CN102030673B - New crystal form of agomelatine and preparation method thereof - Google Patents
New crystal form of agomelatine and preparation method thereof Download PDFInfo
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- CN102030673B CN102030673B CN201010573150.3A CN201010573150A CN102030673B CN 102030673 B CN102030673 B CN 102030673B CN 201010573150 A CN201010573150 A CN 201010573150A CN 102030673 B CN102030673 B CN 102030673B
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Abstract
The invention relates to a new crystal form of agomelatine and a preparation method thereof, belonging to the technical field of chemical synthesis of drugs. The invention discloses a new crystal form of the agomelatine which is a drug for treating depression, and has a single absorption peak near 108 DEGC through differential scanning thermoanalysis. The invention further discloses a method for preparing the new crystal form of the agomelatine in tetrahydrofuran.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, relate to a kind of new crystal of thymoleptic Agomelatine and preparation method.
Background technology
Agomelatine (Agomelatine) be first rake of French Servier company exploitation to the thymoleptic of melatonin hormone, be also simultaneously as MT1 and MT2 melatonin receptor agonist and 5-HT
2cthe first thymoleptic of antagonist.Compare with serotonin NRI (SNRI) thymoleptic with traditional selective serotonin reuptake inhibitor (SSRI), there is more remarkable antidepressant curative effect, can make the serious disorderly biorhythm of patients with depression again recover normal, and in major depressive disorder patient, the antidepressant curative effect of Agomelatine is better than the fluoxetine of SSRI class.A large amount of clinical research confirmations, Agomelatine Cure of depression good effect, anxiety symptom rapid-action, that improvement is followed simultaneously; Can improve the people that sleep, on the alertness on daytime without impact; Security and better tolerance, especially little on the impact of sexual function, thymoleptic had more advantage more in the past.
Agomelatine, chemical name is n-[2-(7-methoxy-1-naphthyl) ethyl] ethanamide, its structural formula is as follows:
About Agomelatine, have many pieces of bibliographical informations: in European patent specification EP0447285A, described and take 7-methoxyl group-ALPHA-tetralone as the method for starting raw material through the synthetic Agomelatine of 7 steps reaction.Novel method with the synthetic Agomelatine of 7-methyl isophthalic acid-naphthols has been described in EP2151428A.Acta Cryst, 1994, C50, is described in detail crystal formation I in 907～910.Chinese patent specification sheets CN1680284 has recorded by the method for ethanol/water mixed solution recrystallization and has prepared agomelatine crystal form II.Chinese patent specification sheets CN1907959 has recorded the preparation of the new crystal III of Agomelatine, both Agomelatine has been heated to fine melt at 110 ℃ after Slow cooling until crystallization.CN1907957 is cooling rapidly between 50～70 ℃ after having described Agomelatine being dissolved completely, and maintains at 70 ℃ the method that about 5h prepares form IV.Chinese patent specification sheets CN1907958 has described the method for preparing crystal form V.In CN101429134, recorded the preparation method of crystal form V I.
The inventor, in research process, has found to be different from the New crystal form of agomelatine of existing bibliographical information, has obtained X-ray powder diffraction spectrum.This crystal formation purity is high, and good stability has superiority in explained hereafter, is applicable to preparation technical process and lays in for a long time.
Summary of the invention
One object of the present invention is to provide a kind of New crystal form of agomelatine, and the quality of the pharmaceutical preparations of preparing with it is stable, favorable reproducibility.
Another object of the present invention has been to provide the preparation method of New crystal form of agomelatine.
An agomelatine crystal form, the analysis of poor formula scanning calorimeter has single absorption peak near 108 ℃, and this crystal form X-ray powder diffraction feature is expressed as follows with 2 θ diffraction angle, spacing D and relative intensity:
The preparation method of New crystal form of agomelatine of the present invention, is characterized in that Agomelatine to be dissolved in tetrahydrofuran (THF), in system, drips water, filters, dry.
In above-mentioned preparation process, between 10～20 ℃, drip water best results.Owing to making in its crystallization process adding water to Agomelatine tetrahydrofuran solution, solution system can heat release, now easily occurs mixed crystal phenomenon, and it is necessary therefore solution being cooled to 10～20 ℃.
In above-mentioned preparation process, the consumption of tetrahydrofuran (THF), with respect to 1g Agomelatine, is preferably 2～4ml.Experimental studies have found that, when the consumption of tetrahydrofuran (THF) is 2～4ml with respect to 1g Agomelatine, Agomelatine tetrahydrofuran solution can form saturated solution at 10～20 ℃.
In above-mentioned preparation process, the consumption of water, with respect to 1ml tetrahydrofuran (THF), is preferably 8～10ml.Experimental studies have found that, when the consumption of water is 8～10ml with respect to 1ml tetrahydrofuran (THF), tetrahydrofuran (THF) water mixed solution does not almost have solvability to Agomelatine.
No matter which kind of crystal habit the Agomelatine before dissolving is, whether be solvate, by above-mentioned preparation process, all obtain this New crystal form of agomelatine.
Agomelatine crystal disclosed by the invention has the purposes identical with known Agomelatine compound itself.Mouse test shows, after New crystal form of agomelatine mouse of the present invention administration, in blood plasma, MT content is apparently higher than control group.
New crystal has the effect of melatonin receptors agonist, also be serotonin 2C receptor antagonist, can be used for treatment depression, Serious depression, seasonal affective disorder, somnopathy, cardiovascular pathology and physiological clock adjusting etc., is the medicine that can be used for manufacturing Cure of depression.
