CN106928082A - A kind of new agomelatine synthesis and purification process - Google Patents
A kind of new agomelatine synthesis and purification process Download PDFInfo
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- 229960002629 agomelatine Drugs 0.000 title claims abstract description 66
- YJYPHIXNFHFHND-UHFFFAOYSA-N agomelatine Chemical compound C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 YJYPHIXNFHFHND-UHFFFAOYSA-N 0.000 title claims abstract description 66
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 57
- 238000003786 synthesis reaction Methods 0.000 title claims description 26
- 238000000746 purification Methods 0.000 title description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 72
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 47
- 239000013078 crystal Substances 0.000 claims abstract description 36
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 239000000047 product Substances 0.000 claims abstract description 31
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 23
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000001257 hydrogen Substances 0.000 claims abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
- 239000012043 crude product Substances 0.000 claims abstract description 17
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 12
- 235000019441 ethanol Nutrition 0.000 claims abstract description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims abstract description 7
- 239000001632 sodium acetate Substances 0.000 claims abstract description 7
- 235000017281 sodium acetate Nutrition 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 63
- 239000000243 solution Substances 0.000 claims description 41
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- 238000000967 suction filtration Methods 0.000 claims description 21
- 238000005984 hydrogenation reaction Methods 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 18
- 238000002425 crystallisation Methods 0.000 claims description 17
- 230000008025 crystallization Effects 0.000 claims description 17
- 239000012065 filter cake Substances 0.000 claims description 17
- 239000007789 gas Substances 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 13
- 238000005406 washing Methods 0.000 claims description 13
- 238000012544 monitoring process Methods 0.000 claims description 12
- 239000000725 suspension Substances 0.000 claims description 12
- 238000001556 precipitation Methods 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000007868 Raney catalyst Substances 0.000 claims description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 10
- 239000012452 mother liquor Substances 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 5
- 230000008676 import Effects 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000012805 post-processing Methods 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 5
- 230000002194 synthesizing effect Effects 0.000 abstract description 4
- 238000002474 experimental method Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 206010013786 Dry skin Diseases 0.000 description 6
- 239000000370 acceptor Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 5
- 230000033764 rhythmic process Effects 0.000 description 5
- 102100024959 5-hydroxytryptamine receptor 2C Human genes 0.000 description 4
- 101710138093 5-hydroxytryptamine receptor 2C Proteins 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 230000007958 sleep Effects 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 238000004140 cleaning Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102000001419 Melatonin receptor Human genes 0.000 description 2
- 108050009605 Melatonin receptor Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- -1 allyl ester Chemical class 0.000 description 1
- 230000000049 anti-anxiety effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 210000002752 melanocyte Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 210000001009 nucleus accumben Anatomy 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 210000002442 prefrontal cortex Anatomy 0.000 description 1
- 230000002360 prefrontal effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000001020 rhythmical effect Effects 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of new method for synthesizing II crystal formation agomelatine, first with compound (I) as raw material, reacted with hydrogen in ammonia/ethanol system, obtain compound (II)；Then by compound (II) in sodium acetate/ethanol system with acetic anhydride, obtain compound (III) crude product, absolute ethyl alcohol/ethyl acetate system is recrystallized to give the agomelatine of II crystal formation.The invention discloses a kind of method (two-step method) for synthesizing II crystal formation agomelatine, experiment condition of the present invention is simple and safe, and energy-conserving and environment-protective, post processing is simple, and product is easy to get and high income, and purity is big, the low suitable industrialized production of process costs.
Description
Technical field
The present invention relates to agomelatine synthesis technical field, specially a kind of new agomelatine synthesizes and purifying side
Method.
Background technology
1st, agomelatine is first melatonin receptor activator, is also the antagonist of 5HT-2c acceptors.A large amount of animals
Experiment be proved its can antianxiety, antidepression and adjustment sleep cycle circulation the rhythm and pace of moving things, can night adjust patient Sleep architecture
And improve the health care of sleep.Its appearance is the new breakthrough in treating depression field.Effect machine of the innovation of agomelatine in its uniqueness
System -- regulation patient sleeps' wake cycle.It breaks through the monoamine neurotransmitter systemic effect of traditional antidepressants, and it is mainly by taking off
The excitement of melanocyte acceptor MT1, MT2 and to the synergy of 5-HT2C antagonisms, and the disorderly biological rhythm of patient is recovered normal.
