CN102001960A - Method for preparing agomelatine - Google Patents
Method for preparing agomelatine Download PDFInfo
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- CN102001960A CN102001960A CN2010105731700A CN201010573170A CN102001960A CN 102001960 A CN102001960 A CN 102001960A CN 2010105731700 A CN2010105731700 A CN 2010105731700A CN 201010573170 A CN201010573170 A CN 201010573170A CN 102001960 A CN102001960 A CN 102001960A
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- agomelatine
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- acetyl chloride
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Abstract
The invention discloses a method for preparing agomelatine, and belongs to the technical field of chemical synthesis of medicines. The invention discloses a method for preparing an agomelatine medicine for treating depression. NaBH4/I2 is adopted to reduce methoxy-1-naphthylacetonitrile, acetylchloride is selected as an acylation reagent, and the agomelatine is prepared.
Description
Technical field
The invention belongs to the pharmaceutical chemistry synthesis technical field, relate to a kind of preparation method of thymoleptic Agomelatine.
Background technology
Agomelatine (Agomelatine) is the thymoleptic of first rake of French Servier company exploitation to the melatonin hormone, also is 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), has more remarkable antidepressant curative effect, can make the serious disorderly biorhythm of patients with depression recover normal again, and in the major depressive disorder patient, the antidepressant curative effect of Agomelatine is better than the fluoxetine of SSRI class.Vast amount of clinical confirms, Agomelatine treatment dysthymia disorders good effect, rapid-action, improve the anxiety symptom of following simultaneously; Can improve sleep, the alertness on daytime is not had influence; Security and better tolerance, especially little to the influence of sexual function, thymoleptic had more advantage more in the past.
Agomelatine, chemical name are N-[2-(7-methoxyl group-1-naphthyl) ethyl] ethanamide, its structural formula is as follows:
Having described Agomelatine preparation and therepic use thereof among the EP0447285A, is starting raw material with 7-methoxyl group-1-Tetralone an intermediate of Sertraline, and through the synthetic Agomelatine of eight steps reaction, total recovery is lower than 30%.Use the bigger ethyl bromoacetate of pungency in the first step, be unfavorable for environmental protection.Second middle aromizing is incomplete, is difficult to after the saponification obtain than straight product.The 7th step reduction reaction adopts high top pressure operation, needs to carry out under 300 normal atmosphere, and is higher to equipment requirements, considers not ideal enough from cost and environmental.
Put down in writing the novel synthesis of Agomelatine among the CN1680284, wherein preparing intermediate 2-(7-methoxyl group-1-naphthyl) ethamine is to carry out under the hydrogen-pressure of 30Bar, and condition is wayward, not as react suitable industrial application under normal pressure.
Disclose the novel method of synthetic Agomelatine among the CN101643433, wherein 2-(7-methoxyl group-1-naphthyl) ethamine is to carry out under the hydrogen-pressure of 10～50Bar in the medium of Raney nickel, does not also have to solve the problem of preparation Agomelatine under normal pressure.
In the existing bibliographical information, mainly be preparation Agomelatine intermediate 2-(7-methoxyl group-1-naphthyl) ethamine under the hydrogen-pressure of 10～50Bar, find a kind of method for preparing under normal pressure, especially economic and suitable industrialized preparation method is particularly important.
Summary of the invention
The purpose of this invention is to provide the method for preparing Agomelatine and intermediate thereof a kind of economy, that be fit to scale operation.
The invention provides the Agomelatine preparation method may further comprise the steps:
Formula (I) compound is containing NaBH
4And I
2Solvent in the reduction obtain formula (II) compound, formula (II) compound and excess acetyl chloride obtain formula (III) compound.NaBH wherein
4And I
2Reaction generates BH earlier in solvent
3It has than strong reducing property, make the reaction can be than carrying out under the mild conditions, help the raising of reaction yield, reference Tetrahedron 48 (22) 1992Convenient Methods for the Reduction of Amides, Nitriles, Carboxylic Esters, Acids andHydroboration of Alkenes Using NaBH
4/ I
2System.
Formula (I) compound and NaBH
4And I
2Be that reduction obtains formula (II) compound in tetrahydrofuran (THF), formula (II) compound and Acetyl Chloride 98Min. obtain formula (III) compound in methylene dichloride.
Further concrete reaction provided by the invention is:
With formula (I) compound, NaBH
4And I
2Stir in tetrahydrofuran (THF), 0 ℃ drips I down
2Tetrahydrofuran solution, drip complete back flow reaction, alkali liquid washing, ethyl acetate extraction, evaporate to dryness get formula (II) compound.
