CN104030992B - A kind of Dicyclanil drug crystal forms II and preparation method thereof - Google Patents
A kind of Dicyclanil drug crystal forms II and preparation method thereof Download PDFInfo
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- CN104030992B CN104030992B CN201410105315.2A CN201410105315A CN104030992B CN 104030992 B CN104030992 B CN 104030992B CN 201410105315 A CN201410105315 A CN 201410105315A CN 104030992 B CN104030992 B CN 104030992B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
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- C07D239/50—Three nitrogen atoms
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Abstract
The invention belongs to medicinal chemistry art, be specifically related to a kind of crystal form II of a kind of adaptation drug development of novel Dicyclanil and preparation method thereof.It is characterized in that the DMF solvate of Dicyclanil medicine.The crystal space group of the Dicyclanil drug crystal forms II that the present invention prepares is oblique system, and 1 Dicyclanil molecule and 1 DMF are by forming the basic structural unit of Dicyclanil drug crystal forms II together with hydrogen bonded.Selected by drug crystal forms II preparation process of the present invention, solvent is DMF, and employing method is saturated solution lowering temperature crystallization, due to heating volatilization solution is reached capacity, therefore solvent cooling and volatilization process in namely have crystal to separate out.Drug crystal forms II prepared by the present invention can stop outside the speciality such as larvae development pupa worm or adult of various fly, mosquito and flea, and its solvability, stability and bioavailability have obvious change.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of novel Dicyclanil and adapt to a kind of crystal form II of pharmaceutical analysis and preparation method thereof.
Background technology
Dicyclanil (dicyclanil) has another name called the third worm pyridine, chemical name: 4,6-diamino-2-cyclopropylamino pyrimidine-5-nitrile, molecular formula: C
8h
10n
6, Dicyclanil is Novel insect growth regulator, emphasizes to control pest population and regulate, and optionally effective pest control, can keep normal natural, ecological can not cause environmental pollution again.As veterinary drug of new generation, have the powerful market requirement, because this medicine not easily tolerates, residual value is low, has very high Ecological Society benefit, meets requirement and the target of current environment friendly agricultural.Structural formula is as follows:
At present, patent WO9910333A1 discloses eight kinds of crystal formations of Dicyclanil, is respectively A, B, C, D, E, F, G, H crystal form.Wherein A crystal formation is stable not, is easily converted into other crystal formation.G, C crystal form are that these two kinds of crystal formation reaction times are long, and temperature is high, is unfavorable for suitability for industrialized production by A crystal formation 80 DEG C of stirrings 16h and 40 DEG C of stirring 24h in water respectively.B crystal form is obtained by C crystal form nitrogen drying at 25 DEG C.Form D first generates crystal seed could be used for industrial production.F crystal formation is added to by A crystal formation to obtain containing stirring at room temperature in water, polyoxyethylene glycol, sorbitanic, mono laurate ester solvent.
Patent AU2010201828A1 discloses a kind of new crystal of Dicyclanil, is to add some tensio-active agents and viscosity by Dicyclanil to modify and obtain.
Affect a lot of because have of the crystal formation of medicine, different crystal formations is obtained as by change solvent, temperature, illumination etc., because of the difference of crystalline network, there is notable difference in same its physical properties of medicine different crystal forms, thus can have an impact to Drug safety, validity.At present, drug crystal forms research has become hot research work.
The solvate of medicine is a kind of new crystal that active constituents of medicine and reagent are formed by Intermolecular Forces (as hydrogen bond), it can improve physico-chemical property and the bioavailability of active constituents of medicine, there is the feature of good stability, so in recent years about the research of drug solvent compound has become the large focus of pharmaceutical field one.
Therefore, find solubleness good, bioavailability is high, and stable, 4, the 6-diamino-2-cyclopropylamino pyrimidine-5-nitrile new crystal being conducive to suitability for industrialized production are very necessary.
Summary of the invention
The object of the invention is on the basis of existing technology, a kind of DMF solvate of Dicyclanil medicine of novel texture is provided.Drug crystal forms prepared by the present invention inherit original Dicyclanil medicine to dipteral insect and flea have height killing action, can stop outside the speciality such as larvae development pupa worm or adult of various fly, mosquito and flea, its solvability, stability and bioavailability have obvious change.