SCN (SCN) is the regulation maincenter of rhythmic system, is dispersed with abundant MT1, MT2 and 5-HT2C acceptor.In evening
Between because without light stimulus, to pineal suppression, therefore the secretion of epiphysin increases, and stimulates MT1, MT2 acceptor, by epiphysin
The effect regulation biological rhythm of signal path after acceptor.It has now been found that the patient symptom order of severity is disorderly with its biological rhythm
Degree is significantly correlated, and a large amount of animals and human experimentation research show that agomelatine is by the agonism to melatonin receptor
The biological rhythm of disorder can be made to recover normal, and then play antidepressant effects.
Agomelatine is simultaneously the neutral antagonist of 5-HT2C acceptors, collection cerebral hippocampus in position in connection, amygdaloid nucleus
And prefrontal cortex, the suppression that light stimulus can be prevented its antagonism to synthesize epiphysin, the DA levels of prefrontal lobe are improved, also
The adrenergic secretion level of nucleus ceruleus can be accelerated, this can promote the regrowth of nerve, swash the more stability and stabilizations of pituitary secretion
Element, and on the DA of corpus straitum and nucleus accumbens septi without influence.Zooscopy shows that the agomelatine of reduced levels is that 5-HT2C is received
Body has blocking effect, and its signal transduction can be made to recover normal, without suppress its signal transduction so that its drop to baseline values with
Under.While this unique mechanism of action makes it quickly and efficiently play antidepressant effect, medicine poison is reduced to greatest extent
Side effect.
2nd, the original of agomelatine grinds design route as follows (CN200510071611.6)
3rd, 3, the improved process program (101759591A [P]) such as Zhou Shiwei
4th, Zhang Guisen etc. is to proposing new process program (WO2010012208A1)
5th, the new process program (CN103058879A) of the proposition such as Zhou Ruguo
1st, original is ground route and is had the drawback that：A) route of reaction is long, and the synthesis of intermediate 2 needs 200 DEG C high
Temperature and the up to pressure of 300atm, reaction condition are difficult to operate and realize in industrialized production；B) and with poisonous methyl-prop
Olefin(e) acid allyl ester makees dehydrogenating agent, harmful to environment.
2nd, the shortcoming of the route of Zhou Shiwei is：A) it is dehydrogenating agent to have used expensive and relatively hazardous DDQ；B) use
Subzero 78 degree of ultralow temperature and dangerous butyl lithium higher, realization of industrialization difficulty are big.
3rd, the shortcoming of the route of Zhang Guisen is：A) it with pyridine is solvent in being carried out at -10 DEG C that sulfonylation is, and actual
Should be tried one's best in production and avoid the pyridine and cryogenic conditions of stench；B) macromolecule alkali for hydrolysis with 80% hydrazine hydrate belong to hypertoxic type material, easily
Set off an explosion, if will be reduced instead of yield with NaOH；C) many using solvent in whole piece route, overall yield is not high.
4th, the shortcoming of the route of Zhou Ruguo is：A) toxic solvents such as toluene, chloroform are used in reacting；B) second step is anti-
Ying Zhong, it is larger using chloroacetic chloride/triethylamine system excitant.
The content of the invention
It is an object of the invention to provide a kind of new method for synthesizing II crystal formation agomelatine, two-step method synthesis, step
Few efficiency high；Side reaction is few, high income, and post processing is simple；Solvent usage amount is few, and recoverable, environmentally friendly, and drop
Low cost, to solve the problems, such as to be proposed in above-mentioned background technology.
