CN101735091A - Preparation method of Agomelatine - Google Patents
Preparation method of Agomelatine Download PDFInfo
- Publication number
- CN101735091A CN101735091A CN200910244386A CN200910244386A CN101735091A CN 101735091 A CN101735091 A CN 101735091A CN 200910244386 A CN200910244386 A CN 200910244386A CN 200910244386 A CN200910244386 A CN 200910244386A CN 101735091 A CN101735091 A CN 101735091A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- iii
- reaction
- synthesis type
- 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.)
- Pending
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of Agomelatine, which aims at economically preparing the Agomelatine on a large scale. The preparation method is characterized by comprising the following steps of: carrying out the dehydrogenation on a compound in a formula (I) under the action of DDQ to obtain a compound in a formula (II), reducing the compound in the formula (II) by sodium borohydride to obtain a compound in a formula (III), and reacting the compound in the formula (III) with acetylchloride to obtain a compound in a formula (IV), that is to say, the compound in the formula (IV) is the Agomelatine.
Description
Technical field
The present invention relates to the preparation method of Agomelatine.
Background technology
Agomelatine, or N-[2-(7-methoxyl group-1-naphthyl) ethyl] ethanamide is first melatonin receptors agonist, has good antidepressant effect.Its onset is very fast, symptoms such as depression and the anxiety of following, insomnia are all had curative effect preferably, and untoward reaction is few, and is safe, for clinical treatment MDD provides novel method, has the very pharmacological properties of high value, and its structural formula is as follows:
Agomelatine
Agomelatine is developed by Servier company, in May, 2009 granted listing in Europe.
Agomelatine preparation and therepic use thereof have been described among the EP0447285; with 7-methoxyl group-1-Tetralone an intermediate of Sertraline is starting material; react through Reformatsky with ethyl bromoacetate; the sulphur dehydroaromatizationof makes (7-methoxyl group-1-naphthyl) ethyl acetate; through hydrolysis, chloride, ammonification, dehydration elimination, reduction, acetylize synthetic Agomelatines of totally eight reactions steps, yield is lower than 30% again.The first step uses the bigger ethyl bromoacetate of pungency, is unfavorable for environmental protection.The second step aromizing is incomplete, and is rare to purer product after the saponification.In addition, the 7th step was adopted high top pressure operation, needed to carry out under 300 normal atmosphere, and is higher to equipment requirements, is difficult to be applied to industrialization.
Document Synthesis of Naphthalenic Melatonin Receptor Ligands has put down in writing above-mentioned formula (II) compound, i.e. the three-step approach synthetic method of (7-methoxyl group-1-naphthyl) acetonitrile, and the first step is solvent with THF, with LiCH
2The CN effect ,-78 ℃ of following reactions are carried out, and very low temperature operates in and is difficult in the industrialization realize.The 3rd step, use benzene to reflux in the dehydrating step, from cost and environmental consideration, do not meet industrial production requirement.
Put down in writing the synthetic method of Agomelatine intermediate (7-methoxyl group-1-naphthyl) acetonitrile among the US5194614, it is solvent that benzene is adopted in the first step reaction, considers from the environment aspect, does not meet industrial production requirement.
Put down in writing the novel synthesis of Agomelatine among the CN200510071611.6, its Chinese style (III) compound, it is the synthetic method of 2-(7-methoxyl group-1-naphthyl) ethamine, under the hydrogen-pressure of 30Bar, react, not as reaction under the condition of normal pressure among the present invention is more suitable for industrial production requirement.
The Agomelatine intermediates preparation is disclosed among the CN101161638A, be that formula (II) compound (7-methoxyl group-1-naphthyl) acetonitrile adopts palladium charcoal fusion dehydrogenation reaction at high temperature to prepare, the palladium charcoal costs an arm and a leg, easily spontaneous combustion, pay particular attention in the use, pyroreaction is carried out under needing 200 ℃, is unfavorable for industrialized conversion.
The market outlook and the economic efficient latent of Agomelatine are huge, therefore seek a kind of economy, preparation method capable of being industrialized just more seems particularly important.
Summary of the invention
The purpose of this invention is to provide a kind of economy, prepare the method for Agomelatine and intermediate thereof on a large scale.
