CN102942501B - The production method of Agomelatine is prepared in a kind of hydrogenation - Google Patents
The production method of Agomelatine is prepared in a kind of hydrogenation Download PDFInfo
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- CN102942501B CN102942501B CN201210532003.0A CN201210532003A CN102942501B CN 102942501 B CN102942501 B CN 102942501B CN 201210532003 A CN201210532003 A CN 201210532003A CN 102942501 B CN102942501 B CN 102942501B
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Abstract
The invention provides the industrial production novel method that Agomelatine is prepared in a kind of hydrogenation, it is in anhydrous solvent, formula (II) is mixed with acylating reagent; add acid binding agent; catalyzer, passes into plant hydrogen under stirring, is obtained by reacting compound (I) under a certain pressure.The present invention for raw material, adds acylating agent and acid binding agent with (7-methoxy-1-naphthyl) acetonitrile, and catalytic hydrogenation prepares target compound N-[2-(7-methoxynaphthalene-1-base) ethyl] ethanamide.Compared with prior art, the reaction times is short in the present invention, and byproduct of reaction is few, and reaction yield is high, and aftertreatment is simple, constant product quality, production cost are low, is suitable for large-scale industrial production.
Description
Technical field
The invention belongs to organic chemical synthesis technical field, relate to a kind of preparation method of bulk drug, especially a kind of preparation method of Agomelatine of applicable suitability for industrialized production newly.
Background technology
Agomelatine or N-[2-(7-methoxy-1-naphthyl) ethyl] ethanamide possess valuable pharmacological property, and it is first melatonin receptors agonist, is also serotonin 2C (S-HTx) receptor antagonist.Animal experiment and clinical study show that this medical instrument has central nervous system activity, and especially have antidepressant, anxiety, adjustment sleep rhythm and regulate the effects such as physiological clock, its untoward reaction is simultaneously few, has no adverse effects to sexual function, also have no withdrawal reaction.
That prepare Agomelatine through eight steps, its average yield is lower than 30%, and severe reaction conditions, production cost are high, are unfavorable for suitability for industrialized production with 7-methoxyl group-ALPHA-tetralone for starting raw material compared with the synthetic method reported in patent EP0447285.
First synthetic intermediate (7-methoxy-1-naphthyl) acetonitrile of synthetic method of the Agomelatine that patent CN 101735091A reports; resynthesis 2-(7-methoxy-1-naphthyl) ethamine, last acylation reaction generates N-[2-(7-methoxy-1-naphthyl) ethyl] ethanamide.Reaction mass is still more, complicated operation, and carries out acylation reaction under opening condition, and three-waste pollution is comparatively large, and overall yield is on the low side.
Chinese Journal of Pharmaceuticals 2008 is solvent with tetrahydrofuran (THF) in 39 (3), and diacetyl oxide is that Agomelatine (Compound I) is prepared in acylating agent single stage method hydrogenation in autoclave.This technique, in actually operating, just generate the dimer impurity of 10%-15%, and the generation of this impurity is irreversible, has a strong impact on quality product and yield, adds production cost in the reaction initial stage.
Patent CN 101643433A reports that " treating different things alike " prepares the synthesis technique of Agomelatine, namely in Special high-voltage hydrogenation equipment, under Raney-Ni, 70 DEG C and 30bar hydrogen atmosphere, slowly add diacetyl oxide and (7-methoxyl group 1-naphthyl) acetonitrile, reduction reaction obtains Agomelatine.Mention in document and adopt this technique the formation of dipolymer can be minimized, but fine work yield is also only 89%, and used the high-pressure hydrogenation equipment needing continuously feeding, be difficult to reach under common working condition.