Formula (II) compound is dissolved in methylene dichloride, adds triethylamine, 0 ℃ of following dripping acetyl chloride, room temperature reaction, reaction finishes and tells organic layer, concentrates the crude product that obtains formula (III) compound.
With recrystallization in the crude product ethanol.
Embodiment
The preparation of embodiment 1:2-(7-methoxyl group-1-naphthyl) ethamine
In reactor, add 125g 7-methoxyl group-1-naphthalene second cyanogen, 70g sodium borohydride and 150mL anhydrous tetrahydro furan.240g iodine is dissolved in the 400ml anhydrous tetrahydro furan, splashes into reactor under 0 ℃.Dropwise, be warming up to backflow.Reaction finishes, and adds dilute hydrochloric acid, destroys unreacted sodium borohydride, adds sodium hydroxide solution then, regulates pH value to 9.Use ethyl acetate extraction, dried over mgso, evaporate to dryness gets oily matter 119g, yield 93%.
The preparation of embodiment 2:2-(7-methoxyl group-1-naphthyl) ethamine
In reactor, add 250g 7-methoxyl group-1-naphthalene second cyanogen, 140g sodium borohydride and 400mL anhydrous tetrahydro furan.480g iodine is dissolved in the 1L anhydrous tetrahydro furan, splashes into reactor under 0 ℃.Dropwise, be warming up to backflow.Reaction finishes, and adds dilute hydrochloric acid, destroys unreacted sodium borohydride, adds sodium hydroxide solution then, regulates pH value to 9.Use ethyl acetate extraction, dried over mgso, evaporate to dryness gets oily matter 238g, yield 93%.
Embodiment 3: the preparation of Agomelatine (N-[2-(7-methoxyl group-1-naphthyl) ethyl] ethanamide)
2-(7-methoxyl group-1-naphthyl) the ethamine oily matter of 119g is dissolved in methylene dichloride, adds the 128g triethylamine, drip the 60g Acetyl Chloride 98Min. down at 0 ℃.Dropwise and rise to room temperature.After reaction finishes, in reaction system, add entry, and use dichloromethane extraction, concentrate the evaporate to dryness organic phase and get the Agomelatine crude product, use ethyl alcohol recrystallization, get Agomelatine 152g, productive rate 98.7%, fusing point: 108 ℃.
Embodiment 4: the preparation of Agomelatine (N-[2-(7-methoxyl group-1-naphthyl) ethyl] ethanamide)
2-(7-methoxyl group-1-naphthyl) the ethamine oily matter of 238g is dissolved in methylene dichloride, adds the 256g triethylamine, drip the 119g Acetyl Chloride 98Min. down at 0 ℃.Dropwise and rise to room temperature.After reaction finishes, in reaction system, add entry, and use dichloromethane extraction, concentrate the evaporate to dryness organic phase and get the Agomelatine crude product, use ethyl alcohol recrystallization, get Agomelatine 300g, productive rate 98%, fusing point: 108 ℃.
Should be appreciated that these embodiment only are the explanations to preferred version of the present invention, and also limit protection scope of the present invention never in any form.Those skilled in the art under the prerequisite that does not deviate from the present invention's spirit and purport, can carry out suitable modification and improvement to the present invention under the instruction of the disclosed content of the present invention, these all will fall within the scope of the present invention.
Claims (7)
1. the preparation method of an Agomelatine:
It is characterized in that formula (I) compound is containing NaBH
4And I
2Solvent in the reduction obtain formula (II) compound, formula (II) compound and excess acetyl chloride obtain formula (III) compound.
2. the described preparation method of claim 1 is characterized in that formula (I) compound and NaBH
4And I
2Be that reduction obtains formula (II) compound in tetrahydrofuran (THF), formula (II) compound and Acetyl Chloride 98Min. obtain formula (III) compound in methylene dichloride
3. claim 1, or 2 described preparation methods is characterized in that comprising triethylamine in formula (II) compound and the excess acetyl chloride system.
4. claim 1, or 2, or 3 described preparation methods, it is characterized in that formula (I) compound, NaBH
4And I
2In tetrahydrofuran (THF), stir, drip I
2Tetrahydrofuran solution, drip complete back flow reaction, alkali liquid washing, ethyl acetate extraction, evaporate to dryness get formula (II) compound; Formula (II) compound is dissolved in methylene dichloride, adds triethylamine, dripping acetyl chloride, room temperature reaction, reaction finishes and tells organic layer, concentrates the crude product that obtains formula (III) compound.
