CN108821989A - The preparation method of agomelatine intermediate body - Google Patents
The preparation method of agomelatine intermediate body Download PDFInfo
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- CN108821989A CN108821989A CN201810576062.5A CN201810576062A CN108821989A CN 108821989 A CN108821989 A CN 108821989A CN 201810576062 A CN201810576062 A CN 201810576062A CN 108821989 A CN108821989 A CN 108821989A
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- naphthyl
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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
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides a kind of preparation methods of 2- (7- methoxy-1-naphthyl) ethamine, including raw material 4- toluenesulfonic acid 1- (cyano methyl) -7- methoxynaphthalene -2- base ester is reduced to 2- (7- methoxy-1-naphthyl) ethamine, reducing agent used is BH (OR)2, R is propoxyl group or isopropoxy.Reaction step of the present invention is few, high income, purity is high, post-processes simply.
Description
Technical field
The present invention relates to the preparation methods of agomelatine intermediate body 2- (7- methoxy-1-naphthyl) ethamine.
Background technique
Agomelatine has double grading, and one side is the agonist of melatonin energy system receptor, on the other hand,
It is 5-HT again2CThe antagonist of receptor.These properties make it have central nervous system activity, and more particularly make it have
Treat Serious depression, seasonal Emotional Disorders, sleep disturbance, cardiovascular pathologies, digestive system symptom, the mistake as caused by the time difference
It sleeps and fatigue, the activity of dysorexia and obesity.
Disclose more synthetic method in the prior art, as in European patent EP 0447285 and EP1564202 to algebraic oriented language
Mei Lating, its preparation and its in the treatment application be described.Starting material mainly has, (7- methoxy-1-naphthyl)
Acetonitrile, (7- methoxy-1-naphthyl) ethyl alcohol etc., as patent specification EP0447285 is described by 7- methoxyl group -1-tetralone
Start to prepare agomelatine through eight steps, for another example in patent specification EP1564202, applicant, which develops one kind, to be had
Effect much and route of synthesis capable of being industrialized, only there are four steps.These techniques disclose the most important of agomelatine
Intermediate 2- (7- methoxy-1-naphthyl) ethamine, but because the raw material of these techniques skeleton and non-aromatic ring, it is such as common former
Expect that 7- methoxyl group -1-tetralone, process requirement aromatisation always become problem with the step for industrial point.
CN105793224 discloses a kind of synthetic method of agomelatine, and this method is this from 7- methoxyl group-naphthalene -2- alcohol starting
New raw material has the advantages that simple and easily can largely obtain the raw material at lower cost, it is often more important that 7- methoxyl group-
Naphthalene -2- alcohol also has the advantage that：There is naphthalene nucleus system, this avoids the introducings of the aromatisation step in synthesis in its structure.
Processing step in CN105793224 is more, including elder generation is in (1), phenolic hydroxyl group ortho position introducing substituent group, then carries out
Sulfonylation (before or after walking herein, also needing to modify 1 bit substituent) obtains formula IV compound, and it is anti-then to carry out deoxidation
Compound V should be obtained, finally converts amine for the side chain on naphthalene nucleus 1, wherein deoxygenation is its most characteristic reaction, real
Reaction condition used in border is summarised in from power 9-11, makees catalyst using transition metal, reducing agent is that (embodiment only makes hydride
Restored with sodium borohydride), H2, alkaline-earth metal, its unfortunate process recovery ratio is not high, and post-processes complicated, it usually needs
Multiple silica gel chromatography.
Boron compound is the substance for needing further to be excavated its purposes, common for borine and its derivative, such as amido
Borine, alkoxy borine, boron hydride etc., studying at present more is boron hydride, and such as lithium aluminium hydride reduction is more active, can
Restore a variety of functional groups, including alkene, aldehyde radical, ester group, cyano, ketone group etc., aminoboranes, alkoxy borine purposes then compare
It is limited, for example the condition of aminoboranes ester reduction is harsher, the reducing property of alkoxy borine is more difficult to determine, is typically considered to
It is difficult to ester reduction, cyano etc., many times for Suzuki type coupling reaction or for synthetic catalyst MeCBS.
Summary of the invention
The present invention is off the beaten track, provides a kind of method of completely new synthesis 2- (7- methoxy-1-naphthyl) ethamine, reaction step
Suddenly less, yield and purity is high, post-processing it is simple.