Summary of the invention
The object of the invention is to for solving in prior art the shortcoming that exists with not enough, provide a kind of easy to operate, cost is low, be applicable to the novel preparation method of industrial Agomelatine, is particularly suitable for large-scale industrial production.For achieving the above object, the invention discloses following technical scheme:
A kind of industrialized process for preparing of Agomelatine, it is characterized in that under the condition of anhydrous solvent, compound (II) is mixed with acylating reagent, add acid binding agent, plant hydrogen gas is passed under stirring, hydrogen exchange air 3 times, pressure hydration is obtained by reacting compound (I);
Wherein said Compound II per is 7-methoxynaphthalene acetonitrile;
Described solvent comprises tetrahydrofuran (THF), toluene, DMSO etc.;
Described acid binding agent comprises triethylamine, pyridine, quadrol, ammonia, salt of wormwood, sodium carbonate, potassium hydroxide, the organic basess such as sodium hydroxide and mineral alkali;
The ratio of described compound (II) and anhydrous solvent is 1: 1-10, preferably 1: 4;
Described compound (II) and acylating reagent ratio are 1: 1-5, preferably 1: 2;
Described compound (II) and acid binding agent ratio are 1: 1-5, preferably 1: 2;
Described compound (II) and catalyst ratio are 1: 0.1-0.5, preferably 1: 0.2;
Described reaction pressure is 0.5-3MPa, preferred 1-1.5MPa;
The described reaction times is 1-5h, preferential 1-2h;
Described temperature of reaction is 20-100 DEG C, preferential 35-60 DEG C.
The present inventor has determined the industrialized preparing process adopting acylating reagent to add acid binding agent under certain temperature, pressure to prepare Agomelatine through test of many times.The present invention prepares the low and non-polymer of the Agomelatine bulk drug foreign matter content of gained and occurs, without the need to through complicated aftertreatment; Product purity is high, and reaction yield, up to 98%, significantly reduces production cost, decreases the pollution to environment.Through repeatedly industrial production checking, the present invention is applicable to large-scale commercial production completely.
The concrete step of the present invention is as follows:
In autoclave, add Compound II per, reaction solvent, acylating agent, acid binding agent, Raney-Ni, stir, at the uniform velocity pass into H
2gas (industrial steel cylinder air feed, purity > 99%), displaced air 3 times, be pressurized to 0.5-3MPa, temperature control 20-100 DEG C, react stopped reaction after 2-8 hour, reaction solution is cool to room temperature in tank, is extracted out by reaction solution, Filtration of catalyst, mother liquor concentrating under reduced pressure, add acetic acid ethyl dissolution, with soda lye wash, separatory, organic phase is dry, and evaporated under reduced pressure solvent obtains Compound I.
Wherein, described reaction solvent, preferred tetrahydrofuran (THF).Described acylating reagent, preferred diacetyl oxide.The preferred triethylamine of described acid binding agent, pyridine.Described reaction pressure scope is 0.5-3MPa, and range of reaction temperature described in preferred 1-1.5MPa is 20-100 DEG C, preferred 35-60 DEG C.Described reaction time range is 1-5 hour, preferred 1-2 hour.
Hydrogenation disclosed by the invention prepares Agomelatine production method compared with prior art, has the following advantages and technique effect:
(1) the present invention for starting raw material with (7-methoxyl group 1-naphthyl) acetonitrile, under anhydrous solvent, adds Raney-Ni, acylating agent, acid binding agent, while hydrogenation, carries out acylation reaction.In reaction process, remain faintly alkaline reaction environment, effectively keep catalyst activity, bearing reaction is carried through to the end with speed forward faster, efficiently avoid the generation of by product, shorten the reaction times, improve reaction yield, and use lower hydrogen pressure to make reaction more simple, reduce the particular requirement to equipment, decrease potential safety hazard.
(2) Raney-Ni used in reaction of the present invention is cheap, be easy to get, and cost almost can be ignored after 10-12 time is applied mechanically repeatedly.
(3) hydrogenation in reaction of the present invention, acidylate two-step reaction carry out in autoclave simultaneously, reduce three waste discharge, decrease pollution to environment.
(4) products obtained therefrom yield of the present invention is high, purity good, and average yield reaches 98%, and content in crude product reaches 99%-99.5%, and by product dimer content is lower than 0.1%.
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.These embodiments should be understood only be not used in for illustration of the present invention and limit the scope of the invention.Wherein (7-methoxyl group 1-naphthyl) acetonitrile, Raney-Ni, dehydrated alcohol, tetrahydrofuran (THF), Acetyl Chloride 98Min., aceticanhydride, pyridine, triethylamine, Anhydrous potassium carbonate etc. all has commercially available, is described in detail below below with preferred embodiment.
