CN105218433A - A kind of doxylamine succinate new crystal and its preparation method and application - Google Patents
A kind of doxylamine succinate new crystal and its preparation method and application Download PDFInfo
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- CN105218433A CN105218433A CN201510697951.3A CN201510697951A CN105218433A CN 105218433 A CN105218433 A CN 105218433A CN 201510697951 A CN201510697951 A CN 201510697951A CN 105218433 A CN105218433 A CN 105218433A
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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Abstract
The invention discloses a kind of doxylamine succinate new crystal and its production and use.Described doxylamine succinate crystal formation called after crystal form A, use in the X-ray powder diffraction pattern of Cu-K α radiation detection at 11.0 ° (± 0.2 °), 11.5 ° (± 0.2 °), 11.9 ° (± 0.2 °), 12.6 ° (± 0.2 °), 16.8 ° (± 0.2 °), 17.3 ° (± 0.2 °), 18.5 ° (± 0.2 °), 19.6 ° (± 0.2 °), 20.1 ° (± 0.2 °), 20.5 ° (± 0.2 °), 21.4 ° (± 0.2 °), 21.6 ° (± 0.2 °), there is characteristic peak at 22.3 ° (± 0.2 °) and 24.3 ° of (± 0.2 °) (2 θ) places.The present invention also provides a kind of method preparing doxylamine succinate crystal form A, easy, favorable reproducibility, and gained doxylamine succinate crystal form A good stability, purity are high, are suitable for suitability for industrialized production.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to new crystal of a kind of ethanol class antihistamine drug doxylamine succinate and its preparation method and application.
Background technology
Doxylamine succinate belongs to ethanol class antihistamine drug, and have antihistamine effect, cholinolytic effect and significant sedative-hypnotic property, it is applicable to multiple anaphylaxis dermatosis, spring fever, allergic rhinitis, asthmatic bronchitis etc.; Because it produces sleepiness by suppressing central nervous system, be therefore also used as the short-term treatment of soporific for insomnia.
In October, 1978, FDA ratified the doxylamine succinate 25mg tablet listing of CHATTEM company, alleviated difficulty falling asleep for helping.Within 1979, become OTC (nonprescription drugs).In September, 1996 is ratified, and in August, 2004, LNK company was as imitation medicine official listing.The OTC antihistamine drug that doxylamine succinate is slept as assisting therapy, its clinical safety is effective, general reaction rate is high, better tolerance.
The document of existing doxylamine succinate is confined to synthesis technique more, and not yet has the report of crystal formation.In recent years, the polymorphism of drug molecule more and more causes the attention of scientist.Due to different polycrystalline kenels in stability, liberation degree, bioavailability is first-class very large difference; therefore be necessary to carry out polymorphic research as much as possible to drug molecule; to guarantee to obtain best crystalline form; thus obtain higher stability, liberation degree, bioavailability etc., thus produce higher biological activity.CN201310456159 and CN201010275180 etc. patent discloses the synthetic route of doxylamine succinate, the fusing point of the doxylamine succinate prepared in an embodiment is within the scope of 101 DEG C ~ 103 DEG C, but X powder ray diffraction (XRPD) collection of illustrative plates not disclosing this crystal formation does not report doxylamine succinate can which kind of crystalline forms yet.An object of the present invention be to disclose a kind ofly be easy to that preparation, good stability, purity are high, the doxylamine succinate crystal form A of favorable reproducibility and preparation method thereof.Significant to the suitability for industrialized production of doxylamine succinate.
Summary of the invention
The invention discloses that a kind of good stability, purity are high, the crystal habit of formula (I) doxylamine succinate of favorable reproducibility, hereinafter referred to as crystal form A, also disclose the preparation method of doxylamine succinate crystal form A.
The X-ray powder diffraction figure of doxylamine succinate crystal form A of the present invention is at 11.0 ° (± 0.2 °), 11.5 ° (± 0.2 °), 11.9 ° (± 0.2 °), 12.6 ° (± 0.2 °), 16.8 ° (± 0.2 °), 17.3 ° (± 0.2 °), 18.5 ° (± 0.2 °), 19.6 ° (± 0.2 °), 20.1 ° (± 0.2 °), 20.5 ° (± 0.2 °), 21.4 ° (± 0.2 °), 21.6 ° (± 0.2 °), 22.3 ° (± 0.2 °) and 24.3 ° (± 0.2 °) 2 θ angle have characteristic peak.
