chemical stability and poor crystallinity, so that the pharmacokinetics and bioavailability are not high.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide the A crystal form of the polysubstituted diphenylethane phosphate sodium salt EBTP and the preparation method thereof.
The purpose of the invention can be realized by the following technical scheme: a crystal form A of polysubstituted diphenyl ethane phosphate sodium salt EBTP has the following structure:
the X-ray powder diffraction pattern expressed in terms of 2 θ angle has distinct characteristic diffraction peaks at 2.94 °, 5.94 °, 7.78 °, 8.32 °, 11.94 °, 15.00 °, 15.96 °, 18.02 °, 21.08 °, 22.48 °, and 23.63 °, with an error of ± 2 °.
Further, the infrared absorption spectrum of the EBTP crystal form A measured by KBr tabletting is 3419cm-1、2935cm-1、2905cm-1、2845cm-1、1584cm-1、1514cm-1、1478cm-1、1458cm-1、1417cm-1、1234cm-1、1130cm-1、811cm-1、693cm-1And 572cm-1Has an absorption peak.
The differential scanning thermal spectrum of the A crystal form of the EBTP has an endothermic peak at 130-140 ℃.
The appearance of the A crystal form of the EBTP is a white crystal, and the impurity content is 0.1-0.4%.
A preparation method of the A crystal form of the polysubstituted diphenyl ethane phosphate sodium salt EBTP comprises the following steps:
(1) dissolving 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate (EBTH) in acetone or an alcohol solvent;
(2) adding sodium alkoxide or sodium hydroxide to form salt;
(3) crystallizing;
(4) filtering and drying to obtain the crystal form A of the EBTP.
Furthermore, the dosage of the alcohol solvent is generally required to be capable of completely dissolving the EBTH to form a uniform solution, the weight ratio of the EBTH to the alcohol solvent is generally 1: 2-8, and the dissolving temperature in the step (1) is 0-35 ℃, preferably 10-35 ℃; the molar ratio of the sodium alkoxide to the EBTH in the step (2) is 2-3: 1, and the molar ratio of the sodium hydroxide to the EBTH is 2-4: 1.
And (4) crystallizing at the temperature of 15-60 ℃ for 0.5-72 h. Preferably, the operation is to firstly preserve heat for 5-72 h at 35-60 ℃, then reduce the temperature to below 15 ℃ and preserve heat for 0.5-4 h, and crystallize.
The preparation method of the A crystal form of the polysubstituted diphenyl ethane phosphate sodium salt EBTP comprises the following steps:
(1) 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate is suspended and dissolved in water, and a proper amount of sodium alkoxide, sodium hydroxide or sodium carbonate is added for salification;
(2) evaporating to dryness, adding acetone or alcohol solvent, and heating for dissolving;
(3) cooling and crystallizing;
(4) filtering and drying to obtain the crystal form A of the EBTP.
The preparation method of the A crystal form of the polysubstituted diphenyl ethane phosphate sodium salt EBTP comprises the following steps:
(1) 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate is suspended and dissolved in water, and a proper amount of sodium alkoxide, sodium hydroxide or sodium carbonate is added for salification;
(2) evaporating to dryness, adding acetone or alcohol solvent, and pulping at room temperature;
(3) filtering and drying to obtain the crystal form A of the EBTP.
The alcohol solvent comprises methanol, ethanol or isopropanol, and preferably absolute methanol or absolute ethanol; the sodium alkoxide comprises sodium methoxide and sodium ethoxide; the drying is vacuum drying, and the vacuum drying temperature is 40-60 ℃.
The synthesis method of 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate (EBTH) refers to patent CN 110642885A and patent CN 101885738B.
The invention provides a crystal form A of polysubstituted diphenylethane phosphate sodium EBTP and a preparation method thereof, and the prepared crystal form has good crystallinity and strong chemical stability, improves the pharmacokinetics and bioavailability of the medicament and is more favorable for clinical application.
Compared with the prior art, the invention has the following advantages:
1. the A crystal form of the EBTP has good crystallinity, strong chemical stability, easy industrial production and stable and reliable quality;
2. the preparation method is simple, and the acetone or alcohol reagent is used as a solvent, so that the safety and operability are strong, and the cost is low;
3. the invention can provide research foundation for the development of more EBTP dosage forms;
4. compared with other synthesis methods, the invention has high crystal form yield and high purity;
5. the invention provides reference basis for the development of other disodium phosphate crystal forms.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of a crystal form A of a polysubstituted diphenylethane phosphate sodium salt EBTP of the invention;
FIG. 2 is a TG/DSC spectrum of a crystal form A of the sodium salt EBTP of polysubstituted diphenylethane phosphate;
FIG. 3 is an infrared spectrum of the A crystal form of the sodium salt of polysubstituted diphenylethane phosphate EBTP of the invention.
