CN104341315A - Preparation method of agomelatine crystal form I - Google Patents
Preparation method of agomelatine crystal form I Download PDFInfo
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- CN104341315A CN104341315A CN201310345234.5A CN201310345234A CN104341315A CN 104341315 A CN104341315 A CN 104341315A CN 201310345234 A CN201310345234 A CN 201310345234A CN 104341315 A CN104341315 A CN 104341315A
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- organic solvent
- agomelatine
- aqueous solution
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Abstract
The invention discloses a preparation method of an agomelatine crystal form I. The method comprises the following steps: adding agomelatine to a mixed solvent of an organic solvent and acetic acid; heating to completely dissolve agomelatine; adding the obtained solution to another organic solvent to separate out crystal; filtering, and adjusting the pH of a filter cake to 7-7.5 by virtue of an alkali liquor; and filtering and drying to obtain solid. According to the preparation method, the high-purity agomelatine crystal form I can be stably obtained; and the method is simple to operate, good in repeatability and suitable for industrial mass production.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to the preparation method of a kind of agomelatine crystal form I.
Technical background
Agomelatine (Agomelatine), chemistry N-by name [2-(7-methoxy-1-naphthyl) ethyl] ethanamide, in February, 2009 is used for the treatment of major depression's disease, trade(brand)name Valdoxan, shown in the following formula I of chemical structure by the approval of European Drug Administration office (EMA):
Agomelatine (Agomelatine) is the first development of French Shi Weiya company, in 2009 in listings such as Germany, Britain, is used for the treatment of dysthymia disorders.It has double action mechanism, is melatonin receptor agonist, is also serotonin 2c(5-HT2C) receptor antagonist.These character make it possess central nervous system activity, especially make it have the activity for the treatment of severe depression, seasonal affective disorder, obstacle sleep, cardiovascular disorder, digestive system, insomnia that the time difference causes and fatigue, appetite disorder and obesity etc.The Preparation method and use of Agomelatine has been reported in European patent EP 0447285.
Acta cryst, 1994, c50, the 97-910 reported first single crystal data of agomelatine crystal form I, but do not have related manufacturing processes to report.
WO2011054917A reports the preparation method of agomelatine crystal form I, and the method dissolves Agomelatine with single water-miscible organic solvent, and then add water precipitation solid, obtains required crystal formation.CN101704763A reports and is dissolved in hydrophilic organic solvent by Agomelatine crude product, and filter, filtrate under agitation instills in water, separates out solid, dry agomelatine crystal form I.CN101921205A reports and is dissolved in DMF by Agomelatine crude product, and filter, filtrate is poured in the distilled water of rapid stirring, maintains 15 ~ 45 minutes, filters, dry must agomelatine crystal form I.Experiment finds that the method circulation ratio of above-mentioned patent report is poor, and can not obtain highly purified crystal formation I.
Summary of the invention
The object of this invention is to provide a kind of favorable reproducibility and the method preparing agomelatine crystal form I of applicable suitability for industrialized production.
Technical scheme provided by the invention is as follows:
A method of agomelatine crystal form I, comprises the following steps:
A) added by Agomelatine in the mixed solvent of acetic acid and organic solvent A, heating makes it dissolve completely; Heating temperature be 25 DEG C to solvent reflux temperature, preferably 35 ~ 80 DEG C further;
Described organic solvent A is selected from: normal hexane, normal heptane, methylcyclohexane, toluene, ethyl acetate, butylacetate, n-propyl acetate, isobutyl acetate, methyl tertiary butyl ether, ethylene glycol monomethyl ether, propylene glycol monomethyl ether, 2-methyltetrahydrofuran, cyclopentyl-methyl ether, methyl-phenoxide or isopropyl ether; The preferred cyclopentyl-methyl ether of organic solvent A, methyl tertiary butyl ether, or ethyl acetate;
The volume ratio of described organic solvent A and acetic acid is: 1:0.01 ~ 1, further preferred 1:0.05 ~ 0.5;
B) above-mentioned solution is joined in another kind of organic solvent B, separate out solid; In adition process, the temperature of organic solvent B maintains-35 DEG C ~ 40 DEG C, more preferably-35 DEG C ~ 35 DEG C, is more preferably-35 DEG C ~ 10 DEG C;
Described organic solvent B is selected from: normal hexane, normal heptane, methylcyclohexane, toluene, ethyl acetate, butylacetate, n-propyl acetate, isobutyl acetate, methyl tertiary butyl ether, ethylene glycol monomethyl ether, propylene glycol monomethyl ether, 2-methyltetrahydrofuran, cyclopentyl-methyl ether, methyl-phenoxide or isopropyl ether;
The volume ratio of described organic solvent A and organic solvent B is 1:0.1 ~ 10, more preferably 1:0.5 ~ 5.