To achieve the above object, the present invention provides following technical scheme：1. it is a kind of to synthesize the new of II crystal formation agomelatine
Method, comprises the following steps：
1) (7- methoxy-1-naphthyls) acetonitrile is added in hydrogenation reaction cauldron, after anhydrous alcohol solution, Raney nickel is added,
(7- methoxy-1-naphthyls) acetonitrile is 0.01-0.095 with the mass ratio of Raney nickel；Ammonia, ammonia are imported toward hydrogenation reaction cauldron
Gas air-flow steadily keeps 0.1-5h afterwards；Then hydrogen is replaced 1-5 times, closed reactor；
2) hydrogenation reaction cauldron is placed in 30-55 DEG C, and stirring reaction is overnight under the conditions of 0.1-4.0MPa Hydrogen Vapor Pressures；
3) TLC monitorings reaction is until reacting complete；
4) reaction solution and suction filtration, appropriate 95% ethanol rinse are poured out；Concentration filtrate, is dissolved with ethyl acetate, is led in solution
Enter hydrogen chloride gas, control the pH value of mother liquor for 8.0-9.0, it is in suspended liquid status to separate out a large amount of off-white color precipitations；
5) suction filtration suspension, after filter cake is with ethyl acetate drip washing, dry compound (II)；
6) compound (II) (1.0eq) anhydrous alcohol solution, adds sodium acetate 0.4-1.0eq, acetic anhydride 0.7-
Stirring reaction at 1.0eq, 50-80 DEG C, TLC monitorings are complete until reaction；
7) reaction solution is poured into saturated sodium bicarbonate aqueous solution, separates out a large amount of light yellowish brown precipitations；
8) suction filtration suspension, filter cake water wash, dry agomelatine crude product；
9) agomelatine crude product dissolves in absolute ethyl alcohol/ethyl acetate (v/v is 4/6-7/3) system, stirs at room temperature
After mixing, crystallization obtains II crystal formation agomelatine.
Preferably, in compound (II) synthesis, Raney nickel mass ratio 0.01-0.095 needed for compound (I)；
Preferably, 30-55 DEG C of compound (II) the synthetic reaction temperature control；
Preferably, Hydrogen Vapor Pressure 0.1-4.0MPa needed for compound (II) synthesis；
Preferably, the compound (II), the concentration of reaction solution after filtering, with ethyl acetate dissolve, import hydrogen chloride gas into
Salt crystallization, the pH value for controlling mother liquor is 8.0-9.0；
Preferably, 50-80 DEG C of the agomelatine finished product synthetic reaction temperature control；
Preferably, the reaction solution of the synthesis of the agomelatine finished product need to be poured into saturated sodium bicarbonate aqueous solution；
Preferably, the drip washing solvent of the agomelatine crude product is water；
Preferably, the finished product crystallization solvent is absolute ethyl alcohol/ethyl acetate (v/v is 4/6-7/3) system；
Preferably, the finished product recrystallization temperature is room temperature；
Preferably, the finished product is II crystal formation.
To test route, principle of the invention is further illustrated.
1：As above, synthesized using intermediate, only need the synthesis of two steps.Simplified synthesis step, improves reaction efficiency；
2：Using hydro-reduction, hydrogenation pressure need to only be more than 0.1Mpa, and the reaction of intermediate is totally safe, post processing letter
It is single, high income；
3：Purification of intermediate is crystallized using hydrogen chloride gas into salt, and purity is high, easy to operate；
4：The synthesis reaction solution of finished product is by concentration, filtering, filter cake cleaning and the treatment such as dries, and directly carries out recrystallizing
To the finished product and the crystal formation of needs of purity satisfaction；
5：Reaction cost is dropped, has been adapted to industrialized production；
6：Recycled solvent, reduces environmental pollution.
Further, in compound (II) synthesis, Raney nickel mass ratio 0.01-0.095 needed for compound (I) is reduced
The usage amount of heavy metal, reduces the pollution to environment.
Further, 30-55 DEG C of temperature control of intermediate synthesis, 0.1-4.0MPa, temperature by-products content high rises；
Further, in purification of intermediate, the concentration of reaction solution after filtering, with ethyl acetate dissolve, import hydrogen chloride gas into
Salt crystallization, controls the pH value of mother liquor for 8.0-9.0, and otherwise accessory substance starts into salt crystallization and separates out；
Further, 50-80 DEG C of agomelatine finished product synthetic reaction temperature control, reaction temperature is low, greatly reduces by-product
The generation of thing, and yield is improve, reaction solution purity is up to 99%.
