CN106831467B - The preparation method of agomelatine - Google Patents
The preparation method of agomelatine Download PDFInfo
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- CN106831467B CN106831467B CN201611123031.1A CN201611123031A CN106831467B CN 106831467 B CN106831467 B CN 106831467B CN 201611123031 A CN201611123031 A CN 201611123031A CN 106831467 B CN106831467 B CN 106831467B
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- agomelatine
- methoxy
- naphthyl
- reduction reaction
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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 methods of agomelatine, including raw material 4- toluenesulfonic acid 1- (cyano methyl) -7- methoxynaphthalene -2- base ester is reduced directly to 2- (7- methoxy-1-naphthyl) ethamine, it is then further converted into agomelatine.Reaction step of the present invention is few, yield/purity is high, post-processes simply.
Description
Technical field
The present invention relates to the preparation methods of field of medicaments more particularly to agomelatine.
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.
More synthetic method is disclosed in the prior art, and starting material mainly has 7- methoxyl group -1-tetralone, (7-
Methoxy-1-naphthyl) acetonitrile, (7- methoxy-1-naphthyl) ethyl alcohol etc., 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
It asks someone to develop a kind of much effective and capable of being industrialized route of synthesis, only there are four steps.These techniques disclose Ah
Important as precursors 2- (7- methoxy-1-naphthyl) ethamine of Ge Meilating, but these process requirement aromatisation, for industrial point
The step always becomes problem.
CN105793224 discloses a kind of synthetic method of agomelatine, and this method is from 7- methoxyl group-naphthalene -2- alcohol
Starting, this new raw material have the advantages that simple and easily can largely obtain the raw material, 7- methoxyl group-at lower cost
Naphthalene -2- alcohol, which also has the advantage that, has naphthalene nucleus system in its structure, this avoids the introducings of the aromatisation step in synthesis.
The patent provides a series of sulfonate intermediates, such as 4- toluenesulfonic acid 1- (cyano methyl) -7- methoxynaphthalene -2- base ester.
Processing step in CN105793224 is more, for example first passes through reduction and slough sulfonate group (actually embodiment is only
It confirms and uses H2, sodium borohydride restored), then convert amine for the side chain on naphthalene nucleus 1, and post-process complicated, lead to
Multiple silica gel chromatography is often needed, total recovery is not high.Separately through retrieving, at present about in the document for preparing agomelatine,
Catalytic hydrogenation or metal double oxide reduction method are used when restoring cyano, and (method of reduction cyano is also in CN105793224
Conventional thought).Catalytic hydrogenation is usually required using high pressure hydrogen, and metal double oxide such as lithium aluminium hydride reduction is excessively active, when reduction
Heat release causes impurity to generate.
Summary of the invention
The present invention is directed to overcome the deficiencies of existing technologies, a kind of method of completely new synthesis agomelatine is provided.
Agomelatine preparation method of the invention, including by 4- toluenesulfonic acid 1- (cyano methyl) -7- methoxynaphthalene -
2- base ester is reduced directly to 2- (7- methoxy-1-naphthyl) ethamine (calling raw material A in the following text), is then further converted into the drawing of algebraic oriented language U.S.
Spit of fland.
Preferably, the reducing agent that the reduction reaction uses is the borine that borane derivative replaces, such as one or two
The borine that alkoxy replaces, 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 after prefabricated and participate in reduction reaction) is connect, can also be indirect form (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, it can be chlorination such as nickel salt or platinum salt that the reduction reaction, which uses the salt of transition metal as catalyst,
Nickel, nickel chloride can be with NiCl2·6H2The form of O provides.
Preferably, the molar ratio of the reducing agent and the raw material A is 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 molar ratio of the catalyst and the raw material A is 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-naphthyl) ethamine
At salt crystallization, such as hydrochloric acid salt or nitrate.Its salt is precipitated directly as an example, the aqueous solution of hydrochloric acid or nitric acid can be added,
Precipitation Temperature can be low temperature, such as 0 DEG C, and the time, which is precipitated, can be 1-2h depending on speed of separating out.
