CN101704763B - Preparation method of agomelatine I type crystal - Google Patents
Preparation method of agomelatine I type crystal Download PDFInfo
- Publication number
- CN101704763B CN101704763B CN2009102286835A CN200910228683A CN101704763B CN 101704763 B CN101704763 B CN 101704763B CN 2009102286835 A CN2009102286835 A CN 2009102286835A CN 200910228683 A CN200910228683 A CN 200910228683A CN 101704763 B CN101704763 B CN 101704763B
- Authority
- CN
- China
- Prior art keywords
- agomelatine
- water
- preparation
- organic solvent
- hydrophilic organic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- YJYPHIXNFHFHND-UHFFFAOYSA-N CC(NCCc1cccc(cc2)c1cc2OC)=O Chemical compound CC(NCCc1cccc(cc2)c1cc2OC)=O YJYPHIXNFHFHND-UHFFFAOYSA-N 0.000 description 1
Images
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a preparation method of an agomelatine I type crystal which is an anti-depressant. The preparation method comprises the following steps of: dissolving crude agomelatine in a hydrophily organic solvent, filtering, dropping the filtrate into water under stirring, separating out solids and drying; wherein the weight part ratio of the hydrophily organic solvent to the water is 1:2-50. The agomelatine I type crystal prepared by the invention has excellent quality, good reproducibility, and high purity of HPLC normalization method to be above 99 percent, and is more suitable for large-scale industrialization production.
Description
Technical field
The invention belongs to the pharmaceutical chemistry synthesis technical field, relate to the preparation method of agomelatine I type crystal.
Background technology
Agomelatine (Agomelatine) is the first development of French Shi Weiya company and is the agonist of unique melatonin 1,2 (MT1MT2) acceptor, also is the antagonist of serotonin 2c (5HT2c) acceptor simultaneously.Be mainly used in the outbreak of treatment dysthymia disorders.Its unique mechanism of action and the antidepressant drug that generally adopts at present as: selective serotonin reuptake inhibitor (SSRI) and serotonin-NRI (SNRI) are fully different: SSRI and SNRI class thymoleptic are realized the antidepressant curative effect through increase serotonin concentration; But this has also brought many spinoffs; Change like body weight; Sexual dysfunction, drug withdrawal syndrome etc.And the drug molecular structure of Agomelatine is direct and serotonin 2c (5HT2c) receptors bind of nerve synapse caudacoria, thereby brings into play its antidepressant curative effect, and does not increase the serotonin concentration of synaptic cleft.The mechanism of action of this uniqueness makes Agomelatine when bringing into play its antidepressant curative effect quickly and effectively, has avoided the generation of drug side effect to greatest extent.
The another one unique effect target spot of Agomelatine shows the melatonin receptors aspect.MT1 MT2 acceptor dense distribution is at the mankind's suprachiasmatic nucleus, the sleep rhythm that this nerve nucleus major control is human.Agomelatine is the agonist of MT1 MT2 acceptor.Through the agonism to MT1 MT2 acceptor, Agomelatine has improved patient's sleep quality well, has improved patient's waking state in the daytime simultaneously.The relation that lapses to reciprocal causation of dormant quality and dysthymia disorders.It is reported that 80% patients with depression all exists the problem of somnopathy to some extent.The improvement of sleep quality has directly promoted the improvement of patients with depression overall clinical situation.Vast amount of clinical is verified: Agomelatine has ideal shot and long term curative effect, and this medicine onset is rapid, and significantly reduces the recurrence recrudescence rate of depressive patient; Security significantly is superior to SSRI, SNRI class medicine, in alleviate depression disease core symptom, has significantly improved patient's sleep quality, has improved the daystart waking state.Undoubtedly, the appearance of Agomelatine is that doctor and patient are bringing new selection approach aspect the selection of treatment dysthymia disorders medicine.