The preparation method of 2- (7- methoxy-1-naphthyl) ethamine of the invention, including by raw material 4- toluenesulfonic acid 1- (cyanogen
Ylmethyl) -7- methoxynaphthalene -2- base ester is reduced directly to 2- (7- methoxy-1-naphthyl) ethamine, and reducing agent used is alkoxy
Substituted borane derivative BH (OR)2, such as dipropoxy borine or diisopropoxy borine.
Optionally, the reduction reaction uses the salt of transition metal as catalyst, such as nickel salt, can be nickel chloride, chlorination
The form of nickel can be 6 water forms.Optionally, the molar ratio of the catalyst and the raw material is 1:1.
Optionally, the temperature of the reduction reaction is 10-30 DEG C, such as 30 DEG C.
Optionally, the molar ratio of the reducing agent and the raw material is 20:1.
Optionally, the time of the reduction reaction is 2 hours.
Optionally, the preparation method includes the post-processing after reduction reaction, and the post-processing includes making 2- (7- methoxy
Base -1- naphthalene) ethamine at salt crystallization, can be real by way of aqueous hydrochloric acid solution being added, its salt is precipitated directly such as hydrochloric acid salt
Existing, Precipitation Temperature can be low temperature, such as -10 DEG C, and it can be 1-2h that the time, which is precipitated,.
Beneficial effects of the present invention essentially consist in that：
Present inventors have unexpectedly found that alkoxy borine has good activity to raw material of the invention, can by direct-reduction, one
Step has converted the feedstock to 2- (7- methoxy-1-naphthyl) ethamine, simplifies experimental procedure, substantially increases reaction yield and production
Object purity, relative energy-saving environmental protection；The present invention also optimizes the reaction conditions such as reducing agent, reduction temperature, has advanced optimized reaction
Yield and product purity, and post-processing approach is very easy, by salt crystallization, in addition, by the way that salt is made in product
Conducive to saving, transporting, obtained salt can also be converted into agomelatine, be suitble to industrial application.
Specific embodiment
Embodiment 1：
To 100mL, the borine of diisopropoxy containing 100mmol methanol solution in, the 6 water nickel chlorides of 10mmol are added, then
4- toluenesulfonic acid 1- (cyano methyl) -7- methoxynaphthalene -2- base ester 10mmol is added to be stirred to react controlled at 10 DEG C
Then 2h is down to 0 DEG C and is concentrated, add the hydrochloric acid 200mL of 1mol/L and stir so that product is cooled to -10 DEG C at salt, after
Continuous stirring 1h, analyses to obtain solid 2.24g, is detected as 2- (7- methoxy-1-naphthyl) ethylamine hydrochloride (MS：m/z 202(M+1)；
It is attached after nuclear magnetic data), reference substance detects product assay up to 85%, calculates to obtain molar yield about 80%.
1HNMR(DMSO-d6)δ：8.05 (s, 1H), 7.93 (d, 1H), 7.79 (d, 1H), 7.60 (d, 1H), 7.48 (d,
1H), 7.38 (d, 1H), 7.28 (dd, 1H), 4.10 (s, 1H), 3.53 (dd, 1H), 3.14 (dd, 1H).
Embodiment 2,3 and its with counter-example Contrast on effect：
| Experiment | Reducing agent | Reduction temperature/degree | Target product content | Molar yield |
| Embodiment 2 | Dipropoxy borine | 10 | 92% | 90% |
| Embodiment 3 | Dipropoxy borine | 30 | 95% | 95% |
| Comparative example | Dimethylamine borane | 10 | It is not detected | 0 |
Note：Except condition listed in table, other reaction conditions are the same as embodiment 1.
Claims (10)
1. the preparation method of agomelatine intermediate body, including by raw material 4- toluenesulfonic acid 1- (cyano methyl) -7- methoxyl group
Naphthalene -2- base ester is reduced to 2- (7- methoxy-1-naphthyl) ethamine, and reducing agent used is BH (OR)2, R is propoxyl group or isopropyl oxygen
Base.
2. preparation method as described in claim 1, which is characterized in that the reduction reaction uses the salt of transition metal as urging
Agent.
3. preparation method as claimed in claim 2, which is characterized in that the catalyst is nickel salt, such as nickel chloride, preferably 6
Water nickel chloride.
4. preparation method as claimed in claim 3, which is characterized in that the molar ratio of the catalyst and the raw material is 1:1.
