CN106831467A - The preparation method of agomelatine - Google Patents
The preparation method of agomelatine Download PDFInfo
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- CN106831467A CN106831467A CN201611123031.1A CN201611123031A CN106831467A CN 106831467 A CN106831467 A CN 106831467A CN 201611123031 A CN201611123031 A CN 201611123031A CN 106831467 A CN106831467 A CN 106831467A
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- CN
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- Prior art keywords
- salt
- agomelatine
- methoxy
- reduction reaction
- ethamine
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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
- C07C213/02—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
Abstract
The present invention relates to a kind of preparation method of agomelatine, including the base ester of raw material 4 toluene sulfonic acide 1 (cyano methyl) 7 methoxynaphthalene 2 is reduced directly into 2 (naphthyl of 7 methoxyl group 1) ethamine, agomelatine is then further converted into.Reactions steps of the present invention are few, yield/purity is high, post processing is simple.
Description
Technical field
The present invention relates to field of medicaments, more particularly to agomelatine preparation method.
Background technology
Agomelatine has double grading, and on the one hand it is the activator of melatonin energy system receptor, on the other hand,
It is again 5-HT2CThe antagonist of acceptor.These properties make it have central nervous system activity, and more particularly make it have
Treatment Serious depression, SAD, sleep-disorder, cardiovascular pathologies, digestive system symptom, due to caused by the time difference lose
The activity slept with fatigue, dysorexia and obesity.
More synthetic method is disclosed in the prior art, and initiation material mainly has 7- methoxyl groups-ALPHA-tetralone, (7-
Methoxy-1-naphthyl) acetonitrile, (7- methoxy-1-naphthyls) ethanol etc., such as patent specification EP0447285 is described by 7- first
Oxy-1-tetralone starts to prepare agomelatine through eight steps, for another example in patent specification EP1564202, Shen
Ask someone to develop route of synthesis a kind of much effective and capable of being industrialized, it only has four steps.These techniques disclose Ah
Important as precursors 2- (7- methoxy-1-naphthyls) ethamine of Ge Meilating, but these techniques need aromatisation, for industrial point
The step always turns into problem.
CN105793224 discloses a kind of synthetic method of agomelatine, and this method is from 7- methoxyl groups-naphthalene -2- alcohol
Starting, this new raw material has the advantages that simple and easily can largely obtain the raw material at lower cost, 7- methoxyl groups-
Naphthalene -2- alcohol also has the advantage that：There is naphthalene nucleus system, this avoids the introducing of the aromatisation step in synthesis in its structure.
The patent provides a series of sulfonate intermediates, such as 4- toluene sulfonic acides 1- (cyano methyl) -7- methoxynaphthalene -2- base esters.
Processing step in CN105793224 is more, such as first pass through reduction and slough sulfonate group (actually embodiment is only
Confirm and use H2, sodium borohydride reduced), then the side chain on naphthalene nucleus 1 is converted into amine, and post processing is complicated, leads to
Multiple silica gel chromatography is often needed, total recovery is not high.It is another through retrieval, at present in the document for preparing agomelatine,
Using catalytic hydrogenation or metal double oxide reducing process, (method of reduction cyano group is also in CN105793224 during reduction cyano group
Conventional thought).Catalytic hydrogenation generally needs to use high pressure hydrogen, and metal double oxide such as lithium aluminium hydride reduction is excessively active, during reduction
Heat release, causes impurity to produce.
The content of the invention
It is contemplated that overcoming the defect of prior art, there is provided a kind of method of brand-new synthesis agomelatine.
Agomelatine preparation method of the invention, including by 4- toluene sulfonic acides 1- (cyano methyl) -7- methoxynaphthalenes -
2- base esters are reduced directly to 2- (7- methoxy-1-naphthyls) ethamine (calling raw material A in the following text), are then further converted into the U.S. drawing of algebraic oriented language
Spit of fland.
Preferably, the borine that the reducing agent that the reduction reaction is used replaces for borane derivative, such as one or two
The borine of alkoxy substitution, the alkoxy can be the alkoxy of C1-C4, such as methoxy or ethoxy, as an example, of the invention
Reducing agent be dimethoxy borine BH (OCH3)2Or diethoxy borine BH (OC2H5)2.Alkoxy borine herein, can be straight
Form (directly feed intake participation reduction reaction after prefabricated) is connect, or indirect form is (by interim in the system of reduction reaction
Reduction reaction is participated in after generation again), such as diborane is passed through in the methanol solution of raw material A, without prefabricated dimethoxy borine
Solution.
Preferably, the reduction reaction uses the salt of transition metal as catalyst, such as nickel salt or platinum salt, can be chlorination
Nickel, nickel chloride can be with NiCl2·6H2The form of O is provided.
Preferably, the reducing agent and the mol ratio of the raw material A are 10-20:1, such as 15:1.
Preferably, the temperature of the reduction reaction is 10-60 DEG C, such as 30-50 DEG C.