Technical scheme of the present invention is: a kind of Dicyclanil drug crystal forms II, for the N of Dicyclanil medicine, dinethylformamide solvate, Powder XRD pattern is that 13.3 ± 0.2 °, 14.18 ± 0.2 °, 15.97 ± 0.2 °, 16.76 ± 0.2 °, 20.22 ± 0.2 °, 21.20 ± 0.2 °, 23.68 ± 0.2 °, 24.49 ± 0.2 °, 26.83 ± 0.2 °, 27.32 ± 0.2 °, 28.76 ± 0.2 °, 29.65 ± 0.2 °, 31.98 ± 0.2 ° places have characteristic peak at diffraction angle 2 θ.
Using Dicyclanil as active constituents of medicine, take DMF as the crystal of solvent, formation, the spacer of crystal is oblique system, axial length a=7.3744 ~ 7.7744, b=17.105 ~ 17.505, c=10.950 ~ 11.350, α=90, β=96.73 ~ 98.73, γ=90.
Powder XRD pattern is 9.44 ± 0.2 ° at diffraction angle 2 θ, 13.3 ± 0.2 °, 14.18 ± 0.2 °, 15.97 ± 0.2 °, 15.16 ± 0.2 °, 16.76 ± 0.2 °, 19.34 ± 0.2 °, 20.22 ± 0.2 °, 21.20 ± 0.2 °, 21.60 ± 0.2 °, 23.68 ± 0.2 °, 24.49 ± 0.2 °, 25.87 ± 0.2 °, 26.83 ± 0.2 °, 27.32 ± 0.2 °, 28.76 ± 0.2 °, 29.65 ± 0.2 °, 31.98 ± 0.2 °, 33.33 ± 0.2 °, 40.65 ± 0.2 °, there is characteristic peak at 42.10 ± 0.2 ° of places.
Infared spectrum is at 3423.91 ± 0.2cm
-1, 3331.94 ± 0.2cm
-1, 3203.18 ± 0.2m
-1, 2194.82 ± 0.2cm
-1, 1636.29 ± 0.2cm
-1, 1564.38 ± 0.2cm
-1, 1472.41 ± 0.2cm
-1, 1343.65 ± 0.2cm
-1, 778.43 ± 0.2cm
-1there is absorption peak at place.
1 Dicyclanil molecule and 1 N in crystal, dinethylformamide forms the basic structural unit of Dicyclanil medicine crystal by hydrogen bonded together, atom N in one of them Dicyclanil molecule is as the donor of hydrogen bond, the O atom of a DMF molecule as hydrogen bond receptor and form a hydrogen bond.
A preparation method for described Dicyclanil drug crystal forms II, comprises the steps:
(1) Dicyclanil of A crystal formation is dissolved in DMF solvent, when heated and stirred is to the hypersaturated state reached at this temperature, filters;
(2) seal the vessel port that Dicyclanil solution is housed with film, establish volatilization aperture at film, leave standstill volatilization after 5-7 days, separate out colorless plate crystal in container, isolation of crystalline and get final product.
Heating temperature is: 80-153 DEG C.
Dicyclanil drug crystal forms II thermogravimetric curve, first step is decomposed from 80 DEG C, and 190 DEG C of decomposition complete, weightless 28.42%, this step is for losing DMF molecule, second largest step is that 210 ~ 330 DEG C of decomposition complete, and weightless 66.95.7%, this step is Dicyclanil decompose themselves.Drug crystal forms II prepared by this present invention inherit original Dicyclanil medicine to dipteral insect and flea have height killing action, can stop outside the speciality such as larvae development pupa worm or adult of various fly, mosquito and flea, its solvability, stability and bioavailability have obvious change.
The preparation method of drug crystal forms II of the present invention is saturated solution lowering temperature crystallization, and selected solvent is DMF solvent, due to heating volatilization solution is reached capacity, therefore solvent cooling and volatilization process in namely have crystal to separate out.
Accompanying drawing explanation
Fig. 1 is Dicyclanil medicine crystal structural unit schematic diagram.
As shown in the figure, 1 Dicyclanil molecule and 1 DMF are by forming the basic structural unit of Dicyclanil medicine crystal together with hydrogen bonded, and the atom N in one of them Dicyclanil molecule is as the donor of hydrogen bond, a N, the O atom of dinethylformamide molecule as hydrogen bond receptor and form a hydrogen bond, its axial length a=7.3744 ~ 7.7744, b=17.105 ~ 17.505, c=10.950 ~ 11.350, α=90, β=96.73 ~ 98.73, γ=90.