Further, use in the X-ray powder diffraction pattern of Cu-K α radiation detection, there is following characteristics peak, its 2 θ angle value and relative intensity as shown in the table:
Doxylamine succinate crystal form A of the present invention has X powder diffraction collection of illustrative plates as shown in Figure 1.
Doxylamine succinate crystal form A of the present invention, as shown in Figure 3, dsc analysis collection of illustrative plates is presented at about 105.8 ~ 106.5 DEG C of places endotherm(ic)peak, shows that it starts meltings at about about 105.8 DEG C, occurs endotherm(ic)peak.
Doxylamine succinate crystal form A of the present invention has thermogravimetric analysis collection of illustrative plates as shown in Figure 2 and Figure 3 and dsc analyzes collection of illustrative plates.
Doxylamine succinate crystal form A of the present invention has infrared absorption spectrum as shown in Figure 4, and it is 23421.4, and 3029.2,2975.5,2937.4,2888.0,2464.8,1913.9,1721.0,1625.6,1471.9,1421.9,1313.5,1181.2,995.3,926.9,702.8, there is absorption peak at 627.6 places.
The present invention provides a kind of method preparing doxylamine succinate crystal form A simultaneously, and the method comprises:
A doxylamine succinate heating is dissolved in a kind of solvent by (), be configured to saturated solution; Described organic solvent is selected from ethanol, methylene dichloride, tetrahydrofuran (THF), Virahol, acetone, ethyl acetate;
B () is slowly down to 0-30 DEG C, separate out solid, filtration drying obtains doxylamine succinate new crystal A.
Above two kinds of preparation methods of the present invention, the quantity of solvent used in step (b) and the middle solvent for use amount volume ratio of step (a) are (1.5-10): 1, preferably (2-5): 1.
Above two kinds of preparation methods of the present invention, step (a) Heating temperature is 40-70 DEG C, and step (b) recrystallization temperature is 0-25 DEG C.
A kind of medicinal compositions, said composition comprises pharmaceutically acceptable adjuvant, diluent or carrier mixes with doxylamine succinate crystal form A Compound Phase.
Described doxylamine succinate crystal form A is the purposes for preventing, treating anaphylaxis dermatosis, spring fever, allergic rhinitis, asthmatic bronchitis, insomnia drug in production antihistamine drug or production.
The method preparing doxylamine succinate crystal form A provided by the present invention, simple to operate, favorable reproducibility, obtains that crystal form A purity is high, good stability, can meet large-scale industrial production.
Accompanying drawing explanation
Fig. 1 is the X powder diffraction collection of illustrative plates of doxylamine succinate crystal form A;
Fig. 2 is the thermogravimetric analysis collection of illustrative plates of doxylamine succinate crystal form A;
Fig. 3 is that the dsc of doxylamine succinate crystal form A analyzes collection of illustrative plates;
Fig. 4 is the infrared absorption spectrum of doxylamine succinate crystal form A.
Embodiment
Following embodiment can make explanation specifically to content of the present invention, but protection scope of the present invention is not limited to following specific embodiment.Every technology, technique realized based on content of the present invention all belongs to scope of the present invention.