Preferably, the catalyst and the mol ratio of the raw material A are 1-3:1, more preferably 1:1.
Preferably, the time of the reduction reaction is 0.5-1.5 hours, such as 1 hour.
Preferably, the reduction reaction includes post processing, and the post processing includes making 2- (7- methoxy-1-naphthyls) ethamine
Into salt crystallization, such as hydrochloric acid salt or nitrate.As an example, can add hydrochloric acid or the nitre aqueous acid its salt is directly separated out,
Precipitation Temperature can be low temperature, such as 0 DEG C, separate out depending on time visual speed of separating out, can be 1-2h.
Preferably, the operation for being converted into agomelatine is included 2- (7- methoxy-1-naphthyls) ethamine or its salt
Acetylation is carried out, acetylation herein includes one-step acylation, also acetylation is obtained again including carrying out after a series of chemical modifications
Agomelatine.Acetylation can be using as conventional method such as EP0447285, for another example, by 2- (7- methoxy-1-naphthyls) ethylamine salt
Hydrochlorate is in the presence of alkali (such as sodium acetate) and acetic anhydride.
The beneficial effects of the present invention are：
1st, the present invention looks for another way, and by direct-reduction, a step has converted the feedstock to agomelatine precursor 2- (7- first
Oxy-1-naphthyl) ethamine, experimental implementation is enormously simplify, improve reaction yield and product purity；
2nd, the present invention also optimizes the reaction conditions such as reducing agent, reduction temperature, further optimizes reaction yield and product
Purity；
3rd, the present invention has also explored very easy post-processing approach, and agomelatine precursor is by into salt crystallization
Can, the salt for obtaining can be converted into agomelatine, and whole process is without complicated, expensive chromatogram purification.
Specific embodiment
In order to effect of the invention and its acquired is better described, done furtherly below in conjunction with specific embodiment
It is bright, but the scope of the present invention is not limited to the concrete scheme of embodiment.
The preparation of 2- (7- methoxy-1-naphthyls) ethylamine hydrochloride：
Embodiment 1：
To in the methanol solution (100mL) of the borine of dimethoxy containing 100mmol, the NiCl of 10mmol is added2·6H2O, then
4- toluene sulfonic acides 1- (cyano methyl) -7- methoxynaphthalene -2- base ester 10mmol are added, it is 50 DEG C, stirring reaction to control temperature
1h；After concentration, room temperature is down to, adds the hydrochloric acid 200mL of 1mol/L, be cooled to 0 DEG C, stir 1h, analyse to obtain solid 2.237g, through inspection
Survey is 2- (7- methoxy-1-naphthyls) ethylamine hydrochloride, purity 85%, molar yield 80%.
MS：m/z 202(M+1)
1HNMR(DMSO-d6)δ：8.09 (s, 1H), 7.98 (d, 1H), 7.79 (d, 1H), 7.63 (d, 1H), 7.48 (d,
1H), 7.42 (d, 1H), 7.28 (dd, 1H), 4.06 (s, 1H), 3.55 (dd, 1H), 3.15 (dd, 1H).
Embodiment 2：
To in the methanol solution (100mL) of the borine of diethoxy containing 100mmol, the NiCl of 10mmol is added2·6H2O, then
4- toluene sulfonic acides 1- (cyano methyl) -7- methoxynaphthalene -2- base ester 10mmol are added, it is 50 DEG C, stirring reaction to control temperature
1h；After concentration, room temperature is down to, adds the hydrochloric acid 200mL of 1mol/L, be cooled to 0 DEG C, stir 1h, analyse to obtain solid 2.377g, through inspection
Survey for 2- (7- methoxy-1-naphthyls) ethylamine hydrochloride (MS,1HNMR data are basic with embodiment 1), purity 90%, mole receipts
Rate 90%.
Embodiment 3：
To in the methanol solution (100mL) of the borine of diethoxy containing 150mmol, the NiCl of 10mmol is added2·6H2O, then
4- toluene sulfonic acides 1- (cyano methyl) -7- methoxynaphthalene -2- base ester 10mmol are added, it is 50 DEG C, stirring reaction to control temperature
1h；After concentration, room temperature is down to, adds the hydrochloric acid 200mL of 1mol/L, be cooled to 0 DEG C, stir 1h, analyse to obtain solid 2.377g, through inspection
Survey for 2- (7- methoxy-1-naphthyls) ethylamine hydrochloride (MS,1HNMR data are basic with embodiment 1), purity 95%, mole receipts
Rate 95%.
Embodiment 4：
To in the methanol solution (100mL) of the borine of diethoxy containing 200mmol, the NiCl of 10mmol is added2·6H2O, then
4- toluene sulfonic acides 1- (cyano methyl) -7- methoxynaphthalene -2- base ester 10mmol are added, it is 50 DEG C, stirring reaction to control temperature
1h；After concentration, room temperature is down to, adds the hydrochloric acid 200mL of 1mol/L, be cooled to 0 DEG C, stir 1h, analyse to obtain solid 2.485g, through inspection
Survey for 2- (7- methoxy-1-naphthyls) ethylamine hydrochloride (MS,1HNMR data are basic with embodiment 1), purity 92%, mole receipts
Rate 88%.