Detailed Description
The invention is described in detail below with reference to the figures and specific embodiments. The following examples are carried out on the premise of the technical scheme of the invention, and detailed embodiments and specific operation processes are given, but the scope of the invention is not limited to the following examples.
The reagents used in the following examples are commercially available and the drug substance is produced by Shanghai Huali biomedical corporation.
In the invention:
the term "XRPD" refers to powder X-ray diffraction;
the term "IR" refers to infrared spectroscopy;
the term "DSC" refers to differential scanning calorimetry;
the term "HPLC" refers to high performance liquid chromatography;
in the present invention, the operation is carried out at room temperature unless otherwise specified. The room temperature is 0-35 ℃, preferably 20-30 ℃.
The 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate (EBTH) used in the invention is synthesized and prepared by referring to a method of Chinese patent CN201910900508.X, and the purity of the crystal form A of the EBTP is detected by adopting a high pressure liquid phase (HPLC) method: column Diamonsil 5. mu. m C18(2), 250X 4.6 mm; wavelength 276 nm; the flow rate is 1.5 mL/min; the sample volume is 20 mu L; mobile phase A, 0.1% trifluoroacetic acid water, mobile phase B: 0.1% trifluoroacetic acid acetonitrile, all of which are HPLC area normalization purity, unless otherwise noted.
Example 1
Dissolving 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate (EBTH, 100g for short) in absolute ethyl alcohol (200mL), cooling in an ice bath, adding 34.65g of sodium ethoxide in batches, naturally heating to room temperature after the addition is finished, stirring and crystallizing for 24h, filtering, washing a solid by using a small amount of pre-cooled absolute ethyl alcohol, and drying in vacuum at 40 ℃ for 3h to obtain 105.27g of 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate sodium salt (EBTP), which is crystalline powder and is defined as crystal form A. The yield was 95.13% and the HPLC purity was 99.53%.
Example 2
Dissolving 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate (EBTH, 100g for short) in absolute ethyl alcohol (100mL), cooling in an ice bath, slowly adding 100mL of ethanol solution containing sodium ethoxide (34.65g), naturally raising the temperature to room temperature after the addition is finished, stirring for 24h, filtering, washing the solid with a small amount of precooled absolute ethyl alcohol, and drying in vacuum at 40 ℃ for 3h to obtain 106.35g of 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate sodium salt (EBTP), wherein the yield is 96.10% and the HPLC purity is 99.54%. The powder diffraction and infrared spectra were consistent with the results of example 1.
Example 3
Dissolving 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate (EBTH, 100g for short) in absolute ethyl alcohol (100mL), cooling in an ice bath, slowly adding 100mL of ethanol solution containing sodium hydroxide (21.5g), naturally raising the temperature to room temperature after adding, stirring for 24h, filtering, washing the solid with a small amount of precooled absolute ethyl alcohol, and drying in vacuum at 40 ℃ for 3h to obtain 105.35g of 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate sodium salt (EBTP), wherein the yield is 95.20 percent and the HPLC purity is 99.37 percent. The powder diffraction and infrared spectra were consistent with the results of example 1.
Example 4
Dissolving 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate (EBTH, 100g for short) in anhydrous methanol (200mL), cooling in an ice bath, adding sodium methoxide (21.5g) in batches, naturally heating to room temperature after the addition is finished, stirring for 2h, dropwise adding acetone (400mL), stirring for crystallization for 24h, filtering, washing a solid with a small amount of acetone which is pre-cooled, and drying in vacuum at 40 ℃ for 3h to obtain 105.69g of 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate sodium salt (EBTP), wherein the yield is 95.50% and the HPLC purity is 99.76%. The powder diffraction and infrared spectra were consistent with the results of example 1.
Example 5
Dissolving 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate (EBTH, 100g for short) in anhydrous methanol (100mL), cooling in an ice bath, slowly adding 100mL of methanol solution containing sodium hydroxide (21.5g), naturally raising the temperature to room temperature and stirring for 1h, dropwise adding acetone (400mL), stirring and crystallizing for 24h, filtering, washing the solid with a small amount of pre-cooled acetone, and drying in vacuum at 40 ℃ for 3h to obtain 106.13g of 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate sodium salt (EBTP), wherein the yield is 95.90% and the HPLC purity is 99.69%. The powder diffraction and infrared spectra were consistent with the results of example 1.