One, doxylamine succinate is prepared shown in the following reaction equation of doxylamine succinate preparation method:
The 2-pyridinylphenyl carbinol methine of 20g is dissolved in 100mL dimethylbenzene, pass into nitrogen protection, 22.2g sodium amide is added at 0-5 DEG C, stir 15-30 minute, add 107g dimethylamino monochloroethane hydrochloride, 0-5 DEG C is stirred 15-30 minute, slowly be warming up to 140 DEG C, return stirring reaction 1h, react complete and be cooled to 0-5 DEG C, drip 20-30% ammonium chloride 50ml, stir 30 minutes, stratification, discard water layer, add 3-5% dilute hydrochloric acid 30ml, abundant mixing 15 minutes, stratification, abandon organic phase, aqueous phase adds 30ml, 20-30% aqueous sodium carbonate and 100mL ethyl acetate, stratification after abundant mixing, anhydrous sodium sulfate drying ethyl acetate layer, suction filtration underpressure distillation removing ethyl acetate, obtain N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine yellow oil 26.6g.By the N of 26g, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine is dissolved in 100mL acetone (volume ratio 1:1) in 20-30 DEG C, stirring adds 12g succsinic acid, be warming up to 60 DEG C, stirring reaction 0.5-1 hour, slow cooling is to 0-5 DEG C, stirring and crystallizing 3-5 hour, suction filtration under nitrogen protection, filter cake 30mL0-5 DEG C of washing with acetone, filter cake is at p > 0.08, 45-50 DEG C of drying under reduced pressure 6-8 hour, obtain N, N-dimethyl-2-[1-phenyl-1-(2-pyridine) oxyethyl group] ethamine succinate off-white color solid 35.2g, again use 80mL acetone recrystallization, obtain white solid 28.8g, content 99.99%.
Embodiment 1:
Get doxylamine succinate 10g prepared by aforesaid method, under being warming up to 60-70 DEG C of condition, add ethanol, add-on equality of temperature should stir 30min so that doxylamine succinate can be made to be dissolved as completely, then slowly 0-5 DEG C is down to, filter, dry doxylamine succinate crystal form A 7.5g, purity 99.85%, yield 75%.
Embodiment 2:
Get doxylamine succinate 10g prepared by aforesaid method, under being warming up to 40-45 DEG C of condition, add methylene dichloride, add-on equality of temperature should stir 30min so that doxylamine succinate can be made to be dissolved as completely, then slowly 0-5 DEG C is down to, filter, dry doxylamine succinate crystal form A 6.8g, purity 99.86%, yield 68%.
Embodiment 3:
Get doxylamine succinate 10g prepared by aforesaid method, under being warming up to 60-65 DEG C of condition, add tetrahydrofuran (THF), add-on equality of temperature should stir 30min so that doxylamine succinate can be made to be dissolved as completely, then slowly 25-30 DEG C is down to, filter, dry doxylamine succinate crystal form A 8.3g, purity 99.89%, yield 83%.
Embodiment 4:
Get doxylamine succinate 10g prepared by aforesaid method, under being warming up to 65-70 DEG C of condition, add Virahol, add-on equality of temperature should stir 30min so that doxylamine succinate can be made to be dissolved as completely, then slowly 25-30 DEG C is down to, filter, dry doxylamine succinate crystal form A 8.5g, purity 99.92%, yield 85%.
Embodiment 5:
Get doxylamine succinate 10g prepared by aforesaid method, under being warming up to 55-60 DEG C of condition, add acetone, add-on equality of temperature should stir 30min so that doxylamine succinate can be made to be dissolved as completely, then slowly 25-30 DEG C is down to, filter, dry doxylamine succinate crystal form A 8.2g, purity 99.95%, yield 82%.
Embodiment 6:
Get doxylamine succinate 10g prepared by aforesaid method, under being warming up to 60-70 DEG C of condition, add ethyl acetate, add-on equality of temperature should stir 30min so that doxylamine succinate can be made to be dissolved as completely, then slowly 25-30 DEG C is down to, filter, dry doxylamine succinate crystal form A 9.0g, purity 99.85%, yield 90%.
The doxylamine succinate crystal form A that aforesaid method prepares, as shown in Figure 1, as shown in Figure 2, dsc analyzes collection of illustrative plates as shown in Figure 3 to thermogravimetric analysis collection of illustrative plates to X powder diffraction collection of illustrative plates; Infrared absorption spectrum as described in Figure 4.