Embodiment 5：
To in the methanol solution (100mL) of the borine of diethoxy containing 200mmol, the NiCl of 10mmol is added2·6H2O, then
4- toluene sulfonic acides 1- (cyano methyl) -7- methoxynaphthalene -2- base ester 10mmol are added, it is 30 DEG C, stirring reaction to control temperature
1h；After concentration, room temperature is down to, adds the hydrochloric acid 200mL of 1mol/L, be cooled to 0 DEG C, stir 1h, analyse to obtain solid 2.377g, through inspection
Survey for 2- (7- methoxy-1-naphthyls) ethylamine hydrochloride (MS,1HNMR data are basic with embodiment 1), purity 92%, mole receipts
Rate 92%.
The preparation of agomelatine：
By 2.377g 2- (7- methoxy-1-naphthyls) ethylamine hydrochloride solid of the gained of embodiment 5, the acetic acid of 20mmol
Sodium is dissolved in the ethanol of 50mL, adds 11mmol acetic anhydrides, and flow back 1h, cools down reaction solution, adds 100mL water, ethyl acetate extraction
Take (50mL*3), merge organic phase, add anhydrous magnesium sulfate to dry, filter drier, filtrate decompression is concentrated to give solid, adds first
Benzene: n-hexane volume ratio is recrystallized for 2: 1 mixed solvent, obtains agomelatine crystal 2.132g, purity 99.6%, mole receipts
Rate 95%.
Comparative example：
To in the methanol solution (100mL) containing 100mmol dimethylamine boranes, the NiCl of 10mmol is added2·6H2O, then add
Enter 4- toluene sulfonic acides 1- (cyano methyl) -7- methoxynaphthalene -2- base ester 10mmol, it is 50 DEG C, stirring reaction 1h to control temperature；
After concentration, room temperature is down to, adds the hydrochloric acid 200mL of 1mol/L, be cooled to 0 DEG C, stir 1h, have no that solid is separated out, detection concentration
Front and rear product mixed liquor also has no 2- (7- methoxy-1-naphthyls) ethamine or its hydrochloride.
Claims (10)
1. the preparation method of agomelatine, including by raw material 4- toluene sulfonic acides 1- (cyano methyl) -7- methoxynaphthalene -2- bases
Ester is reduced directly to 2- (7- methoxy-1-naphthyls) ethamine, is then further converted into agomelatine.
2. the method for claim 1, it is characterised in that the reducing agent that the reduction reaction is used is borane derivative,
Such as the borine of one or two alkoxy substitution, the alkoxy can be the alkoxy of C1-C4, such as methoxy or ethoxy.
3. method as claimed in claim 2, it is characterised in that the reduction reaction uses the salt of transition metal as catalysis
Agent, such as nickel salt or platinum salt, can be nickel chloride.
4. method as claimed in claim 2, it is characterised in that the reducing agent is 10-20 with the mol ratio of the raw material:1,
Such as 15:1.
5. the method as described in any one of Claims 1-4, it is characterised in that the temperature of the reduction reaction is 10-60 DEG C,
Such as 30-50 DEG C.
6. the method for claim 1, it is characterised in that the catalyst is 1-3 with the mol ratio of the raw material:1, it is excellent
Elect 1 as:1.
7. the method for claim 1, it is characterised in that the time of the reduction reaction is 0.5-1.5 hour, as 1 small
When.
8. the method for claim 1, it is characterised in that the reduction reaction includes post processing, the post processing includes
Make 2- (7- methoxy-1-naphthyls) ethamine into salt crystallization, such as hydrochloric acid salt or nitrate.
9. method as claimed in claim 8, it is characterised in that described to include adding the water-soluble of hydrochloric acid or nitric acid into salt crystallization
Liquid.
10. the method for claim 1, it is characterised in that the operation for being converted into agomelatine is included 2- (7-
Methoxy-1-naphthyl) ethamine or its salt carries out acetylation.
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Citations (3)
| 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 |
| CN103058879A (en) * | 2012-12-20 | 2013-04-24 | 安徽悦康凯悦制药有限公司 | Preparation method of agomelatine |
| WO2015082847A1 (en) * | 2013-12-05 | 2015-06-11 | Les Laboratoires Servier | Novel method for the synthesis of agomelatine |
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2016
- 2016-12-08 CN CN201611123031.1A patent/CN106831467B/en active Active
Patent Citations (3)
| 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 |
| CN103058879A (en) * | 2012-12-20 | 2013-04-24 | 安徽悦康凯悦制药有限公司 | Preparation method of agomelatine |
| WO2015082847A1 (en) * | 2013-12-05 | 2015-06-11 | Les Laboratoires Servier | Novel method for the synthesis of agomelatine |
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