Embodiment 1:
With Acetyl Chloride 98Min. be acylating agent, triethylamine is that acid binding agent prepares Agomelatine (Compound I)
In the 100L autoclave of drying, add (7-methoxyl group 1-naphthyl) acetonitrile 9.85kg (50mol), anhydrous tetrahydro furan 39.4L, Raney-Ni 1.2kg, Acetyl Chloride 98Min. 4.32Kg (55mol), triethylamine 11.1Kg (110mol), vacuumize after stirring and change to nitrogen, vacuumize and change to hydrogen (industrial steel cylinder air feed, purity > 99%), control hydrogen pressure 1-1.5Mpa, temperature control 45 DEG C, reacts 2 hours.React complete, by reaction solution sucking-off from autoclave, after evaporated under reduced pressure, be dissolved in ethyl acetate, the washing of saturated sodium bicarbonate water liquid is extremely neutral, stratification, and organic phase evaporated under reduced pressure is Compound I, heavy 11.5kg, purity is 99% (HPLC), crude yield 95%.
Embodiment 2:
With acetic anhydride be acylating agent, pyridine is that acid binding agent prepares Agomelatine (Compound I) in the 100L autoclave of drying; add (7-methoxy-1-naphthyl) acetonitrile 9.85kg (50mol), anhydrous tetrahydro furan 39.4L, Raney-Ni 1kg, acetic anhydride 5.6Kg (55mol), pyridine 8.7Kg (110mol); vacuumize after stirring and change to nitrogen; vacuumize and change to hydrogen (industrial steel cylinder air feed; purity > 99%); control hydrogen pressure 1-1.2Mpa; temperature control 40 DEG C, reacts 1.5 hours.React complete, by reaction solution sucking-off from autoclave, evaporated under reduced pressure, resistates is dissolved in ethyl acetate, the washing of saturated sodium bicarbonate water liquid is to neutral, stratification, organic phase evaporated under reduced pressure obtains Compound I, crude product 11.9kg, purity 99.5% (HPLC), yield 98%, fusing point 106-108 DEG C
1hNMR (DMSO): 1.86 (S, 3H), 3.16 (t, 2H), 3.27 (q, 2H), 3.97 (s, 3H), 7.14 ~ 7.81 (m, 6H), 8.11 (br, 1H).
Embodiment 3:
With toluene be reaction solvent, acetic anhydride is acylating agent, triethylamine is that acid binding agent prepares Agomelatine (Compound I)
In the 100L autoclave of drying, add (7-methoxyl group 1-naphthyl) acetonitrile 9.85kg (50mol), anhydrous tetrahydro furan 39.4L, Raney-Ni 1kg, acetic anhydride 5.6Kg (55mol), triethylamine 11.1Kg (110mol), vacuumize after stirring and change to nitrogen, vacuumize and change to hydrogen (industrial steel cylinder air feed, purity > 99%), control hydrogen pressure 1-1.5Mpa, temperature control 60 DEG C, reacts 3 hours.React complete, by reaction solution sucking-off from autoclave, after evaporated under reduced pressure, resistates is dissolved in ethyl acetate, the washing of saturated sodium bicarbonate water liquid is extremely neutral, stratification, and namely organic phase evaporated under reduced pressure obtains Compound I, heavy 11.9kg, purity is 99.5% (HPLC), crude yield 98%.
Embodiment 4: reference example
The preparation of (7-methoxyl group 1-naphthyl) acetonitrile
Steps A: the preparation of (1-hydroxyl-7-methoxyl group-1,2,3,4-tetrahydrochysene-1-naphthyl) acetonitrile
Under nitrogen protection; 2.45kg acetonitrile, 28.5kg tetrahydrofuran (THF) are joined in dry anhydrous response tank; stir; temperature control less than-78 DEG C; slow dropping n-BuLi 29.82 L, dropwises, then drips the mixing solutions of 7-methoxyl group-ALPHA-tetralone 7.5Kg and 20L tetrahydrofuran (THF); dropwise, be incubated less than-75 DEG C and react 5h.