Agomelatine (agomelatine), chemical name is: N-[2-(7-methoxyl group-1-naphthyl) ethyl] ethanamide, its structural formula is following:
At present, the document description about treatment dysthymia disorders medicine Agomelatine polymorphism mainly comprises: in European patent specification EP0447285, described Agomelatine, its preparation and therepic use thereof; One Chinese patent application number: put down in writing novel synthesis, new crystal and the pharmaceutical composition thereof of Agomelatine in 200510071611.6, its adopts the method for ethyl alcohol recrystallization to prepare agomelatine I I crystal; Agomelatine I crystal wherein by people such as Tinant (Acta Cryst, 1994, C50 907-910.) has carried out detailed description.Application number 200610108396.7 has been put down in writing agomelatine I II crystalline preparation method, and it is to heat the U.S. stretching thawing extremely fully of algebraic oriented language down at 110 ℃, slowly cools off until crystallization then.Application number: put down in writing new crystalline form I V, its preparation method of Agomelatine in 200610108394.8 and comprised its pharmaceutical composition.Application number: put down in writing new crystalline form V, its preparation method of Agomelatine in 200610108395.2 and comprised its pharmaceutical composition, it is that Agomelatine is carried out so-called " high energy " mechanical mill, is prepared into the new crystalline form V of Agomelatine.Application number: put down in writing new crystalline form VI, its preparation method of Agomelatine in 200810174918.2 and comprised its pharmaceutical composition; It is that Agomelatine is heated in isopropyl ether solution; Be quickly cooled to 0 ℃, crystallization 24 hours in vacuum filtration or Agomelatine water/alcohol mixture (50/50) volume then.Although above-mentioned patent has been described the preparation method of different crystal forms Agomelatine, there is the shortcoming of technology stability, poor repeatability in the agomelatine I crystal of above-mentioned literature method introduction, is difficult to be fit to large-scale industrial production.The inventor has developed the preparation agomelatine I crystalline novel method that is different from existing document, and succeeds.
Summary of the invention
The present invention is through adopting hydrophilic organic solvent and water that the Agomelatine bullion is carried out recrystallization, having found agomelatine I type crystal preparation method superior in quality, favorable reproducibility.Adopt the agomelatine I type crystal of the inventive method preparation, HPLC normalization method purity can reach more than 99%, is more suitable for large-scale industrial production.For realizing that above-mentioned purpose the present invention provides following technical scheme:
Agomelatine I type crystal preparation method of the present invention, it is that the Agomelatine bullion is dissolved in the hydrophilic organic solvent, filters, and under agitation splashes in the water then, separates out solid, drying.
Hydrophilic organic solvent add-on of the present invention does not have special requirement, can dissolve the Agomelatine bullion and be as the criterion (can suitably heat sometimes as required).Described hydrophilic organic solvent comprises: alcohols, amides, ketone, nitrile or diol, derivatives class or the like.Alcohols wherein is methyl alcohol, ethanol, absolute ethyl alcohol, Virahol or terepthaloyl moietie; Amides is N DMF (HCON (CH
3)
2), N,N-DIMETHYLACETAMIDE DMAC (CH
3CON (CH
3)
2) hexamethylphosphoramide HMP; Ketone is acetone or 2-butanone; Nitrile is acetonitrile or succinonitrile; The diol, derivatives class is ethylene glycol monomethyl ether, ethylene glycol monoethyl ether or ethylene glycol monobutyl ether.Described hydrophilic organic solvent has also comprised THF, methyl-sulphoxide, N SL 1332 or 1,4 dioxane etc.
Among the preparation method of the present invention, the ratio of weight and number of hydrophilic organic solvent and water is 1: 2-50; Among another preparation method, the ratio of weight and number of hydrophilic organic solvent and water is 1: 5-50.Also among preparation method, the ratio of weight and number of hydrophilic organic solvent and water is 1: 10-40.Also among preparation method, the ratio of weight and number of hydrophilic organic solvent and water is 1: 20-40.
When filtrating of the present invention under agitation splashes in the water, temperature is not had special requirement, general 0-100 ℃ all can, preferred 5-60 ℃.
Of the present invention splashing in the water, water wherein can be common ordinary water, medicinal purified water, water for injection, deionized water or zero(ppm) water, preferably use zero(ppm) water.