Preferably, the operation for being converted into agomelatine includes by 2- (7- methoxy-1-naphthyl) ethamine or its salt
Acetylation is carried out, acetylation herein includes one-step acylation, also includes that acetylation obtains again after carrying out a series of chemical modifications
Agomelatine.The method such as EP0447285 routine can be used in acetylation, for another example, by 2- (7- methoxy-1-naphthyl) ethylamine salt
Hydrochlorate is in the presence of alkali (such as sodium acetate) and acetic anhydride.
The beneficial effects of the present invention are:
1, 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-naphthalene) ethamine, experimental implementation is enormously simplified, reaction yield and product purity are improved；
2, the present invention also optimizes the reaction conditions such as reducing agent, reduction temperature, has advanced optimized reaction yield and product
Purity；
3, the present invention has also explored very easy post-processing approach, and agomelatine precursor by being at salt crystallization
Can, obtained salt can be converted into agomelatine, and whole process is without complicated, expensive chromatogram purification.
Specific embodiment
In order to better illustrate the present invention and its acquired effect, it is 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-naphthyl) ethylamine hydrochloride:
Embodiment 1:
Into the methanol solution (100mL) of the borine of dimethoxy containing 100mmol, the NiCl of 10mmol is added2·6H2O, then
4- toluenesulfonic acid 1- (cyano methyl) -7- methoxynaphthalene -2- base ester 10mmol is added to be stirred to react controlled at 50 DEG C
1h；After concentration, it is down to room temperature, the hydrochloric acid 200mL of 1mol/L is added, is cooled to 0 DEG C, 1h is stirred, solid 2.237g is analysed to obtain, through examining
Survey is 2- (7- methoxy-1-naphthyl) 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:
Into the methanol solution (100mL) of the borine of diethoxy containing 100mmol, the NiCl of 10mmol is added2·6H2O, then
4- toluenesulfonic acid 1- (cyano methyl) -7- methoxynaphthalene -2- base ester 10mmol is added to be stirred to react controlled at 50 DEG C
1h；After concentration, it is down to room temperature, the hydrochloric acid 200mL of 1mol/L is added, is cooled to 0 DEG C, 1h is stirred, solid 2.377g is analysed to obtain, through examining
Survey be 2- (7- methoxy-1-naphthyl) ethylamine hydrochloride (MS,1HNMR data are substantially with embodiment 1), purity 90%, mole receipts
Rate 90%.
Embodiment 3:
Into the methanol solution (100mL) of the borine of diethoxy containing 150mmol, the NiCl of 10mmol is added2·6H2O, then
4- toluenesulfonic acid 1- (cyano methyl) -7- methoxynaphthalene -2- base ester 10mmol is added to be stirred to react controlled at 50 DEG C
1h；After concentration, it is down to room temperature, the hydrochloric acid 200mL of 1mol/L is added, is cooled to 0 DEG C, 1h is stirred, solid 2.377g is analysed to obtain, through examining
Survey be 2- (7- methoxy-1-naphthyl) ethylamine hydrochloride (MS,1HNMR data are substantially with embodiment 1), purity 95%, mole receipts
Rate 95%.
Embodiment 4:
Into the methanol solution (100mL) of the borine of diethoxy containing 200mmol, the NiCl of 10mmol is added2·6H2O, then
4- toluenesulfonic acid 1- (cyano methyl) -7- methoxynaphthalene -2- base ester 10mmol is added to be stirred to react controlled at 50 DEG C
1h；After concentration, it is down to room temperature, the hydrochloric acid 200mL of 1mol/L is added, is cooled to 0 DEG C, 1h is stirred, solid 2.485g is analysed to obtain, through examining
Survey be 2- (7- methoxy-1-naphthyl) ethylamine hydrochloride (MS,1HNMR data are substantially with embodiment 1), purity 92%, mole receipts
Rate 88%.