Fig. 2 is the XRD figure spectrum of Dicyclanil drug crystal forms II.
As shown in the figure, can find out from the X-ray diffraction peak (curve 1) of this crystal form II of synthesis and occur series of features peak at 9.44 °, 13.3 °, 14.18 °, 15.16 °, 15.97 °, 16.76 °, 19.34 °, 20.22 °, 21.20 °, 21.60 °, 23.68 °, 24.49 °, 25.87 °, 26.83 °, 27.32 °, 28.76 °, 29.65 °, 31.98 °, 33.33 °, 40.65 °, 42.10 °.
Fig. 3 is the thermogravimetric collection of illustrative plates of Dicyclanil drug crystal forms II.
This collection of illustrative plates is under the atmosphere test condition of nitrogen, Dicyclanil crystal form II thermogravimetric curve, first step is decomposed from 80 DEG C, 190 DEG C of decomposition complete, and weightless 28.42%, this step is for losing N, dinethylformamide molecule, second largest step is that 210 ~ 330 DEG C of decomposition complete, and weightless 66.95.7%, this step is Dicyclanil decompose themselves.
Fig. 4 is the IR collection of illustrative plates of Dicyclanil drug crystal forms II.
As shown in the figure, the characteristic peak of this new crystal is at 3423.91cm
-1, 3331.94cm
-1, 3203.18cm
-1, 2194.82cm
-1, 1636.29cm
-1, 1564.38cm
-1, 1472.41cm
-1, 1343.65cm
-1, 778.43cm
-1place.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.Following specific embodiment is only further used for the present invention is described, but not for limiting content of the present invention.The instrument of detection of drugs crystal form II structure of the present invention and performance thereof is as follows:
1, crystalline structure is measured by X-ray single crystal diffractometer, and full name is aRigakuSCXminidiffractometer.
2, powder diffractometer is produced by German Bruker company, and model is D8-Discover, Cu-K α (λ=1.54056
), tube voltage 40KV, tube current 30mA, sweep velocity 8 °/min.
3, thermogravimetric curve is produced by METTLERTOLEDO company, and model is STAReSystem, adopts nitrogen atmosphere, temperature rise rate 10 DEG C/min.
4, infrared curve is recorded by Fourier infrared spectrograph, and model is NICOLET5700FT-IR.
The transparent glass instrument that the present invention uses is external import, and capacity is 50ml.
A kind of Dicyclanil drug crystal forms II, its Powder XRD pattern is that 13.3 ± 0.2 °, 14.18 ± 0.2 °, 15.97 ± 0.2 °, 16.76 ± 0.2 °, 20.22 ± 0.2 °, 21.20 ± 0.2 °, 23.68 ± 0.2 °, 24.49 ± 0.2 °, 26.83 ± 0.2 °, 27.32 ± 0.2 °, 28.76 ± 0.2 °, 29.65 ± 0.2 °, 31.98 ± 0.2 ° places have characteristic peak at diffraction angle 2 θ.
Selected by the present invention, bulk drug Dicyclanil is as active constituents of medicine, and the chemical name of Dicyclanil is for having another name called the third worm pyridine, and chinesization formal name used at school is 4,6-diamino-2-cyclopropylamino pyrimidine-5-nitrile, molecular formula C
8h
10n
6, its structural formula is as shown in a; DMF molecular formula C
3h
7oN.
Dicyclanil drug crystal forms II of the present invention is using Dicyclanil as active constituents of medicine, with N, dinethylformamide is the crystal of solvent, formation, and its spacer is oblique system, its axial length a=7.3744 ~ 7.7744, b=17.105 ~ 17.505, c=10.950 ~ 11.350, α=90, β=96.73 ~ 98.73, γ=90.This crystalline structure simplified summary is as follows: 1 Dicyclanil molecule and 1 N, dinethylformamide forms the basic structural unit of Dicyclanil medicine crystal by hydrogen bonded together, atom N in one of them Dicyclanil molecule is as the donor of hydrogen bond, the O atom of a DMF molecule as hydrogen bond receptor and form a hydrogen bond.