Typical embodiment of the present invention adds the Agomelatine bullion in the absolute ethyl alcohol to dissolve, and filters, and filtrating slowly splashes in the zero(ppm) water of stirring (about absolute ethyl alcohol 20 times).Dropwise, stirring at room is filtered, and filter cake is with the distillation washing, and vacuum-drying 10h gets content greater than 99% agomelatine I type crystal.
Another typical embodiment of the present invention joins the Agomelatine bullion in the DMSO 99.8MIN. to dissolve, and filters, and filtrating slowly splashes in the zero(ppm) water of stirring (about DMSO 99.8MIN. 30 times).Dropwise, stirring at room is filtered, and filter cake is with the distillation washing, and vacuum-drying 15h gets content greater than 99% agomelatine I type crystal.
Another typical embodiment of the present invention joins the Agomelatine bullion in the THF and to dissolve, and filters, and filtrating slowly splashes in the zero(ppm) water of stirring (be equivalent to THF 50 times).Dropwise, stirring at room is filtered, and filter cake is with the distillation washing, and vacuum-drying 20h gets content greater than 99% agomelatine I type crystal.
Another typical embodiment of the present invention joins the Agomelatine bullion in the N (DMF), and room temperature dissolving is filtered, and filtrating slowly splashes in the zero(ppm) water of stirring (about DMF 20 times).Dropwise, stirring at room is filtered, and cakes with deionized water is washed, and vacuum-drying 20h gets content greater than 99% agomelatine I type crystal.
Description of drawings:
Fig. 1, Fig. 1-a are agomelatine I type crystal X-ray powder diffraction.
Embodiment
Following examples are with helping understand the present invention, and are not used in and also should be interpreted as the restriction to inventing in the listed claim by any way.Wherein the preparation method of Agomelatine compound bullion prepares with reference to the EP0447285 patent.
Reference implementation example 1:
The preparation of (7-methoxyl group-1,2,3,4-tetrahydrochysene-1-naphthalene thiazolinyl)-ETHYLE ACETATE
85g7-methoxyl group-1-Tetralone an intermediate of Sertraline and 75g activated zinc powder are added in the reaction flask, add 100ml toluene and 2 iodine crystal then, stir, be heated to reflux state.Beginning slowly drips the mixing solutions of 129ml METHYL BROMOACETATE and 100ml toluene, and heating, maintenance reaction solution are in reflux state.Dropwise, continue to reflux stopped reaction 10 minutes.
Reaction solution is cooled to 25 ℃, stirs down to add 1500ml frozen water and 200ml hydrochloric acid, stir after 10 minutes, and layering, water layer with toluene 250mlX2 extraction, merges organic phase again, adds the 70g anhydrous sodium sulfate drying.Next day, filter, add 80g P in the filtrating
2O
5, stirring, reflux were reacted 3 hours.Reaction finishes, and is cooled to 25 ℃, filters, and the filtrate decompression evaporate to dryness gets 100g light brown oily thing, content 90% (HPLC), pure yield 75.8%.
Reference implementation example 2: the preparation of (7-methoxyl group-1-naphthyl)-ETHYLE ACETATE
17.6g elemental sulfur and 90g (7-methoxyl group-1,2,3,4-tetrahydrochysene-1-naphthalene thiazolinyl)-ETHYLE ACETATE are added in the reaction flask, be heated with stirring to 215 ℃, reacted 10 hours.
Reaction finishes, and naturally cools to 60 ℃, adds 500ml ETHYLE ACETATE, and mixture stirs 30min.Filter, with 100ml ETHYLE ACETATE washing leaching cake, merging filtrate, evaporated under reduced pressure gets 92 gram brown oil, and content is 82.4% (HPLC), pure yield 85%.