Claims (9)
1. the crystal habit of formula (I) doxylamine succinate, it is characterized in that the X-ray powder diffraction figure of described formula (I) compound is at 11.0 ° (± 0.2 °), 11.5 ° (± 0.2 °), 11.9 ° (± 0.2 °), 12.6 ° (± 0.2 °), 16.8 ° (± 0.2 °), 17.3 ° (± 0.2 °), 18.5 ° (± 0.2 °), 19.6 ° (± 0.2 °), 20.1 ° (± 0.2 °), 20.5 ° (± 0.2 °), 21.4 ° (± 0.2 °), 21.6 ° (± 0.2 °), 22.3 ° (± 0.2 °) and 24.3 ° (± 0.2 °) 2 θ angle have characteristic peak
2. a crystal habit for formula (I) doxylamine succinate, is characterized in that the X powder diffraction collection of illustrative plates had as shown in Figure 1.
3. the crystal habit of doxylamine succinate as claimed in claim 1 or 2, is characterized in that the compound of described crystal habit is at 145 DEG C of thermal weight losses, and dsc analysis collection of illustrative plates is presented at crystal form A has endotherm(ic)peak at 105.8 ~ 106.5 DEG C of places.
4. the crystal habit of doxylamine succinate as claimed in claim 1 or 2, is characterized in that the compound of described crystal habit has infrared absorption spectrum as shown in Figure 4,3421.4, and 3029.2,2975.5,2937.4,2888.0,2464.8,1913.9,1721.0,1625.6,1471.9,1421.9,1313.5,1181.2,995.3,926.9,702.8,627.6cm
-1there is absorption peak at place.
5. prepare a method for formula described in claim 1 or 2 (I) compound crystal form, its feature comprises:
A doxylamine succinate heating is dissolved in a kind of organic solvent by (), be configured to saturated solution, described organic solvent is selected from ethanol, methylene dichloride, tetrahydrofuran (THF), Virahol, acetone, ethyl acetate;
B () is slowly down to 0-30 DEG C, separate out solid, filtration drying obtains doxylamine succinate crystal formation described in claim 1.
6. as claimed in claim 5, it is characterized in that the quantity of solvent used in described step (a) is (1.5-10) with doxylamine succinate ratio: 1.
7. as claimed in claim 5, it is characterized in that described step (a) Heating temperature is 40-70 DEG C, recrystallization temperature is 0-25 DEG C.
8. a medicinal compositions, the compound any one of claim 1-4 that said composition comprises pharmaceutically acceptable adjuvant, diluent or carrier mixes mutually.
9. the compound any one of claim 1-4 is the purposes for preventing, treating anaphylaxis dermatosis, spring fever, allergic rhinitis, asthmatic bronchitis, insomnia drug in production antihistamine drug or production.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107056685A (en) * | 2017-01-23 | 2017-08-18 | 珠海市海瑞德生物科技有限公司 | A kind of synthetic method of doxylamine succinate |
| CN107098851A (en) * | 2016-02-22 | 2017-08-29 | 南京秾康生物科技有限公司 | A kind of preparation method of doxylamine succinate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102108059A (en) * | 2010-09-03 | 2011-06-29 | 合肥工业大学 | Method for synthesizing doxylamine succinate |
| CN103524403A (en) * | 2013-09-30 | 2014-01-22 | 江苏礼华生物技术有限公司 | Preparation method of doxylamine succinate |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102108059A (en) * | 2010-09-03 | 2011-06-29 | 合肥工业大学 | Method for synthesizing doxylamine succinate |
| CN103524403A (en) * | 2013-09-30 | 2014-01-22 | 江苏礼华生物技术有限公司 | Preparation method of doxylamine succinate |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107098851A (en) * | 2016-02-22 | 2017-08-29 | 南京秾康生物科技有限公司 | A kind of preparation method of doxylamine succinate |
| CN107056685A (en) * | 2017-01-23 | 2017-08-18 | 珠海市海瑞德生物科技有限公司 | A kind of synthetic method of doxylamine succinate |
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Address after: Longmian road Jiangning District of Nanjing City, Jiangsu province 211112 No. 568 Nanjing life science and Technology Innovation Park, building 9, floor 5 Applicant after: Nanjing Ji medicine Polytron Technologies Inc Address before: Longmian road Jiangning District of Nanjing City, Jiangsu province 211112 No. 568 Nanjing life science and Technology Innovation Park, building 1, floor 5 Applicant before: NANJING JIQUN PHARMACEUTICAL SCIENCE AND TECHNOLOGY CO.,LIMITED |
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Application publication date: 20160106 |