React complete, add suitable quantity of water, after temperature rises to 25 DEG C, stop stirring, stratification, water layer has a small amount of solid salt.Organic layer 9kg anhydrous magnesium sulfate drying spends the night.
Cross and filter siccative, a small amount of tetrahydrofuran (THF) filter wash cake, after filtrate merges, evaporated under reduced pressure obtains resistates.Obtain 7.8kg after 10 times of isopropyl ethers are refining, yield 85%, HPLC surveys content > 96.5%, fusing point 88 DEG C.
Step B:(7-methoxyl group 1-naphthyl) preparation of acetonitrile
116kg methylene dichloride, 11.1kg (1-hydroxyl-7-methoxyl group-1,2,3,4-tetrahydrochysene-1-naphthyl) acetonitrile, 11.8Kg DDQ is added in the retort of 200L.Add rear room temperature and answer 24h.
React complete, filtering solid, methylene dichloride uses 20kg water washing once mutually, then washs once with saturated brine 22kg, stratification.Obtain resistates after organic phase evaporated under reduced pressure, 10 times amount toluene dissolve products obtained therefroms, add 0.296KGTSOHH
2o, stirring, reflux 1h.Reaction is finished, and is cooled to room temperature, adds saturated sodium carbonate agitator treating to neutral, stratification, and toluene is mutually with saturated brine 22kg washing, and stratification, organic phase evaporated under reduced pressure obtains resistates.Product (Compound II per) 8.46Kg is obtained, yield 84%, fusing point 83 DEG C after refining with 10 times amount isopropyl ethers.
Embodiment 5
Simultaneous test A: Chinese Journal of Pharmaceuticals 2008 is solvent with tetrahydrofuran (THF) in 39 (3), and diacetyl oxide is that Agomelatine (Compound I) is prepared in acylating agent hydrogenation
Literature procedures: 19.7g (0.1mol) naphthalene acetonitrile, diacetyl oxide (20.4g, 0.2mol) and Raney-Ni (4g) put in autoclave, add tetrahydrofuran (THF) 200ml, are heated to 35 DEG C, pass into H
2, stir 10 hours under 1.1MPa hydrogen pressure, reaction solution is cooled to room temperature, be down to normal pressure, filter, concentrated, add ethyl acetate 200ml, use saturated sodium bicarbonate water liquid (60ml), water (60ml), saturated brine (60ml) to wash successively, steaming desolventizes, residuum alcohol-water (3: 5) recrystallization, dry, obtain white powder 19.9g, 82%, Mp106-108 DEG C.
Be solvent with tetrahydrofuran (THF) in simultaneous test B:CN 101643433A, in Special high-voltage hydrogenation equipment, slowly add diacetyl oxide and (7-methoxyl group 1-naphthyl) acetonitrile, Agomelatine (Compound I) is prepared in hydrogenation
Literature procedures: add 136g Raney-Ni, 2.06 liters of ethanol and 0.23 premium on currency in the reactor of 8 liters.By it while 70 DEG C and 30 bar stirring under hydrogen, slowly add (the 7-methoxyl group 1-naphthyl) acetonitrile (0.8Kg) be dissolved in diacetyl oxide (2.4 liters) wherein.At the end of adding, by this reaction mixture 30 bar stirring under hydrogen 1 hour; Then, this reactor is reduced pressure and liquid is filtered.After this mixture is concentrated, by residue from ethanol/water 35/65 crystalline mixture, thus with 89% yield obtain chemical purity higher than 99% title product.Fusing point: 108 DEG C.
Method of the present invention: with acetic anhydride be acylating agent, pyridine is that Agomelatine (Compound I) is prepared in acid binding agent hydrogenation
Step: in the 100L autoclave of drying, add (7-methoxy-1-naphthyl) acetonitrile 9.85kg (50mol), anhydrous tetrahydro furan 39.4L, Raney-Ni 1kg, acetic anhydride 5.6Kg (55mol), pyridine 8.7Kg (110mol), vacuumize after stirring and change to nitrogen, vacuumize and change to hydrogen (industrial steel cylinder air feed, purity > 99%), control hydrogen pressure 1-1.2Mpa, temperature control 50 DEG C, reacts 1.5 hours.React complete, by reaction solution sucking-off from autoclave, after evaporated under reduced pressure, resistates is dissolved in ethyl acetate, the washing of saturated sodium bicarbonate water liquid is extremely neutral, stratification, and namely organic phase evaporated under reduced pressure obtains Compound I, with alcohol-water (3: 5) recrystallization, dry, obtain white powder 11.5kg, yield 95%, purity is 99.8% (HPLC), Mp108 DEG C.