Reference implementation example 3:
The preparation of 7-methoxyl group-1-naphthyl acetic acid
The 40g dissolution of sodium hydroxide in 1000ml water, is added 1000ml 95% ethanol, mix.Then 50g (7-methoxyl group-1-naphthyl)-ETHYLE ACETATE is joined in the above-mentioned mixing solutions stirring at room 3 hours.Stopped reaction, pressure reducing and steaming ethanol gets brown liquid, after ETHYLE ACETATE 300ml X 2 washings, in water layer, adds 95% ethanol 30ml, stirs down, and it is 2 that the dropping concentrated hydrochloric acid is regulated PH, separates out a large amount of light brown solids.Filter, the dry product 32g that gets, mp154-156 ℃, it is 98.48% that HPLC measures content, yield 72%.
The preparation of reference implementation example 4:7-methoxyl group-1-naphthyl acetamide
50g 7-methoxyl group-1-naphthyl acetic acid is added in the methylene dichloride of 750ml, heating for dissolving keeps reflux state slowly to drip thionyl chloride down, dropwises afterreaction backflow 2h.
Reaction finishes, and the reaction solution evaporated under reduced pressure is got red-brown oily matter, external application frozen water cooling curing.The gained solid is used the 500ml acetic acid ethyl dissolution, and the cooling of external application icy salt solution slowly drips the 47.2ml strong aqua, separates out a large amount of faint yellow solids, filtration, the dry bullion 49.8g that gets.Carry out recrystallization with 747ml 95% ethanol, 37.3g gac, get elaboration 46g, mp201-202 ℃, yield 92.4%.
Reference implementation example 5:
The preparation of 7-methoxyl group-1-naphthyl acetonitrile
30g7-methoxyl group-1-naphthyl acetamide, 120ml THF and 35.7g triethylamine are joined in the reaction flask, stir, the external application cryosel is bathed cooling, slowly drips trifluoroacetic anhydride (TFAA).Drip and finish, continue to stir 15min, remove ice bath then, stirring at room 2h.Reaction finishes, and with the reaction solution evaporate to dryness, adds 200ml water, stirs after 0.5 hour, filters, and the dry bullion 28g that gets with 280ml isopropyl ether, 1.4g gac recrystallization, gets elaboration 22 grams, and mp82-84 ℃, yield 80%.
The preparation of reference implementation example 6:2-(7-methoxyl group-1-naphthyl) ethamine
56g7-methoxyl group-1-naphthyl acetonitrile, 120ml ammoniacal liquor, 332ml 95% ethanol, 20g Raney-Ni are added in the autoclave, vacuumize the back and feed H
2, repeatable operation 3 times.Feed H
2, keep 300 normal atmosphere, 60 ℃ condition, stirring reaction 12 hours.Reaction finishes, and room temperature is spent the night under placing.Vacuumize next day, feeds N
2Gas is opened autoclave, with the reaction solution filtration catalizer, filtrate evaporated under reduced pressure to do light green oily matter 56g, it is 96.95% that HPLC measures content, pure yield is 95%.
Reference implementation example 7:
The preparation of N-[2-(7-methoxyl group-1-naphthyl) ethyl] ethanamide (Agomelatine)
40g 2-(7-methoxyl group-1-naphthyl) ethamine is dissolved in the 250ml pyridine, is heated to 40 ℃ and all dissolves clear.Under the ice bath cooling and stirring, slowly drip the 21.9g Acetyl Chloride 98Min..Drip and finish, remove ice bath, stirring at room 30 minutes.Pour reaction solution in the 300ml frozen water into then, the while vigorous stirring is separated out a large amount of white precipitates, continues to stir 1 hour, filters, and filter cake water 200mlX2 washing gets bullion 48g (the gained bullion is used for following preparation embodiment).
1H NMR (400MHZ, CDCl
3): δ 7.77-7.15 (m 6H); δ 5.61 (s, 1H); δ 3.99 (s, 3H); δ 3.62 (m, 2H); δ 3.25 (t, 2H); δ 1.95 (s, 3H) consistent (J.Med.Chem, 1994,37 (20), 3231-3239 with bibliographical information.