The preparation method who the invention provides Agomelatine may further comprise the steps:
1, formula (I) compound is that dehydrogenation obtains formula (II) compound under the solvent in DDQ (DDQ) effect with the chloroform;
2, formula (II) compound obtains formula (III) compound through sodium borohydride reduction under the nickelous chloride effect;
3, obtain formula (IV) compound under formula (III) compound and Acetyl Chloride 98Min., the triethylamine effect.
Wherein:
Reaction solvent in the first step is methylene dichloride, chloroform, preferred chloroform; Temperature of reaction is 0-60 ℃, preferred 30-40 ℃.
The consumption of catalyzer sodium borohydride is the 10-80% of formula (II) compound weight in second step, preferred 20-30%.The consumption of nickelous chloride is the 20-60% of formula (II) compound weight, preferred 20-45%.Reaction solvent is methyl alcohol, ethanol, Virahol, preferred alcohol.Temperature of reaction is-5-70 ℃, and preferred 20-30 ℃.
In the 3rd step: the consumption of triethylamine is 1-5 times of formula (III) compound amount of substance, and preferred 2-4 doubly.Reaction solvent is methylene dichloride, chloroform, preferred methylene dichloride.Temperature of reaction is-10-60 ℃, and preferred 20-30 ℃.
Further concrete reaction provided by the invention is:
1, formula (I) compound drips its chloroformic solution under DDQ, chloroform stir, and dropwises back flow reaction.Reaction finishes, and behind the suction filtration, alkali liquid washing, revolves to steam and obtains formula (II) compound at the organic phase drying;
2, formula (II) compound obtains formula (III) compound through sodium borohydride reduction under nickelous chloride, ethanol stir;
3, formula (III) compound and Acetyl Chloride 98Min., triethylamine, reaction obtains formula (IV) compound in solvent.
Method process stabilizing of the present invention, simple to operate, reactions steps weak point was 3 steps, yield is to be fit to the method for preparing Agomelatine economic, scale than the EP0447285 height.
Embodiment
Following examples are used to illustrate the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
The preparation of (7-methoxyl group-1-naphthyl) acetonitrile:
Add DDQ 200g in reaction flask, chloroform 2L stirs down, drips the chloroform 0.5L solution of (7-methoxyl group-3,4-dihydro-1-naphthyl) acetonitrile 270g.Dropwise back flow reaction.Reaction finishes, suction filtration, and filtrate is washed with saturated sodium carbonate solution.The organic phase anhydrous sodium sulfate drying, suction filtration, filtrate decompression steams solvent and gets brown solid, and solid stirs in ethanol, and suction filtration, filtration cakes torrefaction get the 251g light yellow solid, yield 95%.
Fusing point: 82-84 ℃
Embodiment 2
The preparation of 2-(7-methoxyl group-1-naphthyl) ethamine:
In reaction flask, add (7-methoxyl group-1-naphthyl) acetonitrile 193g, nickelous chloride 40g, ethanol 1L stirs down, drips the ethanol 0.5L solution of 45g sodium borohydride.Dropwise room temperature reaction.Reaction finishes, and adds hydrochloric acid, and it is soluble in water that evaporated under reduced pressure gets resistates, suction filtration, and filtrate is washed with ethyl acetate.Water is transferred pH9-10 with sodium hydroxide solution, and ethyl acetate extraction is washed to neutrality.The organic phase anhydrous sodium sulfate drying, suction filtration, the filtrate decompression solvent evaporated gets 159g oily matter, yield 80%.
Embodiment 3
The preparation of Agomelatine (N-[2-(7-methoxyl group-1-naphthyl) ethyl] ethanamide):
Add methylene dichloride 1L in reaction flask, 2-(7-methoxyl group-1-naphthyl) ethamine 126g stirs adding triethylamine 95g down, drips the mixing solutions of the 200ml methylene dichloride of 100g Acetyl Chloride 98Min. then, room temperature reaction.Reaction finishes, and the reaction solution decompression steams solvent, adds water, stirring and crystallizing.Suction filtration, filtration cakes torrefaction get the 148g solid, yield 98%.
