CN117720413A - 2, 4-dichlorophenoxyacetic acid eutectic and preparation method and application thereof - Google Patents
2, 4-dichlorophenoxyacetic acid eutectic and preparation method and application thereof Download PDFInfo
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- CN117720413A CN117720413A CN202311711866.9A CN202311711866A CN117720413A CN 117720413 A CN117720413 A CN 117720413A CN 202311711866 A CN202311711866 A CN 202311711866A CN 117720413 A CN117720413 A CN 117720413A
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- dichlorophenoxyacetic acid
- proline
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- 239000005631 2,4-Dichlorophenoxyacetic acid Substances 0.000 title claims abstract description 114
- HXKWSTRRCHTUEC-UHFFFAOYSA-N 2,4-Dichlorophenoxyaceticacid Chemical compound OC(=O)C(Cl)OC1=CC=C(Cl)C=C1 HXKWSTRRCHTUEC-UHFFFAOYSA-N 0.000 title claims abstract description 111
- 230000005496 eutectics Effects 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 229930182821 L-proline Natural products 0.000 claims abstract description 75
- 229960002429 proline Drugs 0.000 claims abstract description 75
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims abstract description 73
- 239000007787 solid Substances 0.000 claims abstract description 19
- 239000013078 crystal Substances 0.000 claims description 74
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 238000000498 ball milling Methods 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 230000003993 interaction Effects 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 239000005648 plant growth regulator Substances 0.000 claims description 3
- 230000005855 radiation Effects 0.000 claims description 3
- 238000012546 transfer Methods 0.000 claims description 3
- 239000004009 herbicide Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 238000000967 suction filtration Methods 0.000 claims description 2
- OVSKIKFHRZPJSS-UHFFFAOYSA-N 2,4-D Chemical compound OC(=O)COC1=CC=C(Cl)C=C1Cl OVSKIKFHRZPJSS-UHFFFAOYSA-N 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- OVSKIKFHRZPJSS-DOMIDYPGSA-N 2-(2,4-dichlorophenoxy)acetic acid Chemical compound OC(=O)[14CH2]OC1=CC=C(Cl)C=C1Cl OVSKIKFHRZPJSS-DOMIDYPGSA-N 0.000 abstract description 3
- 239000004480 active ingredient Substances 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 2
- 239000001257 hydrogen Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 14
- 239000012528 membrane Substances 0.000 description 11
- 238000000113 differential scanning calorimetry Methods 0.000 description 10
- 239000003517 fume Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- 238000007789 sealing Methods 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- 238000010998 test method Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 6
- 239000011521 glass Substances 0.000 description 5
- 238000010586 diagram Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000009878 intermolecular interaction Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- -1 4' -bipyridine Chemical compound 0.000 description 1
- UHBAPGWWRFVTFS-UHFFFAOYSA-N 4,4'-dipyridyl disulfide Chemical compound C=1C=NC=CC=1SSC1=CC=NC=C1 UHBAPGWWRFVTFS-UHFFFAOYSA-N 0.000 description 1
- SPKCEACOZLCRSV-UHFFFAOYSA-N 4-(2-pyridin-4-ylethynyl)pyridine Chemical group C1=NC=CC(C#CC=2C=CN=CC=2)=C1 SPKCEACOZLCRSV-UHFFFAOYSA-N 0.000 description 1
- OGNCVVRIKNGJHQ-UHFFFAOYSA-N 4-(3-pyridin-4-ylpropyl)pyridine Chemical compound C=1C=NC=CC=1CCCC1=CC=NC=C1 OGNCVVRIKNGJHQ-UHFFFAOYSA-N 0.000 description 1
- MGFJDEHFNMWYBD-OWOJBTEDSA-N 4-[(e)-2-pyridin-4-ylethenyl]pyridine Chemical group C=1C=NC=CC=1/C=C/C1=CC=NC=C1 MGFJDEHFNMWYBD-OWOJBTEDSA-N 0.000 description 1
- ALYNCZNDIQEVRV-PZFLKRBQSA-N 4-amino-3,5-ditritiobenzoic acid Chemical compound [3H]c1cc(cc([3H])c1N)C(O)=O ALYNCZNDIQEVRV-PZFLKRBQSA-N 0.000 description 1
- RTLUPHDWSUGAOS-UHFFFAOYSA-N 4-iodopyridine Chemical compound IC1=CC=NC=C1 RTLUPHDWSUGAOS-UHFFFAOYSA-N 0.000 description 1
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960000794 baclofen Drugs 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 230000008635 plant growth Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 1
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000002076 thermal analysis method Methods 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
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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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A40/00—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production
- Y02A40/10—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production in agriculture
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- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a 2, 4-dichlorophenoxyacetic acid eutectic, a preparation method and application thereof, wherein the 2, 4-dichlorophenoxyacetic acid eutectic is a eutectic formed by 2, 4-dichlorophenoxyacetic acid and L-proline according to a molar ratio of 1:1; the 2, 4-dichlorophenoxyacetic acid eutectic is a monoclinic system, and the lattice parameters are as follows: the space group is p121= 9.8940 (4), b= 5.1944 (2), c= 14.4050 (6), alpha=90, beta= 104.883 (4), gamma=90, unit cell volumeThe inventionThe 2, 4-dichlorophenoxyacetic acid and the L-proline eutectic molecule are connected through hydrogen bond, the formation of the pharmaceutical eutectic does not destroy the pharmaceutical active ingredients of the 2, 4-dichlorophenoxyacetic acid, the solid structure is changed, and the solubility is improved by 1.92 times.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical co-crystals, and particularly relates to a 2, 4-dichlorophenoxyacetic acid co-crystal and a preparation method and application thereof.