Preparation embodiment
Embodiment 1
With the 2g Agomelatine mutually article join in the 10ml absolute ethyl alcohol and dissolve, filter, filtrate under room temperature, slowly splash in the 200ml zero(ppm) water of stirring.Dropwise, stirring at room 30 minutes is filtered, and filter cake is with distillation washing, vacuum-drying 10h.Yield 88.5%, content 99.4%, its monocrystalline data and the described I type of document data consistent (ActaCryst, 1994, C50,907-910.); The X-ray powder diffraction is seen Fig. 1.
2g Agomelatine bullion joined in the 5ml DMSO 99.8MIN. dissolve, filter, filtrating slowly splashes in the 200ml zero(ppm) water of stirring.Dropwise, stirring at room 30 minutes is filtered, and filter cake is with distillation washing, vacuum-drying 10h.Yield 87.5%, content 99.7%.The X-ray powder diffraction is seen Fig. 1.
Embodiment 3
2g Agomelatine bullion joined in the 15ml THF dissolve, filter, under agitation, filtrating slowly splashes in the zero(ppm) water of 500ml.Dropwise, stirring at room 30 minutes is filtered, and filter cake is with distillation washing, vacuum-drying 10h.Yield 86.0%, content 99.6%.The X-ray powder diffraction is seen Fig. 1.
Embodiment 4
2g Agomelatine bullion joined in the 20ml acetone dissolve, filter, filtrating slowly splashes in the 400ml of stirring, the 10 ℃ of zero(ppm) water.Dropwise, stirring at room 30 minutes is filtered, and filter cake is with distillation washing, vacuum-drying 10h.Yield 88.0%, content 99%.The X-ray powder diffraction is seen Fig. 1.
Embodiment 5
2g Agomelatine bullion is joined in the 10ml Virahol, and room temperature dissolving is filtered, and filtrating slowly splashes in the zero(ppm) water of 400ml of stirring.Dropwise, stirring at room 30 minutes is filtered, and filter cake is with distillation washing, vacuum-drying 10h.Yield 90.0%, content 99.4%.The X-ray powder diffraction is seen Fig. 1.
Embodiment 6
2g Agomelatine bullion joined in the 10ml terepthaloyl moietie dissolve, filter, filtrating slowly splashes in the 200ml zero(ppm) water of stirring.Dropwise, stirred 30 minutes, filter, filter cake is with distillation washing, vacuum-drying 10h.Yield 89.0%, content 99.0%.The X-ray powder diffraction is seen Fig. 1.
Embodiment 7
2g Agomelatine bullion joined in the 5ml ethylene glycol monobutyl ether dissolve, filter, filtrating slowly splashes in the 250ml zero(ppm) water of stirring.Dropwise, stirring at room 30 minutes is filtered, and filter cake is with distillation washing, vacuum-drying 15h.Yield 90%, content 99.2%.The X-ray powder diffraction is seen Fig. 1.
Embodiment 8
2g Agomelatine bullion is joined dissolving in the 5ml N (DMF), filter, filtrating slowly splashes in the 400ml of stirring, the 60 ℃ of zero(ppm) water.Dropwise, stirring at room 30 minutes is filtered, and filter cake is with distillation washing, vacuum-drying 10h.Yield 87.5%, content 99.3%.The X-ray powder diffraction is seen Fig. 1.
2g Agomelatine bullion joined in the 8ml N SL 1332 dissolve, filter, filtrating slowly splashes in the medicinal water of 500ml of stirring.Dropwise, stirring at room 30 minutes is filtered, and filter cake is with distillation washing, vacuum-drying 15h.Yield 86.2%, content 99.1%.The X-ray powder diffraction is seen Fig. 1.
Embodiment 10
2g Agomelatine bullion joined in the 25ml N SL 1332 dissolve, filter, filtrating slowly splashes in the 500ml deionized water of stirring.Dropwise, stirring at room 30 minutes is filtered, and filter cake is with distillation washing, vacuum-drying 15h.Yield 87.2%, content 99.5%.The X-ray powder diffraction is seen Fig. 1.