Embodiment 5:
Into the methanol solution (100mL) of the borine of diethoxy containing 200mmol, the NiCl of 10mmol is added2·6H2O, then
4- toluenesulfonic acid 1- (cyano methyl) -7- methoxynaphthalene -2- base ester 10mmol is added to be stirred to react controlled at 30 DEG C
1h；After concentration, it is down to room temperature, the hydrochloric acid 200mL of 1mol/L is added, is cooled to 0 DEG C, 1h is stirred, solid 2.377g is analysed to obtain, through examining
Survey be 2- (7- methoxy-1-naphthyl) ethylamine hydrochloride (MS,1HNMR data are substantially with embodiment 1), purity 92%, mole receipts
Rate 92%.
The preparation of agomelatine:
By embodiment 5 resulting 2.377g 2- (7- methoxy-1-naphthyl) ethylamine hydrochloride solid, the acetic acid of 20mmol
Sodium is dissolved in the ethyl alcohol of 50mL, and 11mmol acetic anhydride is added, and flow back 1h, cooling reaction solution, and 100mL water, ethyl acetate extraction is added
It takes (50mL*3), merges organic phase, anhydrous magnesium sulfate drying is added, filter out desiccant, filtrate decompression is concentrated to give solid, and first is added
Benzene: the mixed solvent that n-hexane volume ratio is 2: 1 recrystallizes, and obtains agomelatine crystal 2.132g, purity 99.6%, mole receipts
Rate 95%.
Comparative example:
Into the methanol solution (100mL) of the dimethylamine borane containing 100mmol, the NiCl of 10mmol is added2·6H2O, then plus
Enter 4- toluenesulfonic acid 1- (cyano methyl) -7- methoxynaphthalene -2- base ester 10mmol and is stirred to react 1h controlled at 50 DEG C；
After concentration, it is down to room temperature, the hydrochloric acid 200mL of 1mol/L is added, is cooled to 0 DEG C, stirs 1h, has no that solid is precipitated, detection concentration
The reaction product mixed liquor of front and back also has no 2- (7- methoxy-1-naphthyl) ethamine or its hydrochloride.
Claims (13)
1. the preparation method of agomelatine, including by raw material 4- toluenesulfonic acid 1- (cyano methyl) -7- methoxynaphthalene -2- base
Ester is reduced directly to 2- (7- methoxy-1-naphthyl) ethamine, is then further converted into agomelatine,
Wherein, the reducing agent that reduction reaction uses is dimethoxy borine or diethoxy borine, catalyst NiCl2·6H2O。
2. the method as described in claim 1, which is characterized in that the molar ratio of the reducing agent and the raw material is 10-20:1.
3. the method as described in claim 1, which is characterized in that the molar ratio of the reducing agent and the raw material is 15:1.
4. method as described in any one of claims 1 to 3, which is characterized in that the temperature of the reduction reaction is 10-60 DEG C.
5. method as described in any one of claims 1 to 3, which is characterized in that the temperature of the reduction reaction is 30-50 DEG C.
6. the method as described in claim 1, which is characterized in that the molar ratio of the catalyst and the raw material is 1-3:1.
7. the method as described in claim 1, which is characterized in that the molar ratio of the catalyst and the raw material is 1:1.
8. the method as described in claim 1, which is characterized in that the time of the reduction reaction is 0.5-1.5 hours.
9. the method as described in claim 1, which is characterized in that the time of the reduction reaction is 1 hour.
10. the method as described in claim 1, which is characterized in that the reduction reaction includes post-processing, and the post-processing includes
Make 2- (7- methoxy-1-naphthyl) ethamine at salt crystallization.
11. method as claimed in claim 10, which is characterized in that make 2- (7- methoxy-1-naphthyl) ethamine hydrochloric acid salt or
Nitrate salts crystallization.
12. method as claimed in claim 10, which is characterized in that described at salt crystallization includes hydrochloric acid or nitric acid is added water-soluble
Liquid.
13. the method as described in claim 1, which is characterized in that the operation for being converted into agomelatine includes by 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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