Accompanying drawing explanation
Fig. 1 is agomelatine crystal X-ray powder diffraction.
Fig. 2 is agomelatine crystal DSC endothermic transition collection of illustrative plates.
Embodiment
100 grams of Agomelatines are joined in 200 milliliters of tetrahydrofuran (THF)s, and heated and stirred is dissolved.After dissolving, the tetrahydrofuran solution of gained Agomelatine is cooled between 10 ℃～20 ℃, stirs lower 1600 ml waters that slowly drip, maintain the temperature between 10 ℃～20 ℃.Dropwise, filter crystal, vacuum-drying obtains 99.1 grams of agomelatine crystals, yield: 99.1% for 12 hours.
100 grams of Agomelatines are joined in 300 milliliters of tetrahydrofuran (THF)s, and heated and stirred is dissolved.After dissolving, the tetrahydrofuran solution of gained Agomelatine is cooled between 10 ℃～20 ℃, stirs lower 2400 ml waters that slowly drip, maintain the temperature between 10 ℃～20 ℃.Dropwise, filter crystal, vacuum-drying obtains 99.1 grams of agomelatine crystals, yield: 99.1% for 12 hours.
100 grams of Agomelatines are joined in 400 milliliters of tetrahydrofuran (THF)s, and heated and stirred is dissolved.After dissolving, the tetrahydrofuran solution of gained Agomelatine is cooled between 10 ℃～20 ℃, stirs lower 4000 ml waters that slowly drip, maintain the temperature between 10 ℃～20 ℃.Dropwise, filter crystal, vacuum-drying obtains 99.0 grams of agomelatine crystals, yield: 99.0% for 12 hours.
Embodiment 4
100 grams of Agomelatines are joined in 300 milliliters of tetrahydrofuran (THF)s, and heated and stirred is dissolved.After dissolving, the tetrahydrofuran solution of gained Agomelatine is cooled between 10 ℃～20 ℃, stirs lower 2700 ml waters that slowly drip, maintain the temperature between 10 ℃～20 ℃.Dropwise, filter crystal, vacuum-drying obtains 99.1 grams of agomelatine crystals, yield: 99.1% for 12 hours.
Above embodiment is only not used in the present invention also and should be understood to the restriction to inventing in claim for further explaining.
Claims (2)
1. X-ray powder diffraction feature is as a preparation method for the agomelatine crystal of following table,
It is characterized in that, Agomelatine is dissolved in tetrahydrofuran (THF), in system, drip water, filter, dry, wherein, the consumption of water is 8～10ml with respect to 1ml tetrahydrofuran (THF), and the consumption of tetrahydrofuran (THF) is 2～4ml with respect to 1g Agomelatine.
2. according to preparation method claimed in claim 1, it is characterized in that, between 10～20 ℃, drip water.
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| CN102030673B true CN102030673B (en) | 2014-04-23 |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102557979B (en) * | 2010-12-16 | 2014-11-26 | 北大方正集团有限公司 | Agomelatine crystal form, as well as preparation method, application and medicinal composition thereof |
| FR2978916B1 (en) | 2011-08-10 | 2013-07-26 | Servier Lab | SOLID PHARMACEUTICAL COMPOSITION FOR BUCCAL ADMINISTRATION OF AGOMELATIN |
| CN103130673B (en) * | 2011-11-28 | 2017-05-03 | 重庆医药工业研究院有限责任公司 | Preparation method of agomelatine crystal type I |
| CN103360275B (en) * | 2012-03-30 | 2015-04-22 | 上海创诺制药有限公司 | Method for preparing agomelatine I-type crystal |
| FR3001894A1 (en) | 2013-02-08 | 2014-08-15 | Servier Lab | SOLID PHARMACEUTICAL COMPOSITION FOR BUCCAL ADMINISTRATION OF AGOMELATIN |
| EP3075724B1 (en) | 2015-03-31 | 2023-07-12 | F.I.S.- Fabbrica Italiana Sintetici S.p.A. | Solid form of agomelatine |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1680284A (en) * | 2004-02-13 | 2005-10-12 | 瑟维尔实验室 | New process for the synthesis and new crystalline form of agomelatine and pharmaceutical compositions containing it |
| CN101735091A (en) * | 2009-12-30 | 2010-06-16 | 北京德众万全药物技术开发有限公司 | Preparation method of Agomelatine |
| CN101759591A (en) * | 2009-07-11 | 2010-06-30 | 浙江华海药业股份有限公司 | Preparing method of N-[2-(7- anisyl-1- naphthyl) ethide] acetamide |
| CN101774937A (en) * | 2010-02-05 | 2010-07-14 | 天津市汉康医药生物技术有限公司 | N-[2-(7-methoxyl-1-naphthyl)ethyl]acetamide and compound thereof |
| 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 |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1680284A (en) * | 2004-02-13 | 2005-10-12 | 瑟维尔实验室 | New process for the synthesis and new crystalline form of agomelatine and pharmaceutical compositions containing it |
| CN101759591A (en) * | 2009-07-11 | 2010-06-30 | 浙江华海药业股份有限公司 | Preparing method of N-[2-(7- anisyl-1- naphthyl) ethide] acetamide |
| 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 |
| CN101735091A (en) * | 2009-12-30 | 2010-06-16 | 北京德众万全药物技术开发有限公司 | Preparation method of Agomelatine |
| CN101774937A (en) * | 2010-02-05 | 2010-07-14 | 天津市汉康医药生物技术有限公司 | N-[2-(7-methoxyl-1-naphthyl)ethyl]acetamide and compound thereof |
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