Example 6
Dissolving 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate (EBTH, 100g) in absolute methanol (100mL), cooling in an ice bath, slowly adding 100mL of methanol solution containing sodium hydroxide (21.5g), naturally raising the temperature to room temperature and stirring for 1h, dropwise adding absolute ethanol (400mL), stirring and crystallizing for 24h, filtering, washing the solid with a small amount of precooled absolute ethanol, and drying in vacuum at 40 ℃ for 3h to obtain 105.93g of 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate sodium salt (EBTP), wherein the yield is 95.72% and the HPLC purity is 99.86%. The powder diffraction and infrared spectra were consistent with the results of example 1.
Example 7
2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate (EBTH, 100.00g for short) is suspended and dissolved in 100mL deionized water, 21.50g of sodium hydroxide is added in batches under ice bath cooling, the solution is stirred, dissolved and evaporated to dryness under reduced pressure, the solution is added into absolute ethyl alcohol, the solution is heated and refluxed and dissolved, then ice bath cooling is carried out for crystallization for 24 hours, filtration is carried out, a filter cake is washed by a small amount of glacial ethanol, and vacuum drying is carried out at 40 ℃ to obtain 105.27g of 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate sodium salt (EBTP), the yield is 95.13%, and the HPLC purity is 99.53%. The powder diffraction and infrared spectra were consistent with the results of example 1.
Example 8
2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate (EBTH, 100.00g) is suspended and dissolved in 100mL deionized water, 21.50g of sodium hydroxide is added in batches under ice bath cooling, the solution is stirred, dissolved and cleaned, decompressed and evaporated to dryness, added into absolute ethyl alcohol, pulped for 24h at room temperature, filtered, a filter cake is washed by a small amount of glacial ethanol and dried in vacuum at 40 ℃ to obtain 106.38g of 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate sodium salt (EBTP), the yield is 96.13%, and the HPLC purity is 99.23%. The powder diffraction and infrared spectra were consistent with the results of example 1.
Example 9
2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate (EBTH, 100.00g for short) is suspended and dissolved in 100mL deionized water, 21.50g of sodium hydroxide is added in batches under ice bath cooling, the solution is stirred, dissolved and cleaned, decompressed and evaporated to dryness, added into isopropanol, pulped at room temperature for 24h, filtered, a filter cake is washed by a small amount of ice isopropanol and dried in vacuum at 40 ℃ to obtain 106.38g of 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate sodium salt (EBTP), the yield is 96.13%, and the HPLC purity is 99.23%. The powder diffraction and infrared spectra were consistent with the results of example 1.
Example 10
Dissolving 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate (EBTH, 100g for short) in absolute ethyl alcohol (200mL), cooling in an ice bath, adding 34.65g of sodium ethoxide in batches, heating in a water bath to 60 ℃, stirring for crystallization for 0.5h after adding, filtering, washing a solid with a small amount of precooled absolute ethyl alcohol, and drying in vacuum at 40 ℃ for 3h to obtain 105.67g of 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate sodium salt (EBTP), which is crystalline powder and is defined as crystal form A. The yield was 95.48% and the HPLC purity was 99.65%.
Example 11
Dissolving 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate (EBTH, 100g for short) in absolute ethyl alcohol (200mL), cooling in an ice bath, adding 34.65g of sodium ethoxide in batches, controlling the temperature of a cold well at 15 ℃, stirring for crystallization for 72h after the addition is finished, filtering, washing a solid by using a small amount of pre-cooled absolute ethyl alcohol, and drying in vacuum for 3h at 40 ℃ to obtain 106.42g of 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate sodium salt (EBTP), which is crystalline powder and is defined as crystal form A. The yield was 96.17% and the HPLC purity was 99.73%.
The crystal form a of EBTP prepared in the above examples was subjected to X-ray powder diffraction analysis (XPRD), differential scanning calorimetry analysis, and infrared spectroscopic analysis.
The model of an X-ray powder diffraction testing instrument is D/max2550 VB/PC; and (3) testing conditions are as follows: voltage, Current 40Kv,40mA, Stand-End Position 0-40 degrees 2 theta, Increment 0.02 degrees 2 theta, Time per step 0.5s, test environment: 23 ℃ and a humidity of 40% RH.
The X-ray powder diffraction pattern of form a of EBTP measured using Cu-K radiation at 2 θ is shown in fig. 1, where it can be seen that: 2.94, 5.94, 7.78, 8.32, 11.94, 15.00, 15.96, 18.02, 21.08, 22.48, 23.64, 24.12, 24.68, 25.42, 25.92, 27.22, 28.34, 30.32, 33.44, 36.62, 39.80, 40.14, 43.68 +/-0.2 degrees and the like, and the specific data are shown in table 1.