Fusing point: 105-107 ℃
Embodiment 4
The preparation of Agomelatine:
Add DDQ 100g in reaction flask, chloroform 1L stirs down, drips the chloroform 0.3L solution of (7-methoxyl group-3,4-dihydro-1-naphthyl) acetonitrile 140g.Dropwise back flow reaction.Reaction finishes, suction filtration, and filtrate is washed with saturated sodium carbonate solution.The organic phase anhydrous sodium sulfate drying, suction filtration, filtrate decompression steams solvent and gets brown solid, and solid stirs in ethanol, and suction filtration, filtration cakes torrefaction get the 126g light yellow solid, yield 96%.
In reaction flask, add above-mentioned light yellow solid 126g, nickelous chloride 27g, ethanol 0.7L stirs down, drips the ethanol 0.4L solution of 30g sodium borohydride.Dropwise room temperature reaction.Reaction finishes, and adds hydrochloric acid, and it is soluble in water that evaporated under reduced pressure gets resistates, suction filtration, and filtrate is washed with ethyl acetate.Water is transferred pH9-10 with sodium hydroxide solution, and ethyl acetate extraction is washed to neutrality.The organic phase anhydrous sodium sulfate drying, suction filtration, the filtrate decompression solvent evaporated gets 105g oily matter, yield 81%.
Add methylene dichloride 0.8L in reaction flask, above-mentioned oily matter 105g stirs adding triethylamine 80g down, drips the mixing solutions of the 160ml methylene dichloride of 84g Acetyl Chloride 98Min. then, room temperature reaction.Reaction finishes, and the reaction solution decompression steams solvent, adds water, stirring and crystallizing.Suction filtration, filtration cakes torrefaction get the 122g solid, yield 96%, and total recovery is 75%.
The contrast of the present invention and other patents
| Patent | Reactions steps | Total recovery | Unfavorable operation |
| The present invention | Three steps | ??75％ | No high pressure, high-temperature operation, simple to operate |
| ??EP0447285 | Eight steps | Be lower than 30% | Reaction under high pressure (300atm) |
| ??CN200510071611.6 | Four steps | ??72％ | Reaction under high pressure (30Bar) |
Combined reaction step, yield, operation, method process stabilizing of the present invention as can be known, simple to operate, reactions steps is shorter, is to be fit to the method for preparing Agomelatine economic, scale.
Claims (13)
1. the preparation method of an Agomelatine is specially:
The dehydrogenation under the DDQ effect of formula (I) compound obtains formula (II) compound, and formula (II) compound obtains formula (III) compound through sodium borohydride reduction, and formula (III) compound and excess acetyl chloride obtain formula (IV) compound.
2. preparation method according to claim 1 is specially:
Formula (I) compound is that dehydrogenation obtains formula (II) compound under the solvent in the DDQ effect with the chloroform; Formula (II) compound obtains formula (III) compound through sodium borohydride reduction under the nickelous chloride effect; Obtain formula (IV) compound under formula (III) compound and Acetyl Chloride 98Min., the triethylamine effect.
3. preparation method according to claim 1 is specially: formula (I) compound drips its chloroformic solution under DDQ, chloroform stir, dropwise, back flow reaction, reaction finishes, behind the suction filtration, alkali liquid washing, revolves to steam and obtains formula (II) compound at the organic phase drying; Formula (II) compound obtains formula (III) compound through sodium borohydride reduction under nickelous chloride, ethanol stir; Formula (III) compound and Acetyl Chloride 98Min., triethylamine, reaction obtains formula (IV) compound in solvent.
4. according to claim 1,2 or 3 described synthesis type (II) compound methods, it is characterized in that temperature of reaction is 0-60 ℃.
5. synthesis type according to claim 4 (II) compound method, temperature of reaction is 30-40 ℃.
6. according to claim 1,2 or 3 described synthesis type (III) compound methods, the consumption that it is characterized in that the catalyzer sodium borohydride is the 10-80% of formula (II) compound weight.
7. synthesis type according to claim 6 (III) compound method, the consumption that it is characterized in that the catalyzer sodium borohydride are the 20-30% of formula (II) compound weight.
8. according to claim 1,2 or 3 described synthesis type (III) compound methods, the consumption that it is characterized in that nickelous chloride is the 20-60% of formula (II) compound weight.
9. according to claim 1,2 or 3 described synthesis type (III) compound methods, it is characterized in that temperature of reaction is-5-70 ℃.
10. synthesis type according to claim 9 (III) compound method is characterized in that temperature of reaction is 20-30 ℃.
11. as claim 1,2 or 3 described synthesis type (IV) compound methods, the consumption that it is characterized in that triethylamine is 1-5 a times of formula (III) compound amount of substance.
12., it is characterized in that temperature of reaction is-10-60 ℃ according to claim 1,2 or 3 described synthesis type (IV) compound methods.
13. synthesis type according to claim 11 (IV) compound method is characterised in that temperature of reaction is 20-30 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910244386A CN101735091A (en) | 2009-12-30 | 2009-12-30 | Preparation method of Agomelatine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910244386A CN101735091A (en) | 2009-12-30 | 2009-12-30 | Preparation method of Agomelatine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101735091A true CN101735091A (en) | 2010-06-16 |
Family
ID=42459179
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910244386A Pending CN101735091A (en) | 2009-12-30 | 2009-12-30 | Preparation method of Agomelatine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101735091A (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102001960A (en) * | 2010-11-24 | 2011-04-06 | 威海迪素制药有限公司 | Method for preparing agomelatine |
| CN102030673A (en) * | 2010-11-24 | 2011-04-27 | 威海迪素制药有限公司 | New crystal form of agomelatine and preparation method thereof |
| CN102452951A (en) * | 2010-10-25 | 2012-05-16 | 天津泰普药品科技发展有限公司 | Agomelatine and pharmaceutical composition thereof |
| WO2012070025A1 (en) | 2010-11-26 | 2012-05-31 | Cadila Pharmaceuticals Ltd | Process for the preparation of agomelatine |
| CN103113243A (en) * | 2013-03-08 | 2013-05-22 | 山东方明药业集团股份有限公司 | Synthetic method of 2-(7-methoxyl-1-naphthyl) ethylamine hydrochloride |
| CN103360276A (en) * | 2012-03-29 | 2013-10-23 | 北大方正集团有限公司 | Crystal form, preparation method and application of agomelatine, as well as medicine composition |
| EP2703383A1 (en) | 2012-08-27 | 2014-03-05 | Procos S.p.A. | Process for the preparation of agomelatine |
| CN106543034A (en) * | 2016-10-31 | 2017-03-29 | 苏州弘森药业股份有限公司 | A kind of method of 7 methoxynaphthalene acetonitriles of synthesis |
| CN110041232A (en) * | 2019-04-10 | 2019-07-23 | 丽珠集团新北江制药股份有限公司 | A method of preparing GnRHR key intermediate of medicament compound |
| EP4342879A1 (en) * | 2022-09-21 | 2024-03-27 | F.I.S.- Fabbrica Italiana Sintetici S.p.A. | Very efficient process for the preparation of agomelatine |
-
2009
- 2009-12-30 CN CN200910244386A patent/CN101735091A/en active Pending
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102452951A (en) * | 2010-10-25 | 2012-05-16 | 天津泰普药品科技发展有限公司 | Agomelatine and pharmaceutical composition thereof |
| CN102001960A (en) * | 2010-11-24 | 2011-04-06 | 威海迪素制药有限公司 | Method for preparing agomelatine |
| CN102030673A (en) * | 2010-11-24 | 2011-04-27 | 威海迪素制药有限公司 | New crystal form of agomelatine and preparation method thereof |
| CN102030673B (en) * | 2010-11-24 | 2014-04-23 | 威海迪素制药有限公司 | New crystal form of agomelatine and preparation method thereof |
| WO2012070025A1 (en) | 2010-11-26 | 2012-05-31 | Cadila Pharmaceuticals Ltd | Process for the preparation of agomelatine |
| CN103360276A (en) * | 2012-03-29 | 2013-10-23 | 北大方正集团有限公司 | Crystal form, preparation method and application of agomelatine, as well as medicine composition |