Further, the reaction solution of the synthesis of agomelatine finished product need to be poured into saturated sodium bicarbonate aqueous solution, so as to
Salt in the sufficient separate out of finished product, and dissolving reaction；
Further, the drip washing solvent of agomelatine crude product is water, and cleaning is simple, environment friendly and pollution-free.
Further, finished product concentrate is just heated with a small amount of absolute ethyl alcohol/ethyl acetate (v/v is 4/6-7/3) system
Untill dissolving, cooling crystallization is stirred, in room temperature, temperature is too high to reduce yield to temperature control, and temperature is too low to easily cause impurity
Crystallization is separated out, and the situation of impurity is wrapped up with the caking phenomenon for avoiding static crystallization from producing, so as to ensure to obtain satisfied purity
And crystal formation.
Compared with prior art, the beneficial effects of the invention are as follows：The new method experiment of the crystal formation agomelatine of synthesis II
Condition is simple and safe, and post processing is simple, and product is easy to get and high income, and purity is big, the low suitable industrialized production of process costs.Adopt
Synthesized with intermediate, only need the synthesis of two steps.Simplified synthesis step, improves reaction efficiency；Using hydro-reduction, hydrogenation
Pressure need to only be more than 0.1Mpa, and the reaction of intermediate is totally safe, and post processing is simple, high income；Purification of intermediate uses salt
Acid gas is crystallized into salt, and purity is high, easy to operate；The synthesis reaction solution of finished product is by concentration, filtering, filter cake cleaning and dries etc.
Reason, directly carries out the crystal formation for being recrystallized to give the finished product of purity satisfaction and needing, and has dropped reaction cost, is adapted to industrialized production；
Recycled solvent, reduces the pollution to environment, two-step method synthesis, the few efficiency high of step；Side reaction is few, high income, locates afterwards
Reason is simple；Solvent usage amount is few, and recoverable, environmentally friendly, and reduces cost.
Brief description of the drawings
Fig. 1 is agomelatine reactions steps schematic diagram of the present invention；
Fig. 2 is that agomelatine of the present invention reacts conspectus；
Fig. 3 is the chemical structural formula of agomelatine of the present invention；
Fig. 4 is the relevant material detection figure of finished product agomelatine efficient liquid phase of the present invention；
Fig. 5 is the relevant material detection figure of agomelatine intermediate body efficient liquid phase.
Specific embodiment
Below in conjunction with the accompanying drawing in the embodiment of the present invention, the technical scheme in the embodiment of the present invention is carried out clear, complete
Site preparation is described, it is clear that described embodiment is only a part of embodiment of the invention, rather than whole embodiments.It is based on
Embodiment in the present invention, it is every other that those of ordinary skill in the art are obtained under the premise of creative work is not made
Embodiment, belongs to the scope of protection of the invention.
Fig. 1-5 are referred to, the present invention provides a kind of technical scheme：
1. a kind of new method for synthesizing II crystal formation agomelatine, comprises the following steps：
1) (7- methoxy-1-naphthyls) acetonitrile is added in hydrogenation reaction cauldron, after anhydrous alcohol solution, Raney nickel is added,
(7- methoxy-1-naphthyls) acetonitrile is 0.01-0.095 with the mass ratio of Raney nickel；Ammonia, ammonia are imported toward hydrogenation reaction cauldron
Gas air-flow steadily keeps 0.1-5h afterwards；Then hydrogen is replaced 1-5 times, closed reactor；
2) hydrogenation reaction cauldron is placed in 30-55 DEG C, and stirring reaction is overnight under the conditions of 0.1-4.0MPa Hydrogen Vapor Pressures；
3) TLC monitorings reaction is until reacting complete；
4) reaction solution and suction filtration, appropriate 95% ethanol rinse are poured out；Concentration filtrate, is dissolved with ethyl acetate, is led in solution
Enter hydrogen chloride gas, control the pH value of mother liquor for 8.0-9.0, it is in suspended liquid status to separate out a large amount of off-white color precipitations；
5) suction filtration suspension, after filter cake is with ethyl acetate drip washing, dry compound (II)；
6) compound (II) (1.0eq) anhydrous alcohol solution, adds sodium acetate 0.4-1.0eq, acetic anhydride 0.7-
Stirring reaction at 1.0eq, 50-80 DEG C, TLC monitorings are complete until reaction；
7) reaction solution is poured into saturated sodium bicarbonate aqueous solution, separates out a large amount of light yellowish brown precipitations；
8) suction filtration suspension, filter cake water wash, dry agomelatine crude product；
9) agomelatine crude product dissolves in absolute ethyl alcohol/ethyl acetate (v/v is 4/6-7/3) system, stirs at room temperature
After mixing, crystallization obtains II crystal formation agomelatine.