20g Agomelatine bullion joined in the 200ml THF dissolve, filter, filtrating slowly splashes into 1000ml in the zero(ppm) water of stirring.Dropwise, stirring at room is filtered, and filter cake is with the distillation washing, and vacuum-drying 20h gets content greater than 99.6%, yield 88.0% agomelatine I type crystal, and the X-ray powder diffraction is seen Fig. 1.
Claims (7)
1. the preparation method of agomelatine I type crystal is characterized in that, the X-ray powder diffraction is as shown in Figure 1, and its preparation method is that the Agomelatine bullion is dissolved in the hydrophilic organic solvent, filters, and under agitation splashes in the water then, separates out solid, drying.
2. the described preparation method of claim 1, wherein hydrophilic organic solvent is methyl alcohol, ethanol, absolute ethyl alcohol, Virahol, terepthaloyl moietie, acetone, 2-butanone, acetonitrile, succinonitrile, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether or ethylene glycol monobutyl ether.
3. the described preparation method of claim 1, wherein hydrophilic organic solvent also comprises THF, methyl-sulphoxide, N SL 1332 or 1,4 dioxane.
4. the described preparation method of claim 1, wherein the ratio of weight and number of hydrophilic organic solvent and water is 1: 2-50.
5. the described preparation method of claim 3, wherein the ratio of weight and number of hydrophilic organic solvent and water is 1: 5-50.
6. the described preparation method of claim 4, wherein the ratio of weight and number of hydrophilic organic solvent and water is 1: 10-40.
7. the described preparation method of claim 5, wherein the ratio of weight and number of hydrophilic organic solvent and water is 1: 20-40.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009102286835A CN101704763B (en) | 2009-11-25 | 2009-11-25 | Preparation method of agomelatine I type crystal |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009102286835A CN101704763B (en) | 2009-11-25 | 2009-11-25 | Preparation method of agomelatine I type crystal |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101704763A CN101704763A (en) | 2010-05-12 |
| CN101704763B true CN101704763B (en) | 2012-03-28 |
Family
ID=42375029
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009102286835A Expired - Fee Related CN101704763B (en) | 2009-11-25 | 2009-11-25 | Preparation method of agomelatine I type crystal |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101704763B (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101921205B (en) * | 2010-08-30 | 2013-11-20 | 江苏恩华药业股份有限公司 | Preparation method of agomelatine I crystal form |
| CN102452952A (en) * | 2010-11-03 | 2012-05-16 | 天津药物研究院 | Preparation method of high-purity I-type agomelatine crystal |
| CZ303787B6 (en) * | 2011-01-21 | 2013-05-02 | Zentiva, K.S. | Agomelatine metastable crystal forms and pharmaceutical composition thereof |
| CN102690210A (en) * | 2011-03-23 | 2012-09-26 | 上海医药工业研究院 | Novel crystal form VII of agomelatine, preparation method and application thereof and pharmaceutical composition containing the same |
| WO2012130837A1 (en) * | 2011-03-28 | 2012-10-04 | Ratiopharm Gmbh | Solid agomelatine in non-crystalline form |
| ITMI20111078A1 (en) | 2011-06-15 | 2012-12-16 | Laboratorio Chimico Int Spa | PROCEDURE FOR THE PREPARATION OF CRYSTALLINE FORMS OF AGOMELATIN AND NEW POLIMORFO |
| EP2739605B1 (en) | 2011-08-03 | 2016-04-27 | Laboratorio Chimico Internazionale S.p.A. | Process for the preparation of crystalline form i of agomelatine |
| CN102531942B (en) * | 2011-11-17 | 2014-04-09 | 成都欣捷高新技术开发有限公司 | Preparation method of agomelatine I crystal forms |
| 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 |
| ES2590908T3 (en) | 2012-12-17 | 2016-11-24 | Dr. Reddy's Laboratories Ltd. | Co-crystal of agomelatine with phosphoric acid |
| CN103690499B (en) | 2013-12-23 | 2015-05-06 | 天津泰普药品科技发展有限公司 | Stable crystalline form I agomelatine tablets and preparation method thereof |