5. preparation method as described in claim 3 or 4, which is characterized in that the molar ratio of the reducing agent and the raw material is
20:1。
6. the preparation method as described in any first claim, which is characterized in that the temperature of the reduction reaction is 10-30
DEG C, such as 30 DEG C.
7. preparation method as described in claim 1, which is characterized in that the time of the reduction reaction is 2 hours.
8. preparation method as described in claim 1, which is characterized in that the preparation method include after the reduction reaction after
Processing, the post-processing includes making 2- (7- methoxy-1-naphthyl) ethamine at salt crystallization, such as crystallization after hydrochloric acid salt.
9. preparation method as claimed in claim 8, which is characterized in that described to include addition aqueous hydrochloric acid solution at salt crystallization.
10. preparation method as claimed in claim 8 or 9, which is characterized in that the temperature of the crystallization is low temperature, such as -10 DEG C,
It can be 1-2h that the time, which is precipitated,.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810576062.5A CN108821989A (en) | 2017-05-18 | 2017-05-18 | The preparation method of agomelatine intermediate body |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810576062.5A CN108821989A (en) | 2017-05-18 | 2017-05-18 | The preparation method of agomelatine intermediate body |
| CN201710350704.5A CN107033011B (en) | 2017-05-18 | 2017-05-18 | The preparation method of 2- (7- methoxy-1-naphthyls) ethamine |
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| CN201710350704.5A Division CN107033011B (en) | 2017-05-18 | 2017-05-18 | The preparation method of 2- (7- methoxy-1-naphthyls) ethamine |
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| CN108821989A true CN108821989A (en) | 2018-11-16 |
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| CN201810576062.5A Withdrawn CN108821989A (en) | 2017-05-18 | 2017-05-18 | The preparation method of agomelatine intermediate body |
| CN201710350704.5A Expired - Fee Related CN107033011B (en) | 2017-05-18 | 2017-05-18 | The preparation method of 2- (7- methoxy-1-naphthyls) ethamine |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010026436A2 (en) * | 2008-09-08 | 2010-03-11 | Biovail Laboratories International (Barbados) Srl | Pharmaceutical compounds |
| WO2014056421A1 (en) * | 2012-10-09 | 2014-04-17 | 江西同和药业有限责任公司 | 1-cyan-1-(7-methoxyl-1-naphtyl) methanol ester compound and preparation method and use thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101709036B (en) * | 2009-12-17 | 2012-07-04 | 天津药物研究院 | Preparation of agomelatine midbody, 2-(7-anisyl-1-naphthyl) ethylamine |
| CN102001960A (en) * | 2010-11-24 | 2011-04-06 | 威海迪素制药有限公司 | Method for preparing agomelatine |
| CN102875415B (en) * | 2012-10-09 | 2014-08-20 | 江西同和药业有限责任公司 | Compound and preparation method and application thereof |
| CN103058879B (en) * | 2012-12-20 | 2015-09-09 | 安徽悦康凯悦制药有限公司 | The preparation method of Agomelatine |
| FR3014437B1 (en) * | 2013-12-05 | 2016-12-23 | Servier Lab | NEW PROCESS FOR THE SYNTHESIS OF AGOMELATIN |
-
2017
- 2017-05-18 CN CN201810576062.5A patent/CN108821989A/en not_active Withdrawn
- 2017-05-18 CN CN201710350704.5A patent/CN107033011B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010026436A2 (en) * | 2008-09-08 | 2010-03-11 | Biovail Laboratories International (Barbados) Srl | Pharmaceutical compounds |
| WO2014056421A1 (en) * | 2012-10-09 | 2014-04-17 | 江西同和药业有限责任公司 | 1-cyan-1-(7-methoxyl-1-naphtyl) methanol ester compound and preparation method and use thereof |
Non-Patent Citations (2)
| Title |
|---|
| CHRISTOS I. STATHAKIS ET AL.: "A Scalable of the Antidepressant Agomelatine by a Tandem Allylic Chlorination-Isomerization Process", 《EUROPEAN JOURNAL OF ORGANIC CHEMSITRY》 * |
| WEI ANG ET AL.: "Synthesis and biological evaluation of novel naphthalene compounds as potential antidepressant agents", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
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| Publication number | Publication date |
|---|---|
| CN107033011B (en) | 2018-07-17 |
| CN107033011A (en) | 2017-08-11 |
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Application publication date: 20181116 |