Background
2, 4-dichlorophenoxyacetic acid has both activities of stimulating and inhibiting plant growth, and its herbicidal effect is a manifestation of a strong inhibiting effect. There are two main reports of the crystal forms of 2, 4-dichlorophenoxyacetic acid at present, and in 1976 Smith, G.etc. the single crystal structure of the crystal form I of 2, 4-dichlorophenoxyacetic acid at 295K is reported (J.chem. Soc., perkin Trans.1976,7, 791-792), and in 2022 we report the crystal form II (Cryst. Growth Des.,2022,22,3680-3687). Ligands reported in the literature to form co-crystals or salts with 2, 4-dichlorophenoxyacetic acid are currently: 2-aminopyrimidine, 4' -bipyridine, baclofen, 4-aminobenzoic acid, imidazole, 2-aminopyridine, 3-aminopyridine, isonicotinamide, pyrazinamide, pyrazine, 4-iodopyridine, triethylenediamine, 2' -bipyridine, 1, 2-trans-1, 2-bis (4-pyridyl) ethylene, 1, 2-bis (4-pyridyl) acetylene, 1, 3-bis (-4-pyridyl) -propane, 4' -azobispyridine, 4- (4-pyridyldisulfanyl) pyridine.
The low dose of 2, 4-dichlorophenoxyacetic acid is a plant growth regulator, and the requirements of different plants and different parts of the same plant on the dosage are strict and inconsistent, so that the development of various eutectic crystals or salts capable of regulating the solubility of the 2, 4-dichlorophenoxyacetic acid is necessary.
Disclosure of Invention
Aiming at the current requirement on dosage forms with different solubilities of 2, 4-dichlorophenoxyacetic acid, the invention provides a novel eutectic crystal of 2, 4-dichlorophenoxyacetic acid and L-proline, and the solubility of the novel eutectic crystal is improved by about 1.92 times compared with that of a stable crystal form I of 2, 4-dichlorophenoxyacetic acid.
The invention aims to provide a method for preparing a novel eutectic of 2, 4-dichlorophenoxyacetic acid and L-proline.
In order to achieve the above purpose, the invention provides a 2, 4-dichlorophenoxyacetic acid and L-proline eutectic, wherein the 2, 4-dichlorophenoxyacetic acid eutectic is a eutectic formed by 2, 4-dichlorophenoxyacetic acid and L-proline according to a molar ratio of 1:1;
the 2, 4-dichlorophenoxyacetic acid eutectic is a monoclinic system, and the lattice parameters are as follows: the space group is p121.1, a= 9.8940 (4),
b= 5.1944 (2), c= 14.4050 (6), alpha=90, beta= 104.883 (4), gamma=90, unit cell volume
Preferably, using Cu-kα radiation, the 2, 4-dichlorophenoxyacetic acid co-crystal has an X-ray powder diffraction pattern expressed in diffraction angles 2θ with characteristic peaks at 12.54+ -0.2 °, 13.52+ -0.2 °, 17.62+ -0.2 °, 21.00+ -0.2 °, 24.68 + -0.2 °, 25.60 + -0.2 °, 26.42+ -0.2 °, 27.20+ -0.2 °, 30.88 + -0.2 ° and 32.28+ -0.2 °.
Preferably, using Cu-kα radiation, the 2, 4-dichlorophenoxyacetic acid co-crystal also has characteristic peaks at 18.20+ -0.2 °, 18.86+ -0.2 °, 19.38+ -0.2 °, 28.48+ -0.2 °, 29.46+ -0.2 ° and 30.10+ -0.2 ° in an X-ray powder diffraction pattern expressed in diffraction angle 2θ.
The X-ray powder diffraction pattern of the co-crystal of 2, 4-dichlorophenoxyacetic acid and L-proline is shown in figure 1, which is obtained by using a D/MAX-2500X-ray diffractometer (Rigaku) diffractometer. The measurement conditions were as follows: cu K alpha radiation100mA and 40kV light source, step size 0.02 degree scanning speed 8 degree/min, scanning range 2-40 degree, room temperature 20 ℃.
The invention adopts a Rigaku Saturn 70CCD diffractometer single crystal diffractometer to measure the co-concentration of 2, 4-dichlorophenoxyacetic acid and L-proline at 113KSingle crystal structure of crystal, using graphite monochromator Mo K alpha rayData was collected in a multi-layer scan format, and data recovery and absorption correction was performed using the ShelXL (Sheldrick, 2015) package. The space group is determined according to the extinction law of the system and verified by the refined result. All crystal structures were corrected using a ShelXL (sheldick, 2015) method, directly, with the ShelXL-2018/3 (sheldick 2018) program correcting the structure with a full matrix least squares method, and the hydrogen atom coordinates were added by theoretical calculation. Obtaining a eutectic crystal structure of 2, 4-dichlorophenoxyacetic acid and L-proline, wherein the mole ratio of 2, 4-dichlorophenoxyacetic acid to L-proline in the eutectic structure of 2, 4-dichlorophenoxyacetic acid and L-proline is 1:1, the unit cell is monoclinic, the space group is P1 21 1, a= 9.8940 (4), b= 5.1944 (2), c= 14.4050 (6), alpha=90, beta= 104.883 (4), gamma=90, unit cell volume>The crystal structure is shown in figure 2, the unit cell stacking is shown in figure 3, 2, 4-dichlorophenoxyacetic acid and L-proline molecules are connected through N-H-O and C-H-O intermolecular interactions to form one-dimensional chains, adjacent chains are stacked and extended through O-H-O and C-H-Cl interactions, in addition, proton transfer occurs in the L-proline molecules, and hydroxyl H in the L-proline carboxylic acid group is transferred to N atoms in L-proline. The crystallographic parameters of the eutectic crystal of 2, 4-dichlorophenoxyacetic acid and L-proline are shown in Table 1 below.
TABLE 1
The thermal analysis chart of the 2, 4-dichlorophenoxyacetic acid and L-proline eutectic crystal is shown in fig. 4, wherein an endothermic peak is at an onset point 112.72 ℃, which is completely different from a 2, 4-dichlorophenoxyacetic acid melting peak onset point 139.90 ℃ and an L-proline melting peak onset point 226.33 ℃, and the eutectic crystal is also proved to be obtained.
The solubility of the co-crystal of 2, 4-dichlorophenoxyacetic acid and L-proline according to the invention is compared with that of stable form I of 2, 4-dichlorophenoxyacetic acid as shown in figure 5. The excess 2, 4-dichlorophenoxyacetic acid and L-proline co-crystal powder were suspended in an aqueous solution, stirred at constant temperature of 25℃for 24 hours, left to stand for 1 hour, and the supernatant was taken and filtered with a filter membrane. The solubility was determined by high performance liquid chromatography using a Waters 2695 series HPLC with Agilent extension C18 column (250X 4.6mm,5 μm) at 30 ℃. The UV detection wavelength of 2,4-D was 284nm. The mobile phase of HPLC was a 65:35 (V: V) mixture of methanol and 0.2% H3PO4 (water). The flow rate was set to 1.0mL min -1 The residence time of 2,4-D was 5.3min. A standard curve was obtained using a series of 2,4-D solutions of known concentrations, as shown in fig. 6. The eutectic solubility of the finally obtained 2, 4-dichlorophenoxyacetic acid and L-proline is 0.98mg/mL, the stable crystal form I of the 2, 4-dichlorophenoxyacetic acid has the solubility of 0.51mg/mL, the eutectic of the 2, 4-dichlorophenoxyacetic acid and L-proline plays a role in regulating the solubility, and the solubility is improved by 1.92 times compared with the crystal form I.
The second purpose of the invention is to provide a preparation method of the eutectic of 2, 4-dichlorophenoxyacetic acid and L-proline, which adopts a solution method and comprises the following steps:
2, 4-dichlorophenoxyacetic acid and L-proline are mixed under the stirring condition according to the mol ratio of 1: and 1, dissolving in an organic solvent, filtering to obtain filtrate, and volatilizing and crystallizing the obtained filtrate to obtain the 2, 4-dichlorophenoxyacetic acid eutectic.
The organic solvent comprises methanol or ethanol;
preferably, the organic solvent is added in an amount of 10 to 30g based on 2.21g of 2, 4-dichlorophenoxyacetic acid;
preferably, the preparation method further comprises the step of carrying out suction filtration on the mixture obtained by the volatilization and crystallization, and retaining 2, 4-dichlorophenoxyacetic acid eutectic solid.
The second purpose of the invention is to provide a preparation method of the eutectic of 2, 4-dichlorophenoxyacetic acid and L-proline, which adopts a ball milling method and comprises the following steps:
2, 4-dichlorophenoxyacetic acid and L-proline are mixed according to a mol ratio of 1:1, ball milling under the action of an organic solvent to obtain the 2, 4-dichlorophenoxyacetic acid eutectic.
Preferably, the ball milling is performed in a ball milling tank;
preferably, the organic solvent is methanol or ethanol;
preferably, 20-40. Mu.L of the organic solvent is added dropwise, based on 1g of 2, 4-dichlorophenoxyacetic acid;
preferably, the frequency of the ball milling is 10-40Hz, and the time of the ball milling is 20-60 minutes.
It is a further object of the present invention to provide the use of a co-crystal of 2, 4-dichlorophenoxyacetic acid as defined in one of the objects for the preparation of herbicides or plant growth regulators.
As described above, the excellent effects of the present invention are that:
the 2, 4-dichlorophenoxyacetic acid and the L-proline eutectic molecule are connected through hydrogen bonds, the formation of the pharmaceutical eutectic does not destroy the pharmaceutical active ingredients of the 2, 4-dichlorophenoxyacetic acid, the solid structure is changed, and the possibility of adjusting the solubility of the pharmaceutical is provided.
The preparation method is simple, and the monocrystal of the eutectic of the 2, 4-dichlorophenoxyacetic acid and the L-proline can be obtained through a volatilization crystallization experiment.
Drawings
FIG. 1 is an X-ray powder diffraction Pattern (PXRD) of the co-crystal of 2, 4-dichlorophenoxyacetic acid and L-proline prepared in example 1;
FIG. 2 is a diagram showing the structure of a monomer obtained by single crystal analysis of the eutectic of 2, 4-dichlorophenoxyacetic acid and L-proline obtained in example 1;
FIG. 3 is a unit cell stacking diagram of the co-crystals of 2, 4-dichlorophenoxyacetic acid and L-proline prepared in example 1;
FIG. 4 is a DSC of the co-crystal of 2, 4-dichlorophenoxyacetic acid and L-proline prepared in example 1;
FIG. 5 is a comparison of the solubility of the co-crystals of 2, 4-dichlorophenoxyacetic acid and L-proline prepared in example 1 with the solubility of stable form I;
FIG. 6 is a standard curve of peak area-concentration for measuring 2, 4-dichlorophenoxyacetic acid content by high performance liquid chromatography.
Detailed Description
Other advantages and effects of the present invention will become apparent to those skilled in the art from the following disclosure, which describes the embodiments of the present invention with reference to specific examples. The invention may be practiced or carried out in other embodiments and details within the scope and range of equivalents of the specific features disclosed herein are capable of modifications and variations in various respects, all without departing from the spirit of the invention.
Example 1
2.21g of 2, 4-dichlorophenoxyacetic acid and 1.15g of L-proline are dissolved in 10g of ethanol solution, the solution is stirred and dissolved at room temperature, a 0.22 mu m filter membrane is used for filtering, a clear solution is placed in a 30mL glass bottle, a sealing membrane is used for sealing, a plurality of holes are punched through needles after the sealing membrane is sealed, the solution is placed in a fume hood for slow volatilization and crystallization, a solid is obtained after a period of time, the solid is filtered and separated, and the solid is dried to constant weight under vacuum in the fume hood, so that the eutectic crystal of the 2, 4-dichlorophenoxyacetic acid and the L-proline is obtained.
The co-crystal of 2, 4-dichlorophenoxyacetic acid and L-proline obtained in example 1 was characterized by X-ray powder diffraction (abbreviated as "XRD"), and the spectrum is shown in FIG. 1. Characteristic peaks of 2θ (±0.200°) in the XRD pattern are located at 12.54, 13.52, 17.62, 21.00, 24.68, 25.60, 26.42, 27.20, 30.88 and 32.28 degrees. Specifically, the diffraction patterns of the co-crystals of 2, 4-dichlorophenoxyacetic acid and L-proline in FIG. 1 are summarized in Table 2:
TABLE 2
| 2θ(°) | Relative intensity (%) | 2θ(°) | Relative intensity (%) |
| 12.54 | 36.2 | 25.60 | 56.9 |
| 13.52 | 22.4 | 26.42 | 40.2 |
| 17.62 | 60.9 | 28.48 | 22.4 |
| 18.12 | 24.1 | 29.46 | 21.3 |
| 19.38 | 34.5 | 30.10 | 17.2 |
| 21.00 | 71.8 | 30.88 | 18.4 |
| 24.68 | 100 | 32.28 | 25.3 |
The monomer structure diagram of the co-crystal of 2, 4-dichlorophenoxyacetic acid and L-proline obtained by single crystal analysis is shown in figure 2. FIG. 3 is a unit cell stacking diagram of the co-crystal of 2, 4-dichlorophenoxyacetic acid and L-proline in this example, and it can be seen from FIG. 3: the 2, 4-dichlorophenoxyacetic acid and the L-proline molecule are connected through the intermolecular interaction of N-H-O and C-H-O to form a one-dimensional chain, the adjacent chains are piled up and extended through the intermolecular interaction of O-H-O and C-H-Cl, in addition, proton transfer occurs in the L-proline molecule, and hydroxyl H in the carboxylic acid group of the L-proline is transferred to N atoms in the L-proline.
FIG. 4 shows a differential scanning calorimetric analysis (DSC) of a co-crystal of 2, 4-dichlorophenoxyacetic acid and L-proline in this example, and shows that the set point 112.72 ℃ is an endothermic peak, which is completely different from the set point 139.90 ℃ of the melting peak of 2, 4-dichlorophenoxyacetic acid and the set point 226.33 ℃ of the melting peak of L-proline, and also proves that a co-crystal is obtained.
FIG. 5 shows that the solubility of 2, 4-dichlorophenoxyacetic acid in the co-crystal of 2, 4-dichlorophenoxyacetic acid and L-proline in this example is 0.98mg/mL, while the solubility of 2, 4-dichlorophenoxyacetic acid in the stable crystal form I is 0.51mg/mL, and the co-crystal of 2, 4-dichlorophenoxyacetic acid and L-proline has the effect of adjusting the solubility and is improved by 1.92 times compared with the crystal form I.
Example 2
2.21g of 2, 4-dichlorophenoxyacetic acid and 1.15g L-proline are dissolved in 20g of ethanol solution, the solution is stirred and dissolved at room temperature, a 0.22 mu m filter membrane is used for filtering, clear liquid is placed in a 50mL glass bottle, a sealing membrane is used for sealing, a plurality of holes are punched through needles after the sealing membrane is placed in a fume hood for slow volatilization and crystallization, a solid is obtained after a period of time, the solid is filtered and separated, and the solid is dried to constant weight under vacuum in the fume hood, so that the 2, 4-dichlorophenoxyacetic acid and L-proline eutectic is obtained.
The same test method as in example 1 was used for the co-crystal of 2, 4-dichlorophenoxyacetic acid and L-proline obtained in example 2, and the obtained product was the same co-crystal as in example 1, and the DSC spectrum was also substantially the same as in example 1; the solubility of the compound is improved by about 1.92 times compared with that of the crystal form I.
Example 3
2.21g of 2, 4-dichlorophenoxyacetic acid and 1.15g L-proline are dissolved in 10g of ethanol solution, the solution is stirred and dissolved at room temperature, a 0.22 mu m filter membrane is used for filtering, clear liquid is placed in a 30mL glass bottle, the clear liquid is placed in a fume hood for volatilizing and crystallizing, solid is obtained after a period of time, filtering and separating are carried out, and the solid is dried to constant weight in vacuum under the fume hood, thus obtaining the eutectic of 2, 4-dichlorophenoxyacetic acid and L-proline.
The same test method as in example 1 was used for the co-crystal of 2, 4-dichlorophenoxyacetic acid and L-proline obtained in example 3, and the obtained product was the same co-crystal as in example 1, and the DSC spectrum was also substantially the same as in example 1; the solubility of the compound is improved by about 1.92 times compared with that of the crystal form I.
Example 4
2.21g of 2, 4-dichlorophenoxyacetic acid and 1.15g L-proline are dissolved in 10g of methanol solution, the solution is stirred and dissolved at room temperature, a 0.22 mu m filter membrane is used for filtering, clear liquid is placed in a 30mL glass bottle, a sealing membrane is used for sealing, a plurality of holes are punched through a needle and placed in a fume hood for slow volatilization and crystallization, a solid is obtained after a period of time, filtering and separation are carried out, and the solid is dried to constant weight under vacuum under the fume hood, thus obtaining the eutectic of the 2, 4-dichlorophenoxyacetic acid and the L-proline.
The same test method as in example 1 was used for the co-crystal of 2, 4-dichlorophenoxyacetic acid and L-proline obtained in example 4, and it was found that the obtained product was the same co-crystal as in example 1, and the DSC spectrum was also substantially the same as in example 1; the solubility of the compound is improved by about 1.92 times compared with that of the crystal form I.
Example 5
2.21g of 2, 4-dichlorophenoxyacetic acid and 1.15g L-proline are dissolved in 30g of methanol solution, the solution is stirred and dissolved at room temperature, a 0.22 mu m filter membrane is used for filtering, clear liquid is placed in a 30mL glass bottle, the clear liquid is placed in a fume hood for volatilizing and crystallizing, solid is obtained after a period of time, filtering and separating are carried out, and the solid is dried to constant weight in vacuum under the fume hood, thus obtaining the eutectic of 2, 4-dichlorophenoxyacetic acid and L-proline.
The same test method as in example 1 was used for the co-crystal of 2, 4-dichlorophenoxyacetic acid and L-proline obtained in example 5, and the obtained product was the same co-crystal as in example 1, and the DSC spectrum was also substantially the same as in example 1; the solubility of the compound is improved by about 1.92 times compared with that of the crystal form I.
Example 6
2.21g of 2, 4-dichlorophenoxyacetic acid and 1.15g L-proline are evenly mixed and placed in a ball mill, ball milling is carried out for 30 minutes at the frequency of 20Hz, and then solids are poured out, thus obtaining the eutectic of the 2, 4-dichlorophenoxyacetic acid and the L-proline.
The same test method as in example 1 was used for the co-crystal of 2, 4-dichlorophenoxyacetic acid and L-proline obtained in example 6, and the obtained product was the same co-crystal as in example 1, and the DSC spectrum was also substantially the same as in example 1; the solubility of the compound is improved by about 1.92 times compared with that of the crystal form I.
Example 7
2.21g of 2, 4-dichlorophenoxyacetic acid and 1.15g L-proline are evenly mixed and placed in a ball mill, 20 mu L of ethanol solvent is added dropwise, ball milling is carried out for 30 minutes at the frequency of 20Hz, and then the solid is poured out, thus obtaining the eutectic of the 2, 4-dichlorophenoxyacetic acid and the L-proline.
The same test method as in example 1 was used for the co-crystal of 2, 4-dichlorophenoxyacetic acid and L-proline obtained in example 7, and the obtained product was the same co-crystal as in example 1, and the DSC spectrum was also substantially the same as in example 1; the solubility of the compound is improved by about 1.92 times compared with that of the crystal form I.
Example 8
2.21g of 2, 4-dichlorophenoxyacetic acid and 1.15g L-proline are evenly mixed and placed in a ball mill, 20 mu L of methanol solvent is added dropwise, ball milling is carried out for 30 minutes at the frequency of 20Hz, and then the solid is poured out, thus obtaining the eutectic of the 2, 4-dichlorophenoxyacetic acid and the L-proline.
The same test method as in example 1 was used for the co-crystal of 2, 4-dichlorophenoxyacetic acid and L-proline obtained in example 8, and the obtained product was the same co-crystal as in example 1, and the DSC spectrum was also substantially the same as in example 1; the solubility of the compound is improved by about 1.92 times compared with that of the crystal form I.
The invention discloses and provides a 2, 4-dichlorophenoxyacetic acid eutectic as well as a preparation method and application thereof. While the products and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and appropriate modifications and combinations of the methods and products described herein can be made to practice the techniques of this invention without departing from the spirit or scope of the invention. It is expressly noted that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be included within the spirit, scope and content of the invention.
Claims (10)
1. The 2, 4-dichlorophenoxyacetic acid eutectic is characterized in that the 2, 4-dichlorophenoxyacetic acid eutectic is a eutectic formed by 2, 4-dichlorophenoxyacetic acid and L-proline according to a molar ratio of 1:1;
the 2, 4-dichlorophenoxyacetic acid eutectic is a monoclinic system, and the lattice parameters are as follows: the space group is p121= 9.8940 (4), b= 5.1944 (2), c= 14.4050 (6), alpha=90, beta= 104.883 (4), gamma=90, unit cell volume
2.2, 4-dichlorphenoxyacetic acid co-crystal according to claim 1, characterized in that the X-ray powder diffraction pattern of the 2, 4-dichlorphenoxyacetic acid co-crystal expressed in diffraction angle 2Θ using Cu-ka radiation has characteristic peaks at 12.54±0.2°, 13.52±0.2°, 17.62±0.2°, 18.20±0.2°, 18.86±0.2°, 19.38±0.2°, 21.00±0.2°, 24.68 ±0.2°, 25.60 ±0.2°, 26.42±0.2°, 27.20±0.2°, 28.48±0.2°, 29.46±0.2° and 30.10±0.2°, 30.88 ±0.2° and 32.28±0.2°.
3. The co-crystal of 2, 4-dichlorophenoxyacetic acid according to claim 1, wherein the 2, 4-dichlorophenoxyacetic acid and the L-proline molecule are connected through the interactions between N-H-O and C-H-O molecules to form one-dimensional chains, adjacent chains are piled up and extended through the interactions between O-H-O and C-H-Cl, proton transfer occurs in the L-proline molecule, and hydroxyl H in the L-proline carboxylic acid group is transferred to the N atom in L-proline.
4. The co-crystal of 2, 4-dichlorophenoxyacetic acid of claim 1 having a differential scanning calorimetric DSC profile with an endothermic peak at 112.72 ℃.
5. 2, 4-dichlorophenoxyacetic acid co-crystal according to claim 1, characterized in that the solubility of the 2, 4-dichlorophenoxyacetic acid co-crystal is increased by a factor of 1.92 relative to the 2, 4-dichlorophenoxyacetic acid stable crystal form i.
6. The method for producing 2, 4-dichlorophenoxyacetic acid co-crystal according to any one of claims 1 to 5, comprising the steps of:
2, 4-dichlorophenoxyacetic acid and L-proline are mixed under the stirring condition according to the mol ratio of 1: and 1, dissolving in an organic solvent, filtering to obtain filtrate, and volatilizing and crystallizing the obtained filtrate to obtain the 2, 4-dichlorophenoxyacetic acid eutectic.
7. The method according to claim 6, wherein the organic solvent comprises methanol or ethanol;
preferably, the organic solvent is added in an amount of 10 to 30g based on 2.21g of 2, 4-dichlorophenoxyacetic acid;
preferably, the preparation method further comprises the step of carrying out suction filtration on the mixture obtained by the volatilization and crystallization, and retaining 2, 4-dichlorophenoxyacetic acid eutectic solid.
8. The method for producing 2, 4-dichlorophenoxyacetic acid co-crystal according to any one of claims 1 to 5, comprising the steps of:
2, 4-dichlorophenoxyacetic acid and L-proline are mixed according to a mol ratio of 1:1, ball milling under the action of an organic solvent to obtain the 2, 4-dichlorophenoxyacetic acid eutectic.
9. The method of claim 8, wherein the ball milling is performed in a ball milling tank;
preferably, the organic solvent is methanol or ethanol;
preferably, 20-40. Mu.L of the organic solvent is added dropwise, based on 1g of 2, 4-dichlorophenoxyacetic acid;
preferably, the frequency of the ball milling is 10-40Hz, and the time of the ball milling is 20-60 minutes.
10. Use of the co-crystal of 2, 4-dichlorophenoxyacetic acid according to any one of claims 1 to 5 for the preparation of herbicides or plant growth regulators.
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