| CN108329226B (en) * | 2018-01-05 | 2020-09-08 | 浙江工业大学 | Preparation method of agomelatine crystal form I |
Citations (2)
| 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 |
| CN101781226A (en) * | 2009-12-23 | 2010-07-21 | 天津泰普药品科技发展有限公司 | Agomelatine and medicine composition thereof |
-
2009
- 2009-11-25 CN CN2009102286835A patent/CN101704763B/en not_active Expired - Fee Related
Patent Citations (3)
| 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 |
| CN101041629A (en) * | 2004-02-13 | 2007-09-26 | 瑟维尔实验室 | New process for the synthesis and new crystalline form of agomelatine and pharmaceutical compositions containing it |
| CN101781226A (en) * | 2009-12-23 | 2010-07-21 | 天津泰普药品科技发展有限公司 | Agomelatine and medicine composition thereof |
Non-Patent Citations (2)
| Title |
|---|
| Bernard tinant et al.N-[2-(7-Methoxy-1-naphthyl)ethyl]-acetamide, a Potent Melatonin Analog.《Acta Crystallographica Section C》.1994,第C50卷907-910. * |
| Bernardtinantetal.N-[2-(7-Methoxy-1-naphthyl)ethyl]-acetamide a Potent Melatonin Analog.《Acta Crystallographica Section C》.1994 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101704763A (en) | 2010-05-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101704763B (en) | Preparation method of agomelatine I type crystal | |
| CN101781226B (en) | Agomelatine and medicine composition thereof | |
| CN100591649C (en) | Method of preparing R-(+)-3-chlorophenylpropanol | |
| AU2010335216A1 (en) | New aminotetraline derivatives | |
| CN108947949B (en) | Anxiolytic deuterated compounds and medical application thereof | |
| CN105348262B (en) | A kind of improved method preparing dabigatran etcxilate | |
| EP2392575A1 (en) | A novel synthetic approach to ß-aminobutyryl substituted compounds | |
| CN102234275B (en) | Deuterated imidazo [1, the 2-a] pyridine derivate of Cure for insomnia, preparation method and application thereof | |
| CN113336765B (en) | Curcumenol esterified product, preparation method and application of curcumenol esterified product in medicine for treating colorectal cancer | |
| EP2576563A1 (en) | A NOVEL SYNTHETIC APPROACH TO ß-AMINOBUTYRYL SUBSTITUTED COMPOUNDS | |
| CN103694178A (en) | Dabigatran etexilate analog centered by fluorine-containing-group-modified benzene ring and synthesis method thereof | |
| CN115160341A (en) | Benzoxazine compound and pharmaceutical use thereof | |
| CN102746178B (en) | The preparation method of flutamide | |
| CN109574856A (en) | A kind of new Rimantadine analog and its synthetic method | |
| CN105418436B (en) | A kind of preparation method of melitracen hydrochloride | |
| CN115785057B (en) | Preparation method of ticagrelor intermediate compound and salt thereof | |
| CN104230882B (en) | A kind of preparation method of duloxetine hydrochloride impurity | |
| AU2020343737A1 (en) | MAGL inhibitor, preparation method therefor and use thereof | |
| CN118878491A (en) | Rameiti Process for the preparation of amines | |
| WO2024155846A1 (en) | Compositions useful for modulating splicing | |
| WO2023212239A1 (en) | Compositions useful for modulating splicing | |
| CN102675315B (en) | Substitutive benzene alkyl contained purine compounds and preparation method and application thereof | |
| CN106883223A (en) | A kind of purification process of Brexpiprazole hydrochlorides | |
| CN108456207A (en) | A kind of amide derivatives and its application in treating cardiac and cerebral vascular diseases | |
| WO2023220433A1 (en) | Compositions useful for modulating splicing |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| DD01 | Delivery of document by public notice |
Addressee: Zhao Jian Document name: payment instructions |
|
| DD01 | Delivery of document by public notice | ||
| DD01 | Delivery of document by public notice |
Addressee: Zhao Jian Document name: Notice of patent termination |
|
| DD01 | Delivery of document by public notice | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120328 Termination date: 20211125 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |