CN107459468B - A kind of synthetic method of agomelatine - Google Patents
A kind of synthetic method of agomelatine Download PDFInfo
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- CN107459468B CN107459468B CN201710665347.1A CN201710665347A CN107459468B CN 107459468 B CN107459468 B CN 107459468B CN 201710665347 A CN201710665347 A CN 201710665347A CN 107459468 B CN107459468 B CN 107459468B
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- synthetic method
- agomelatine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
Abstract
The present invention relates to a kind of preparation methods of agomelatine, it is characterised in that 7- methoxyl group naphthylamines is Halogenated, then the substitution of vinyl fluoride potassium borate, ammonification, finally carries out acetyl group and protects to obtain product.Raw material of the present invention is easy to get, concise in technology, and overall yield is high, and by-product is few, and post-processing is simple, is suitble to industrialized production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, more particularly to a kind of synthetic method of agomelatine.
Background technique
Agomelatine (Agomelatine) is the oral tablet developed by Servier pharmaceuticals, and every is 25mg,
Ratify and list in Europe within 2009, for curing various types of depression.It is replaced by the indole ring of melatonin
Obtained for naphthalene nucleus, not only can excitement MT1 and MT2 receptor, can also antagonism 5-HT2C receptor binding site, be a kind of novel antidepression
Drug, compared with current common therapeutic agent, have completely new mechanism of action, treatment depression it is significant in efficacy, it is highly-safe,
On sexual function influence it is small, tolerance is good, and have both improve sleep parameters the effect of.
According to the molecular structure of agomelatine, using molecule retrosynthetic analysis, the formation of amine ethyl and functional group are raw
Production method and the introducing time entire technique of ordered pair and post-processing influence most important.The principal synthetic routes of agomelatine, including
It is several below:
1, in patent EP0447285, agomelatine was ground by Andrieux of Servier company et al. in 1991 for the first time
Hair synthesis.Starting material is that 7- methoxyl group -1-tetralone reacts to obtain ester through Reformatsky under zinc powder/catalysis of iodine
Compound；Then sulphur dehydrogenation constructs aromatic ring, and saponification, chloride, ammonification obtain methoxynaphthalene yl acetamide, again through thunder after dehydration elimination
Buddhist nun's nickel restores to obtain intermediate amine ethyl methoxynaphthalene, and last acetylation obtains final product.
Above method step up to 8 steps, complicated for operation, multistep reaction yield is low, while production needs high temperature (aromatic ring), height
It presses (reduction), is unfavorable for industrialized production.
2, the synthetic route that US20050182276 is announced, equally using 7- methoxyl group -1-tetralone as starting material, with
Then cyanoacetic acid direct polycondensation is reacted by catalytic dehydrogenation of palladium carbon, then be reduced to amine ethyl first under Raney/Ni effect
Oxygroup naphthalene, then target compound is obtained by acetylation.
Under high pressure, equipment requirement is high, increased costs for above method Raney's nickel reduction reaction.
3, in CN101792400, using 7- methoxyl group -1-tetralone as starting material, under that action of n-butyl lithium, with second
Nitrile reaction, then DDQ catalytic dehydrogenation, tetrahydrochysene lithium aluminium reduction cyano obtain amine ethyl methoxynaphthalene, and acetylation obtains the drawing of algebraic oriented language U.S.
Fourth.
This method first step at -78 DEG C, is unfavorable for industrializing using butyl lithium, and risk is high；Tetrahydrochysene lithium aluminium activity is very
Height, side reaction is more, expensive, and cost is too high.
In order to overcome the shortcomings of the prior art, being badly in need of developing a kind of new technique for synthesizing of agomelatine.
Summary of the invention
The present invention provides a kind of new technique for synthesizing of agomelatine, this method raw material is easy to get, concise in technology, overall to receive
Rate is high, and by-product is few, and post-processing is simple, is suitble to industrialized production.
In order to achieve the above-mentioned object of the invention, present invention employs following technical solutions:
A kind of synthetic method of agomelatine, it is characterised in that 7- methoxyl group naphthylamines is first halogenated, then vinyl fluoride boron
Sour potassium substitution, ammonification finally carry out acetyl group and protect to obtain product, and reaction route is as follows:
First step solvent is common polar non-solute, such as dimethyl sulfoxide, n,N-Dimethylformamide, acetonitrile
Deng；Second step alkali is common inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate etc., preferably sodium carbonate；It is Pd with catalyst
(PPh3)4；The molar ratio of vinyl fluoride potassium borate and iodo methoxynaphthalene are as follows: (1-1.3): 1；Third step reaction temperature is 140-
160℃；The acetylation of 4th step, acetylation reagent can be using acetic anhydride, chloroacetic chlorides etc..
Beneficial effects of the present invention:
1) compared with prior art, the raw material of technical solution of the present invention is easy to get, and concise in technology, method route is short, reacts item
Part is mild, and overall yield is high, and by-product is few.
2) compared with prior art, technical solution of the present invention post-processing is simple, easy to operate, is suitble to industrialized production.
Specific embodiment:
Other goals of the invention of the invention, technical scheme and beneficial effects are made below in conjunction with embodiment further detailed
Explanation.
It should be noted that following detailed description is all to have illustratively, it is intended to provide further instruction to the present invention.
It is usually managed unless otherwise indicated, all technical and scientific terms used herein has with the ordinary person in field of the present invention
The identical meanings of solution.
1. the synthesis of compound 2:
At 0 DEG C, by TsOH.H2O (68.8g, 0.36mmol), 7- methoxyl group naphthylamines (20.4g, 0.12mmol) are dissolved in
Then NaNO is added in the suspension of formation in 500mL acetonitrile2(15g, 0.24mmol) and KI (49g, 0.30mmol), then,
Reaction temperature is raised to room temperature reaction 2 hours, TLC monitors fully reacting, and Na is added2SO3Solution, EtOAc (500mL), separation has
Machine phase, water phase are extracted with ethyl acetate (100mL), merge organic phase, dry, concentration, pillar layer separation (petroleum ether/acetic acid second
Ester=20/1) obtain 26.2g, yield 80%.
1. the synthesis of compound 3:
Compound 2 (24g, 84.5mmol), vinyl fluoride potassium borate (13.4g, 100mmol), Na2CO3(10.6g,
100mmol), Pd (PPh3)4(820mg, 1%mmol), 500mL ethyl alcohol are added sequentially to the single port bottle of 1L under the atmosphere of nitrogen
In, it flows back 2 hours, filters, concentration, pillar layer separation (petrol ether/ethyl acetate=20/1) obtains 15.1g, yield 99%.
2. the synthesis of compound 4:
Compound 3 (9.2g, 50mmol), DMSO 100mL, NH3.H2O120mL is placed in the autoclave of 500mL,
150 DEG C of reaction 12h, are diluted with water, EtOA after being cooled to room temperature2Extraction, it is dry, it is concentrated to get crude product and is directly used in next step
Reaction.
3. the synthesis of compound 5:
Compound 4 (crude product) is dissolved in the dehydrated alcohol of 150mL, adds sodium acetate (5.1g), acetic anhydride
After (6.3g) is stirred at room temperature 1 hour, add water and ethyl acetate, extracts, it is dry, it is concentrated to get grease, ethyl alcohol: water=5: 3 weights
Crystallization obtains white solid 7.3g, yield 61% (two steps)
It is pointed out that the technical concepts and features of above-described embodiment only to illustrate the invention, it is ripe its object is to allow
The personage for knowing technique cans understand the content of the present invention and implement it accordingly, and protection model of the invention can not be limited with this
It encloses.Any equivalent change or modification in accordance with the spirit of the invention should be covered by the protection scope of the present invention.
Claims (5)
1. a kind of synthetic method of agomelatine, it is characterised in that 7- methoxyl group naphthylamines is first halogenated, then vinyl fluoride boric acid
Potassium substitution, ammonification finally carry out acetyl group and protect to obtain product, and reaction route is as follows:
Wherein, second step catalyst is Pd (PPh in the synthetic method3)4；
Third step reaction temperature is 140-160 DEG C in the synthetic method.
2. agomelatine synthetic method according to claim 1, it is characterised in that: it is sub- that first step solvent is selected from dimethyl
Sulfone, n,N-Dimethylformamide or acetonitrile.
3. agomelatine synthetic method according to claim 1, it is characterised in that: second step alkali be selected from sodium hydroxide,
Potassium hydroxide or sodium carbonate.
4. agomelatine synthetic method according to claim 1, it is characterised in that: second step medium vinyl potassium fluoborate
Molar ratio with iodo methoxynaphthalene is (1-1.3): 1.
5. agomelatine synthetic method according to claim 1, it is characterised in that: the acetylation of the 4th step, acetylation
Reagent is selected from acetic anhydride or chloroacetic chloride.
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| CN201710665347.1A CN107459468B (en) | 2017-08-07 | 2017-08-07 | A kind of synthetic method of agomelatine |
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| CN107459468B true CN107459468B (en) | 2019-12-03 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101792400A (en) * | 2010-03-16 | 2010-08-04 | 华东师范大学 | Synthetic method for agomelatine |
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2017
- 2017-08-07 CN CN201710665347.1A patent/CN107459468B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101792400A (en) * | 2010-03-16 | 2010-08-04 | 华东师范大学 | Synthetic method for agomelatine |
Non-Patent Citations (3)
| Title |
|---|
| Photoamination of alkenylnaphthalenes with ammonia via electron transfer;Yasuda, Masahide等;《Bulletin of the Chemical Society of Japan》;19981231;第71卷(第7期);第1655-1660页 * |
| Suzuki-Miyaura Cross-Coupling Reactions of Potassium Vinyltrifluoroborate with Aryl and Heteroaryl Electrophiles;Gary A. Molander，Adam R. Brown;《J. Org. Chem.》;20060112;第71卷;第9681-9686页 * |
| The Synthesis of 2-Hydroxy-17-equilenone;W. E. Bachmann，W. J. Horton;《Journal of the American Chemical Society》;19471231;第69卷;第58-61页 * |
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Application publication date: 20171212 Assignee: Guangrao Junchuang Pharmaceutical Co.,Ltd. Assignor: SHANDONG LU NING PHARMACEUTICAL Co.,Ltd. Contract record no.: X2022980021285 Denomination of invention: A Synthetic Method of Agomelatine Granted publication date: 20191203 License type: Common License Record date: 20221112 |
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