TABLE 1X-ray powder diffraction peaks
The infrared absorption spectrum measured by the KBr pellet is characterized by having an infrared absorption spectrum as shown in figure 3, and having characteristic peaks at the following positions: 3419. 2935, 2905, 2845, 1584, 1514, 1478, 1458, 1417, 1234, 1130, 811, 693 and 572cm-1。
As shown in FIG. 2, the differential analysis shows an endothermic peak at 135 ℃. The differential scanning calorimeter involved is STA 449F 3; the test method comprises the following steps: equulibrate at 20 deg.C, Ramp at 10.0 deg.C/min to 250.0 deg.C，N2Flow 40mL/min, aluminum pan, cover. Detecting the environment: 21 ℃ and a humidity of 50% RH.
The chemical stability test was performed on the crystal form a of EBTP prepared in the above examples 1 to 9, and the total impurity content was determined by an area normalization method, and the specific data is shown in table 2:
TABLE 2 Total impurity content variation under light conditions
As can be seen from the table above, the crystal form A of the prepared EBTP has better stability, and the total impurities are basically in the same level (within the error allowable range) under the conditions of illumination and 60 ℃.
The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.
Claims (10)
1. A crystal form A of polysubstituted diphenyl ethane phosphate sodium salt EBTP has the following structure:
the characteristic is that the X-ray powder diffraction pattern expressed by the angle of 2 theta has characteristic peaks at 2.94 degrees, 5.94 degrees, 7.78 degrees, 8.32 degrees, 11.94 degrees, 15.00 degrees, 15.96 degrees, 18.02 degrees, 21.08 degrees, 22.48 degrees and 23.63 degrees, and the error is +/-2 degrees.
2. The polysubstituted diphenylethane phosphoric acid of claim 1The crystal form A of the ester sodium salt EBTP is characterized in that the infrared absorption spectrum of the crystal form A of the EBTP measured by KBr tabletting is 3419cm-1、2935cm-1、2905cm-1、2845cm-1、1584cm-1、1514cm-1、1478cm-1、1458cm-1、1417cm-1、1234cm-1、1130cm-1、811cm-1、693cm-1And 572cm-1Has an absorption peak.
3. The crystal form A of the polysubstituted diphenyl ethane phosphate sodium salt EBTP according to claim 1, wherein the differential scanning thermal spectrum of the crystal form A of EBTP has an endothermic peak between 130 ℃ and 140 ℃.
4. The crystal form A of the polysubstituted diphenyl ethane phosphate sodium salt EBTP according to claim 1, wherein the appearance of the crystal form A of EBTP is white crystal with 0.1-0.4% of impurity content.
5. A method for preparing the crystal form a of polysubstituted diphenylethane phosphate sodium salt EBTP according to claim 1, comprising the steps of:
(1) dissolving 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate in acetone or an alcohol solvent;
(2) adding sodium alkoxide or sodium hydroxide to form salt;
(3) crystallizing;
(4) filtering and drying to obtain the crystal form A of the EBTP.
6. The method for preparing the crystal form A of the polysubstituted diphenylethane phosphate sodium salt EBTP according to claim 5, wherein the molar ratio of the 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate to the sodium alkoxide is 1: 2-3, and the molar ratio of the 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate to the sodium hydroxide is 1: 2-4.
7. The method for preparing the crystal form A of polysubstituted diphenyl ethane phosphate sodium salt EBTP according to claim 5, wherein the crystallization temperature in the step (3) is 15-60 ℃ and the time is 0.5-72 h.
8. A method for preparing the crystal form a of polysubstituted diphenylethane phosphate sodium salt EBTP according to claim 1, comprising the steps of:
(1) 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate is suspended in water and added with sodium hydroxide or sodium carbonate to form salt;
(2) evaporating to dryness, adding acetone or alcohol solvent, and heating for dissolving;
(3) cooling and crystallizing;
(4) filtering and drying to obtain the crystal form A of the EBTP.
9. A method for preparing the crystal form a of polysubstituted diphenylethane phosphate sodium salt EBTP according to claim 1, comprising the steps of:
(1) 2-ethoxy-5- (3,4, 5-trimethoxyphenethyl) phenol phosphate is suspended and dissolved in water, and sodium hydroxide or sodium carbonate is added for salification;
(2) evaporating to dryness, adding acetone or alcohol solvent, and pulping at room temperature;
(3) filtering and drying to obtain the crystal form A of the EBTP.
10. The method for preparing the crystal form A of the polysubstituted diphenyl ethane phosphate sodium salt EBTP according to any one of claims 5 to 9, wherein the alcohol solvent comprises methanol, ethanol or isopropanol, the drying is vacuum drying, and the vacuum drying temperature is 40-60 ℃.
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