C) filter, gained solid alkali liquid washing is to pH7 ~ 7.5;
Described alkali lye can be selected from NaHCO
3the aqueous solution, KHCO
3the aqueous solution, Na
2cO
3the aqueous solution, K
2cO
3the aqueous solution, the KOH aqueous solution, the NaOH aqueous solution, the LiOH aqueous solution or ammoniacal liquor.
D) filter, vacuum-drying obtains agomelatine crystal form I;
Vacuum-drying temperature is preferably 25 ~ 50 DEG C, preferably 35 ~ 45 DEG C further.
The agomelatine crystal form I of gained of the present invention has X-ray powder diffraction pattern as shown in Figure 1, is expressed as follows with 2 θ ° and relative intensity:
| 2θ° | Relative intensity [%] |
| 10.9 | 7.2 |
| 11.3 | 9.6 |
| 12.0 | 41.0 |
| 17.6 | 30.2 |
| 18.5 | 21.6 |
| 18.7 | 15.9 |
| 19.6 | 67.6 |
| 19.9 | 100.0 |
| 20.6 | 18.6 |
| 21.3 | 10.6 |
| 21.9 | 23.0 |
| 22.8 | 13.7 |
| 23.1 | 20.5 |
| 24.1 | 8.3 |
| 24.7 | 11.4 |
| 25.5 | 25.8 |
| 26.5 | 5.2 |
| 27.2 | 6.5 |
| 27.4 | 8.6 |
| 27.8 | 4.2 |
| 30.2 | 5.9 |
| 31.7 | 5.9 |
| 32.1 | 10.9 |
This XRPD test set and method are:
X-ray diffractometer: X ' Pert Pro MPD (Multi-Purpose Diffractometer)
Light pipe type: Empyrean XRD tube Cu LFF HR
Electric current and voltage: 45kV, 40mA
The vertical goniometer of goniometer: PW3050/60, radius 240mm
Slit: DS=2 °, SS=1/2 °, mask=15mm, RS=5.0mm
The super detector of detector: X ' Celerator
Scan pattern: continuous sweep
Sweep limit (2 θ): 3.0-40.0 °
Step-length (2 θ): 0.0167 °
Often walk gate time: 20s
Scanning total time: 6min
The agomelatine crystal form I of gained of the present invention has DSC collection of illustrative plates as shown in Figure 2, and DSC spectrogram is presented at 97.2 ~ 101.6 DEG C of places single endotherm(ic)peak
DSC test set and method:
Unit type: the SDT Q600 of TA company of the U.S.
Heating schedule: 20 ~ 320 DEG C, 10 DEG C/min.
The present invention utilizes Agomelatine to dissolve in organic solvent and vinegar stock solvent, then is added in another kind of solvent and separate out solid, solid again with alkali liquid washing, filter, drying and Absorbable organic halogens obtain highly purified crystal formation I.This method has simple to operate, favorable reproducibility, is applicable to the advantages such as industrialized production.
Accompanying drawing explanation
Fig. 1 is X-ray powder diffraction (XRPD) spectrogram of agomelatine I crystal formation.
Fig. 2 is dsc (DSC) spectrogram of agomelatine I crystal formation.
Embodiment
In order to more detailed description the present invention, provide and prepare example below, but scope of the present invention is not limited to this.
Embodiment 1:
Get Agomelatine (100g), add cyclopentyl-methyl ether (400ml), stir, then add Glacial acetic acid (40ml), be warming up to 35 ~ 40 DEG C, Quan Rong.Added by gained solution in the methyl tertiary butyl ether (400ml) being chilled to-30 DEG C in advance, drip and finish, stir 30min, filter, gained solid is with 5%NaHCO
3the aqueous solution adjusts pH7 ~ 7.5, filters, and filter cake is with water (300ml × 3) washing, and about 40 DEG C, vacuum is dry, obtains Agomelatine 80.2g, yield 80.2%.
Embodiment 2:
Get Agomelatine (150g), add methyl tertiary butyl ether (800ml), stir, then add Glacial acetic acid (40ml), be warming up to 40 ~ 45 DEG C, Quan Rong.Gained solution is added in the methyl tertiary butyl ether (400ml) being chilled to-10 DEG C in advance, drip and finish, stir 30min, filter, gained solid adjusts PH7 ~ 7.5 with the 3%NaOH aqueous solution, filters, filter cake washs with water (200ml × 3), about 35 DEG C, vacuum is dry, obtains Agomelatine 112.8g, yield 75.2%.
Embodiment 3:
Get Agomelatine (300g), add cyclopentyl-methyl ether (1.2L), stir, then add Glacial acetic acid (120ml), be warming up to 40 ~ 45 DEG C, Quan Rong.Added by gained solution in the normal heptane (800ml) of about 10 DEG C, drip and finish, stir 30min, filter, gained solid is with 5%K
2cO
3the aqueous solution adjusts PH7 ~ 7.5, filters, and filter cake is with water (500ml × 2) washing, and about 45 DEG C, vacuum is dry, obtains Agomelatine 234.6g, yield 78.2%.