| CN103360276B (en) * | 2012-03-29 | 2015-02-18 | 北大方正集团有限公司 | Crystal form, preparation method and application of agomelatine, as well as medicine composition |
| EP2703383A1 (en) | 2012-08-27 | 2014-03-05 | Procos S.p.A. | Process for the preparation of agomelatine |
| CN103113243A (en) * | 2013-03-08 | 2013-05-22 | 山东方明药业集团股份有限公司 | Synthetic method of 2-(7-methoxyl-1-naphthyl) ethylamine hydrochloride |
| CN106543034A (en) * | 2016-10-31 | 2017-03-29 | 苏州弘森药业股份有限公司 | A kind of method of 7 methoxynaphthalene acetonitriles of synthesis |
| CN110041232A (en) * | 2019-04-10 | 2019-07-23 | 丽珠集团新北江制药股份有限公司 | A method of preparing GnRHR key intermediate of medicament compound |
| EP4342879A1 (en) * | 2022-09-21 | 2024-03-27 | F.I.S.- Fabbrica Italiana Sintetici S.p.A. | Very efficient process for the preparation of agomelatine |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101735091A (en) | Preparation method of Agomelatine | |
| CN101709036B (en) | Preparation of agomelatine midbody, 2-(7-anisyl-1-naphthyl) ethylamine | |
| CN101759591A (en) | Preparing method of N-[2-(7- anisyl-1- naphthyl) ethide] acetamide | |
| CN102911022A (en) | Method for artificially synthesizing natural curcumin compound | |
| CN102432565A (en) | Method for preparing 2-hydroxyethylpiperazine | |
| CN102001960A (en) | Method for preparing agomelatine | |
| CN105061224A (en) | Synthetic method of L-2-aminobutanol | |
| CN104803958A (en) | Preparation technique for florosa | |
| KR101470874B1 (en) | Agomelatine intermediates and preparation method thereof | |
| CN102206170A (en) | Preparation method for agomelatine | |
| CN105399793A (en) | Cholanic acid preparation method | |
| CN102432571A (en) | Novel method for preparing ramelteon key intermediate | |
| CN101857549A (en) | Synthetic method of (1S)-4,5-Dimethoxy-1-(aminomethyl)benzocyclobutane | |
| CN101863954A (en) | Preparation method of N-tert-butyl-4-aza-5 alpha-androstane-3-ketone-17 beta-formamide | |
| CN105017044A (en) | Preparation method of trans-4-aminomethylcyclohexanecarboxylic acid | |
| CN102993040B (en) | A kind of novel method of synthesizing Agomelatine | |
| CN103772177B (en) | A kind of preparation method of p-methoxy-acetophenone | |
| CN102603545B (en) | Preparation method of 7-methoxy-1-naphthylethylamine | |
| CN101161638B (en) | Method for preparing novel agomelatine key intermediates | |
| CN102229541A (en) | Method for preparing Agomelatine N-[2-(7-methoxynaphthalene-1-yl)ethyl] acetamide | |
| CN102875408B (en) | Method for preparing agomelatine | |
| CN102260180A (en) | Synthesis method of agomelatine intermediate | |
| CN103724166A (en) | Preparation method of 3, 3-diethoxy-1-propanol | |
| CN102964256B (en) | Process for preparing 4-amino-N, N-dimethylbenzylamine | |
| CN102154432B (en) | Method for preparing rasagiline |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| ASS | Succession or assignment of patent right |
Owner name: JIANGSU AVENTIS PHARMA. CO., LTD. Free format text: FORMER OWNER: DEZHONG WANQUAN PHARMACEUTICALS TECH. DEV. CO., LTD., BEIJING Effective date: 20120530 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 100097 HAIDIAN, BEIJING TO: 225300 TAIZHOU, JIANGSU PROVINCE |
|
| TA01 | Transfer of patent application right |
Effective date of registration: 20120530 Address after: 225300 Taizhou City, Jiangsu Province medicine City Avenue, No. 1 Applicant after: Aventis Pharmaceutical (Jiangsu) Co., Ltd. Address before: 100097 Beijing city Haidian District Sijiqing Wanquan Zhuang 3 Building Applicant before: Dezhong Wanquan Pharmaceuticals Tech. Dev. Co., Ltd., Beijing |
|
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20100616 |