The detected result of Agomelatine prepared by three kinds of methods:
Conclusion: by simultaneous test, three kinds of methods can obtain the Compound I that dimer content is less than 0.1% after refining.But in simultaneous test A, hydrogenation generates the dimer impurity of about 12%, and reaction yield is low, produces more chemical waste; In simultaneous test B, need to adopt special high-pressure hydrogenation equipment, the method adopting diacetyl oxide and (7-methoxyl group 1-naphthyl) acetonitrile slowly to add solves dipolymer problem, and fine work yield is only 89%; Adopt the inventive method, react in ordinary high pressure hydriding reactor, significantly can reduce the content of dipolymer in crude product, the selectivity that effective increase reaction forward is carried out, gained crude product purity is increased to 98-99%, and fine work yield is increased to 95%, while the minimizing three wastes, reduce production cost.
Claims (8)
1. a production method for Agomelatine is prepared in hydrogenation, it is characterized in that in anhydrous solvent, formula (II) is mixed with acylating reagent, add acid binding agent, catalyzer, passes into plant hydrogen under stirring, is obtained by reacting compound (I) under a certain pressure;
Wherein said compound (II) is 1: 1-5 with the ratio of weight and number of acylating reagent;
Described anhydrous solvent is tetrahydrofuran (THF), toluene or DMSO;
Described acylating reagent is diacetyl oxide or Acetyl Chloride 98Min.;
Described catalyzer is Raney-Ni;
Described acid binding agent is triethylamine, pyridine, quadrol or ammonia.
2. production method according to claim 1, wherein compound (II) is 1: 1-10 with the ratio of weight and number of anhydrous solvent.
3. production method according to claim 1, wherein said compound (II) is 1: 2 with the ratio of weight and number of acylating reagent.
4. production method according to claim 1, wherein said compound (II) and acid binding agent ratio are 1: 1-5.
5. production method according to claim 1, wherein said compound (II) and catalyst ratio are 1: 0.1-0.5.
6. production method according to claim 1, wherein said reaction pressure is 0.5-3MPa.
7. production method according to claim 1, the wherein said reaction times is 1-5h.
8. production method according to claim 1, wherein said temperature of reaction is 20-100 DEG C.
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| CN107353229A (en) * | 2017-08-08 | 2017-11-17 | 许昌恒生制药有限公司 | A kind of preparation method of agomelatine intermediate body |
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| CN104710259B (en) * | 2015-03-16 | 2016-07-06 | 浙江工业大学 | A kind of synthetic method of amides compound |
| CN109293565B (en) * | 2018-10-26 | 2021-08-06 | 江苏七洲绿色化工股份有限公司 | Preparation method of fluopyram |
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| CN101041629B (en) * | 2004-02-13 | 2010-10-13 | 瑟维尔实验室 | New process for the synthesis and new crystalline form of agomelatine and pharmaceutical compositions containing it |
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| WO2011154140A2 (en) * | 2010-06-10 | 2011-12-15 | Gador S.A. | New process for the preparation of n-[2-(7-methoxy-1-naphthyl)-ethyl]acetamide and new crystalline form |
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| CN101041629B (en) * | 2004-02-13 | 2010-10-13 | 瑟维尔实验室 | New process for the synthesis and new crystalline form of agomelatine and pharmaceutical compositions containing it |
| US20100036161A1 (en) * | 2008-08-05 | 2010-02-11 | Les Laboratoires Servier | Process for the synthesis of agomelatine |
| WO2011154140A2 (en) * | 2010-06-10 | 2011-12-15 | Gador S.A. | New process for the preparation of n-[2-(7-methoxy-1-naphthyl)-ethyl]acetamide and new crystalline form |
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