Further, in compound (II) synthesis, Raney nickel mass ratio 0.01-0.095 needed for compound (I)；
Further, 30-55 DEG C of compound (II) synthetic reaction temperature control；
Further, Hydrogen Vapor Pressure 0.1-4.0MPa needed for compound (II) synthesis；
Further, compound (II), the concentration of reaction solution after filtering is dissolved with ethyl acetate, imports hydrogen chloride gas into salt
Crystallization, the pH value for controlling mother liquor is 8.0-9.0；
Further, 50-80 DEG C of agomelatine finished product synthetic reaction temperature control；
Further, the reaction solution of the synthesis of agomelatine finished product need to be poured into saturated sodium bicarbonate aqueous solution；
Further, the drip washing solvent of agomelatine crude product is water；
Further, finished product crystallization solvent is absolute ethyl alcohol/ethyl acetate (v/v is 4/6-7/3) system；
Further, finished product recrystallization temperature is room temperature；
Further, finished product is II crystal formation.
Embodiment 1：II crystal formation agomelatine is prepared,
The preparation method of the present embodiment, comprises the following steps：
Step 1：The preparation of compound (II)
(7- methoxy-1-naphthyls) acetonitrile (10.0g, 50.7mmol) is added in hydrogenation reaction cauldron, 500ml hydrogen is added to
In reactor, 200ml anhydrous alcohol solutions are used, add Raney's nickel 0.1g, ammonia is imported in hydrogenation reaction cauldron, ammonia air-flow is steady
Keep 0.1-5h；Then hydrogen is replaced 1-5 times, closed reactor；Hydrogenation reaction cauldron is placed in 55 DEG C, 4.0MPa Hydrogen Vapor Pressure conditions
Lower stirring reaction is overnight；TLC monitorings are complete until reaction；Pour out reaction solution, suction filtration, a little drip washing of 95% ethanol；Concentration filtrate,
And dissolved with ethyl acetate, hydrogen chloride gas are imported in solution, the pH value of mother liquor is controlled for 8.0-9.0, separate out a large amount of off-white color precipitations；
Suction filtration suspension, with after ethyl acetate drip washing, 50 DEG C of dryings of filter cake obtain off-white powder, i.e. compound (II) 8.0g to filter cake, receive
Rate 66.4%.
Step 2：The preparation of agomelatine finished product
Compound (II) (4.0g, 16.8mmol), sodium acetate (3.0g, 37.0mmol) are added in 100mL single port bottles, are used
40mL anhydrous alcohol solutions, system is in suspended liquid；Stirring is lower to add acetic anhydride (2.0g, 20.2mmol)；Stirred at 50 DEG C
Reaction is mixed, TLC monitoring reactions are until complete；Reaction solution is poured into saturated sodium bicarbonate aqueous solution, a large amount of light yellowish browns are separated out
Precipitation；Suction filtration suspension, filter cake water wash obtains agomelatine crude product；Agomelatine crude product is in absolute ethyl alcohol/acetic acid second
Dissolved in ester (v/v is 4/6) system, crystallization after stirring at room temperature；The crystal that suction filtration is produced, obtains off-white color and consolidates after 50 DEG C of dryings
Body, i.e. II crystal formation agomelatine 3.6g, yield 88.0%, fusing point：107-108℃.