5. the described preparation method of claim 4 is characterized in that dripping I down at 0 ℃
2Tetrahydrofuran solution.
6. the described preparation method of claim 4 is characterized in that 0 ℃ of following dripping acetyl chloride.
7. the described preparation method of claim 4 is characterized in that recrystallization in the crude product ethanol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010105731700A CN102001960A (en) | 2010-11-24 | 2010-11-24 | Method for preparing agomelatine |
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|---|---|---|---|
| CN2010105731700A CN102001960A (en) | 2010-11-24 | 2010-11-24 | Method for preparing agomelatine |
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| CN102001960A true CN102001960A (en) | 2011-04-06 |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102260180A (en) * | 2011-05-13 | 2011-11-30 | 北京万生药业有限责任公司 | Synthesis method of agomelatine intermediate |
| CN102766063A (en) * | 2012-08-01 | 2012-11-07 | 福建广生堂药业股份有限公司 | Novel method for preparing agomelatine |
| CN102838504A (en) * | 2012-09-12 | 2012-12-26 | 福建广生堂药业股份有限公司 | Novel agomelatine crystal form L and preparation method thereof |
| CN103058879A (en) * | 2012-12-20 | 2013-04-24 | 安徽悦康凯悦制药有限公司 | Preparation method of agomelatine |
| EP2703383A1 (en) | 2012-08-27 | 2014-03-05 | Procos S.p.A. | Process for the preparation of agomelatine |
| CN106831467A (en) * | 2016-12-08 | 2017-06-13 | 江苏豪森药业集团有限公司 | The preparation method of agomelatine |
| CN107033011A (en) * | 2017-05-18 | 2017-08-11 | 郑州职业技术学院 | The preparation method of 2 (naphthyl of 7 methoxyl group 1) ethamine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101709036A (en) * | 2009-12-17 | 2010-05-19 | 天津药物研究院 | Preparation of agomelatine midbody, 2-(7-anisyl-1-naphthyl) ethylamine |
| 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 |
-
2010
- 2010-11-24 CN CN2010105731700A patent/CN102001960A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101709036A (en) * | 2009-12-17 | 2010-05-19 | 天津药物研究院 | Preparation of agomelatine midbody, 2-(7-anisyl-1-naphthyl) ethylamine |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| A.S. BHANU PRASAD ET.AL.: "Convenient Methods for the Reduction of Amides, Nitriles, Carboxylic Esters, Acids and Hydroboration of Alkenes Using NaBH4/I2 System", 《TETRAHEDRON》, vol. 48, no. 22, 31 December 1992 (1992-12-31), XP008122042 * |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102260180A (en) * | 2011-05-13 | 2011-11-30 | 北京万生药业有限责任公司 | Synthesis method of agomelatine intermediate |
| CN102260180B (en) * | 2011-05-13 | 2015-09-02 | 北京万生药业有限责任公司 | The synthetic method of agomelatine intermediate body |
| CN102766063A (en) * | 2012-08-01 | 2012-11-07 | 福建广生堂药业股份有限公司 | Novel method for preparing agomelatine |
| CN102766063B (en) * | 2012-08-01 | 2014-06-18 | 福建广生堂药业股份有限公司 | Novel method for preparing agomelatine |
| EP2703383A1 (en) | 2012-08-27 | 2014-03-05 | Procos S.p.A. | Process for the preparation of agomelatine |
| CN102838504A (en) * | 2012-09-12 | 2012-12-26 | 福建广生堂药业股份有限公司 | Novel agomelatine crystal form L and preparation method thereof |
| CN103058879A (en) * | 2012-12-20 | 2013-04-24 | 安徽悦康凯悦制药有限公司 | Preparation method of agomelatine |
| CN106831467A (en) * | 2016-12-08 | 2017-06-13 | 江苏豪森药业集团有限公司 | The preparation method of agomelatine |
| CN106831467B (en) * | 2016-12-08 | 2019-03-01 | 江苏豪森药业集团有限公司 | The preparation method of agomelatine |
| CN107033011A (en) * | 2017-05-18 | 2017-08-11 | 郑州职业技术学院 | The preparation method of 2 (naphthyl of 7 methoxyl group 1) ethamine |
| CN107033011B (en) * | 2017-05-18 | 2018-07-17 | 郑州职业技术学院 | The preparation method of 2- (7- methoxy-1-naphthyls) ethamine |
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Application publication date: 20110406 |