Further, the Powder XRD pattern of this Dicyclanil drug crystal forms II is 9.44 ± 0.2 ° at diffraction angle 2 θ, 13.3 ± 0.2 °, 14.18 ± 0.2 °, 15.97 ± 0.2 °, 15.16 ± 0.2 °, 16.76 ± 0.2 °, 19.34 ± 0.2 °, 20.22 ± 0.2 °, 21.20 ± 0.2 °, 21.60 ± 0.2 °, 23.68 ± 0.2 °, 24.49 ± 0.2 °, 25.87 ± 0.2 °, 26.83 ± 0.2 °, 27.32 ± 0.2 °, 28.76 ± 0.2 °, 29.65 ± 0.2 °, 31.98 ± 0.2 °, 33.33 ± 0.2 °, 40.65 ± 0.2 °, there is characteristic peak at 42.10 ± 0.2 ° of places.
Further, this Dicyclanil drug crystal forms II has Powder XRD pattern substantially as shown in Figure 2.The infared spectrum of this Dicyclanil drug crystal forms II is at 3423.91 ± 0.2cm
-1, 3331.94 ± 0.2cm
-1, 3203.18 ± 0.2m
-1, 2194.82 ± 0.2cm
-1, 1636.29 ± 0.2cm
-1, 1564.38 ± 0.2cm
-1, 1472.41 ± 0.2cm
-1, 1343.65 ± 0.2cm
-1, 778.43 ± 0.2cm
-1there is absorption peak at place.
The preparation process of Dicyclanil drug crystal forms II of the present invention is as follows:
(1) be dissolved in by Dicyclanil in DMF solvent, heating for dissolving, to reaching hypersaturated state, stirs 30min ~ 60min, filters;
(2) seal the vessel port that Dicyclanil solution is housed with film, establish volatilization aperture at film, leave standstill volatilization after 5-7 days, start in container to separate out colorless plate crystal, be separated this crystal and get final product.
Invention further provides a kind of concrete preparation method of Dicyclanil drug crystal forms II: be dissolved in by Dicyclanil 1.3 ~ 1.7mmol in DMF solvent, as heated and stirred 30min on agitator ~ 60min, filter; Seal beaker mouth with the film of preservative film, on film, prick several aperture with pin, leave standstill volatilization after 5-7 days, start in container to separate out colorless plate shape crystal, i.e. Dicyclanil drug crystal forms II.
Embodiment 1: use Dicyclanil and DMF synthesis crystal form II:
Weigh:
A crystal formation Dicyclanil 300mg feeds intake, and accurately takes with analytical balance.
Bulk drug dissolves:
Accurately measure 20mlN with transfer pipet, dinethylformamide, in 50ml beaker, stirs 30min.
Saturated solution lowering temperature crystallization:
At 153 DEG C, to after can not dissolving on a small quantity in addition, take out stirrer, be filled in a clean 50ml transparent glass bottle with analytical paper, seal bottleneck with preservative film, with the several aperture of pinprick, leave standstill and volatilize.After about 7 days, have in bottle and separate out sheet colourless transparent crystal.
The poisoning of insect is tested: the insect selected is that cotton boll resembles adult
Test method: respectively by drug crystal forms II of the present invention during experiment, certain density suspensoid is made into by formula respectively with raw material, blank group experiment (other is consistent not add this medicine composition any in formula) is set, adopt the method connecing worm after first soaking leaf, take out not contacting after any medicament blade of the same size soaks 5s in the liquid configured, naturally dry, put into insect box, then connect for examination larva, raise under 25 DEG C of conditions, often process and repeat for 3 times, often repeating examination borer population used is 50, establish blank simultaneously, dead borer population is checked in 72h, calculate mortality ratio and corrected mortality.If contrast mortality ratio is greater than 10%, be then considered as invalid experiment.Calculation formula is as follows:
As can be seen from the data of table 1, drug crystal forms II of the present invention in insect toxic action apparently higher than raw material.
Comparative example:
Use acetonitrile, or acetone solvent to do according to the method for embodiment 1 crystal formation data that same experiment obtains respectively be consistent with the crystal formation of raw material, the position at its powder diffraction spectrum peak is: 7.77 °, 9.87 °, 10.9 °, 11 °, 11.85 °, 15 °, 15.5 °, 17.4 °, 18.79 °, 19.24 °, 21.4 °, 22.2 °, 24 °, 26.2 °, 28.01 °, 29.1 °, 30.1 °, 31.4 °, 33.4 °.
Claims (7)
1. a Dicyclanil drug crystal forms II, it is characterized in that, for the N of Dicyclanil medicine, dinethylformamide solvate, Powder XRD pattern is that 13.3 ± 0.2 °, 14.18 ± 0.2 °, 15.97 ± 0.2 °, 16.76 ± 0.2 °, 20.22 ± 0.2 °, 21.20 ± 0.2 °, 23.68 ± 0.2 °, 24.49 ± 0.2 °, 26.83 ± 0.2 °, 27.32 ± 0.2 °, 28.76 ± 0.2 °, 29.65 ± 0.2 °, 31.98 ± 0.2 ° places have characteristic peak at diffraction angle 2 θ.
2. Dicyclanil drug crystal forms II according to claim 1, is characterized in that, using Dicyclanil as active constituents of medicine, with N, dinethylformamide is the crystal of solvent, formation, and the spacer of crystal is oblique system, axial length a=7.3744 ~ 7.7744, b=17.105 ~ 17.505, c=10.950 ~ 11.350, α=90, β=96.73 ~ 98.73, γ=90.
3. Dicyclanil drug crystal forms II according to claim 1, it is characterized in that, Powder XRD pattern is 9.44 ± 0.2 ° at diffraction angle 2 θ, 13.3 ± 0.2 °, 14.18 ± 0.2 °, 15.97 ± 0.2 °, 15.16 ± 0.2 °, 16.76 ± 0.2 °, 19.34 ± 0.2 °, 20.22 ± 0.2 °, 21.20 ± 0.2 °, 21.60 ± 0.2 °, 23.68 ± 0.2 °, 24.49 ± 0.2 °, 25.87 ± 0.2 °, 26.83 ± 0.2 °, 27.32 ± 0.2 °, 28.76 ± 0.2 °, 29.65 ± 0.2 °, 31.98 ± 0.2 °, 33.33 ± 0.2 °, 40.65 ± 0.2 °, there is characteristic peak at 42.10 ± 0.2 ° of places.
4. Dicyclanil drug crystal forms II according to claim 1, it is characterized in that, infared spectrum is at 3423.91 ± 0.2cm
-1, 3331.94 ± 0.2cm
-1, 3203.18 ± 0.2m
-1, 2194.82 ± 0.2cm
-1, 1636.29 ± 0.2cm
-1, 1564.38 ± 0.2cm
-1, 1472.41 ± 0.2cm
-1, 1343.65 ± 0.2cm
-1, 778.43 ± 0.2cm
-1there is absorption peak at place.
5. Dicyclanil drug crystal forms II according to claim 2, it is characterized in that, 1 Dicyclanil molecule and 1 N in crystal, dinethylformamide forms the basic structural unit of Dicyclanil medicine crystal by hydrogen bonded together, atom N in one of them Dicyclanil molecule is as the donor of hydrogen bond, the O atom of a DMF molecule as hydrogen bond receptor and form a hydrogen bond.
6. a preparation method for the Dicyclanil drug crystal forms II described in claim 1 or 2, is characterized in that, comprise the steps:
(1) Dicyclanil of A crystal formation is dissolved in DMF solvent, when heated and stirred is to the hypersaturated state reached at this temperature, filters;
(2) seal the vessel port that Dicyclanil solution is housed with film, establish volatilization aperture at film, leave standstill volatilization after 5-7 days, separate out colorless plate crystal in container, isolation of crystalline and get final product.
7. the preparation method of Dicyclanil drug crystal forms II according to claims 6, it is characterized in that, Heating temperature is: 80-153 DEG C.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1268125A (en) * | 1997-08-27 | 2000-09-27 | 诺瓦提斯公司 | Dicyclanil Polymorphs and hydrates and their preparation |
| CN1713891A (en) * | 2002-10-25 | 2005-12-28 | 弗米克斯有限公司 | Cosmetic and pharmaceutical foam |
| WO2008052263A1 (en) * | 2006-11-01 | 2008-05-08 | Veterinary Encapsulation Biosciences Pty Ltd | Delivery system for remote treatment of an animal |
-
2014
- 2014-03-20 CN CN201410105315.2A patent/CN104030992B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1268125A (en) * | 1997-08-27 | 2000-09-27 | 诺瓦提斯公司 | Dicyclanil Polymorphs and hydrates and their preparation |
| CN1713891A (en) * | 2002-10-25 | 2005-12-28 | 弗米克斯有限公司 | Cosmetic and pharmaceutical foam |
| WO2008052263A1 (en) * | 2006-11-01 | 2008-05-08 | Veterinary Encapsulation Biosciences Pty Ltd | Delivery system for remote treatment of an animal |
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