Embodiment 2：Prepare II crystal formation agomelatine
The preparation method of the present embodiment, comprises the following steps：
Step 1：The preparation of compound (II)
(7- methoxy-1-naphthyls) acetonitrile (10.0g, 50.7mmol) is added in hydrogenation reaction cauldron, 500ml hydrogen is added to
In reactor, 200ml anhydrous alcohol solutions are used, add Raney's nickel 0.5g, ammonia is imported in hydrogenation reaction cauldron, ammonia air-flow is steady
Keep 0.1-5h；Then hydrogen is replaced 1-5 times, closed reactor；Hydrogenation reaction cauldron is placed in 30 DEG C, 0.1MPa Hydrogen Vapor Pressure conditions
Lower stirring reaction is overnight；TLC monitorings are complete until reaction；Pour out reaction solution, suction filtration, a little drip washing of 95% ethanol；Concentration filtrate,
And dissolved with ethyl acetate, hydrogen chloride gas are imported in solution, the pH value of mother liquor is controlled for 8.0-9.0, separate out a large amount of off-white color precipitations；
Suction filtration suspension, with after ethyl acetate drip washing, 50 DEG C of dryings of filter cake obtain off-white powder, i.e. compound (II) 6.5g to filter cake, receive
Rate 53.2%.
Step 2：The preparation of agomelatine finished product
Compound (II) (4.0g, 16.8mmol), sodium acetate (3.0g, 37.0mmol) are added in 100mL single port bottles, are used
40mL anhydrous alcohol solutions, system is in suspended liquid；Stirring is lower to add acetic anhydride (2.0g, 20.2mmol)；Stirred at 80 DEG C
Reaction is mixed, TLC monitoring reactions are until complete；Reaction solution is poured into saturated sodium bicarbonate aqueous solution, a large amount of light yellowish browns are separated out
Precipitation；Suction filtration suspension, filter cake water wash obtains agomelatine crude product；Agomelatine crude product is in absolute ethyl alcohol/acetic acid second
Dissolved in ester (v/v is 5/5) system, crystallization after stirring at room temperature；The crystal that suction filtration is produced, obtains off-white color and consolidates after 50 DEG C of dryings
Body, i.e. II crystal formation agomelatine 3.2g, yield 78.6%, fusing point：107-108℃.
Embodiment 3：Prepare II crystal formation agomelatine
The preparation method of the present embodiment, comprises the following steps：
Step 1：The preparation of compound (II)
(7- methoxy-1-naphthyls) acetonitrile (10.0g, 50.7mmol) is added in hydrogenation reaction cauldron, 500ml hydrogen is added to
In reactor, 200ml anhydrous alcohol solutions are used, add Raney's nickel 0.95g, ammonia is imported in hydrogenation reaction cauldron, ammonia air-flow is put down
It is steady to keep 0.1-5h；Then hydrogen is replaced 1-5 times, closed reactor；Hydrogenation reaction cauldron is placed in 45 DEG C, 2.0MPa Hydrogen Vapor Pressure bars
Stirring reaction is overnight under part；TLC monitoring reactions are until complete；Pour out reaction solution, suction filtration, a little drip washing of 95% ethanol；Concentration filter
Liquid, and dissolved with ethyl acetate, hydrogen chloride gas are imported in solution, the pH value of mother liquor is controlled for 8.0-9.0, separate out a large amount of off-white colors and sink
Form sediment；Suction filtration suspension, with after ethyl acetate drip washing, 50 DEG C of dryings of filter cake obtain off-white powder, i.e. compound (II) to filter cake
8.7g, yield 71.2%, product characters:White powder.Purity：99.52%.