Embodiment 4:
Get Agomelatine (30g), add ethyl acetate (80ml), stir, then add Glacial acetic acid (10ml), be warming up to 40 ~ 45 DEG C, Quan Rong.Gained solution is added in the toluene (80ml) of about 10 DEG C, drip and finish, stir 30min, filter, gained solid adjusts PH7 ~ 7.5 with the 5%LiOH aqueous solution, and filter, filter cake washs with water (100ml × 2), about 40 DEG C, vacuum is dry, obtains Agomelatine 24.8g, yield 82.7%.
Claims (10)
1. a method of preparation I compound agomelatine crystal form I, comprises the following steps:
A) added by Agomelatine in the mixed solvent of acetic acid and organic solvent A, heating makes it dissolve completely; Wherein Heating temperature be 25 DEG C to solvent reflux temperature;
Organic solvent A is selected from: normal hexane, normal heptane, methylcyclohexane, toluene, ethyl acetate, butylacetate, n-propyl acetate, isobutyl acetate, methyl tertiary butyl ether, ethylene glycol monomethyl ether, propylene glycol monomethyl ether, 2-methyltetrahydrofuran, cyclopentyl-methyl ether, methyl-phenoxide or isopropyl ether;
The volume ratio of organic solvent A and acetic acid is: 1:0.01 ~ 1;
B) above-mentioned solution is joined in another kind of organic solvent B, separate out solid; In adition process, the temperature of organic solvent B maintains-35 DEG C ~ 40 DEG C;
Described organic solvent B is selected from: normal hexane, normal heptane, methylcyclohexane, toluene, ethyl acetate, butylacetate, n-propyl acetate, isobutyl acetate, methyl tertiary butyl ether, ethylene glycol monomethyl ether, propylene glycol monomethyl ether, 2-methyltetrahydrofuran, cyclopentyl-methyl ether, methyl-phenoxide or isopropyl ether;
The volume ratio of described organic solvent A and organic solvent B is 1:0.1 ~ 10;
C) filter, gained solid alkali liquid washing is to pH7 ~ 7.5;
D) filter, vacuum-drying obtains agomelatine crystal form I.
2. method according to claim 1, wherein organic solvent A is preferably cyclopentyl-methyl ether, methyl tertiary butyl ether, or ethyl acetate.
3. method according to claim 1, wherein preferred 1:0.05 ~ 0.5 of the volume ratio of organic solvent A and acetic acid.
4. method according to claim 1, wherein organic solvent B is preferably methyl tertiary butyl ether, normal heptane or toluene.
5. method according to claim 1, described organic solvent A and preferred 1:0.5 ~ 5 of the volume ratio of organic solvent B.
6. method according to claim 1, described step b) temperature of organic solvent B maintains-35 DEG C ~ 35 DEG C in adition process.
7. method according to claim 6, described step b) temperature of organic solvent B maintains-35 DEG C ~ 10 DEG C in adition process.
8. method according to claim 1, described alkali lye is selected from NaHCO
3the aqueous solution, KHCO
3the aqueous solution, Na
2cO
3the aqueous solution, K
2cO
3the aqueous solution, the KOH aqueous solution, the NaOH aqueous solution, the LiOH aqueous solution or ammoniacal liquor.
9. method according to claim 1, vacuum-drying temperature is 25 ~ 50 DEG C.
10. method according to claim 9, vacuum-drying temperature is 35 ~ 45 DEG C.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102050755A (en) * | 2009-10-29 | 2011-05-11 | 重庆医药工业研究院有限责任公司 | Novel agomelatine crystal forms and preparation methods of agomelatine crystal forms |
| WO2011128413A1 (en) * | 2010-04-15 | 2011-10-20 | Ratiopharm Gmbh | Process for the production of polymorph form i of agomelatine |
| CN102531942A (en) * | 2011-11-17 | 2012-07-04 | 成都欣捷高新技术开发有限公司 | Preparation method of agomelatine I crystal forms |
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2013
- 2013-08-08 CN CN201310345234.5A patent/CN104341315A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102050755A (en) * | 2009-10-29 | 2011-05-11 | 重庆医药工业研究院有限责任公司 | Novel agomelatine crystal forms and preparation methods of agomelatine crystal forms |
| WO2011128413A1 (en) * | 2010-04-15 | 2011-10-20 | Ratiopharm Gmbh | Process for the production of polymorph form i of agomelatine |
| CN102531942A (en) * | 2011-11-17 | 2012-07-04 | 成都欣捷高新技术开发有限公司 | Preparation method of agomelatine I crystal forms |
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| CB03 | Change of inventor or designer information |
Inventor after: Fang Gan Inventor after: Wang Jubo Inventor after: Si Yongxing Inventor after: Xu Wei Inventor after: Gu Hong Inventor before: Fang Gan Inventor before: Wang Jubo Inventor before: Si Yongxing Inventor before: Xu Wei Inventor before: Wu Wenju Inventor before: Zhang Xini |
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Application publication date: 20150211 |
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