Referring to lower experimental data：
Step 2：The preparation of agomelatine finished product
Compound (II) (4.0g, 16.8mmol), sodium acetate (3.0g, 37.0mmol) are added in 100mL single port bottles, are used
40mL anhydrous alcohol solutions, system is in suspended liquid；Stirring is lower to add acetic anhydride (2.0g, 20.2mmol)；Stirred at 65 DEG C
Reaction is mixed, TLC monitorings are complete until reaction；Reaction solution is poured into saturated sodium bicarbonate aqueous solution, a large amount of light yellowish browns are separated out
Precipitation；Suction filtration suspension, filter cake water wash obtains agomelatine crude product；Agomelatine crude product is in absolute ethyl alcohol/acetic acid second
Dissolved in ester (v/v is 7/3) system, crystallization after stirring at room temperature；The crystal that suction filtration is produced, obtains off-white color and consolidates after 50 DEG C of dryings
Body, i.e. II crystal formation agomelatine 3.8g, yield 92%, product characters：White powder.Purity：99.90%, fusing point：107-
108℃。
Referring to lower experimental data：
In sum, although being described in detail to the present invention with reference to the foregoing embodiments, for the technology of this area
For personnel, it can still modify to the technical scheme described in foregoing embodiments, or to which part technology
Feature carries out equivalent, all any modification, equivalent substitution and improvements within the spirit and principles in the present invention, made etc.,
Should be included within protection scope of the present invention.
Claims (11)
1. it is a kind of synthesize II crystal formation agomelatine new method, it is characterised in that comprise the following steps：
1) (7- methoxy-1-naphthyls) acetonitrile is added in hydrogenation reaction cauldron, after anhydrous alcohol solution, Raney nickel, (7- first is added
Oxy-1-naphthyl) mass ratio of acetonitrile and Raney nickel is 0.01-0.095；Ammonia, ammonia gas are imported toward hydrogenation reaction cauldron
Levelling surely keeps 0.1-5h afterwards；Then hydrogen is replaced 1-5 times, closed reactor；
2) hydrogenation reaction cauldron is placed in 30-55 DEG C, and stirring reaction is overnight under the conditions of 0.1-4.0MPa Hydrogen Vapor Pressures；
3) TLC monitorings reaction is until reacting complete；
4) reaction solution and suction filtration, appropriate 95% ethanol rinse are poured out；Concentration filtrate, is dissolved with ethyl acetate, and salt is imported in solution
Acid gas, controls the pH value of mother liquor for 8.0-9.0, and it is in suspended liquid status to separate out a large amount of off-white color precipitations；
5) suction filtration suspension, after filter cake is with ethyl acetate drip washing, dry compound (II)；
6) compound (II) (1.0eq) anhydrous alcohol solution, adds sodium acetate 0.4-1.0eq, acetic anhydride 0.7-1.0eq, 50-
Stirring reaction at 80 DEG C, TLC monitorings are complete until reaction；
7) reaction solution is poured into saturated sodium bicarbonate aqueous solution, separates out a large amount of light yellowish brown precipitations；
8) suction filtration suspension, filter cake water wash, dry agomelatine crude product；
9) agomelatine crude product dissolves in absolute ethyl alcohol/ethyl acetate (v/v is 4/6-7/3) system, after stirring at room temperature,
Crystallization obtains II crystal formation agomelatine.
2. it is according to claim 1 it is a kind of synthesize II crystal formation agomelatine new method, it is characterised in that：The chemical combination
In thing (II) synthesis, Raney nickel mass ratio 0.01-0.095 needed for compound (I).
3. it is according to claim 1 it is a kind of synthesize II crystal formation agomelatine new method, it is characterised in that：The chemical combination
30-55 DEG C of thing (II) synthetic reaction temperature control.
4. it is according to claim 1 it is a kind of synthesize II crystal formation agomelatine new method, it is characterised in that：The chemical combination
Hydrogen Vapor Pressure 0.1-4.0MPa needed for thing (II) synthesis.
5. it is according to claim 1 it is a kind of synthesize II crystal formation agomelatine new method, it is characterised in that：The chemical combination
Thing (II), the concentration of reaction solution after filtering is dissolved with ethyl acetate, imports hydrogen chloride gas into salt crystallization, and the pH value for controlling mother liquor is
8.0-9.0。
6. it is according to claim 1 it is a kind of synthesize II crystal formation agomelatine new method, it is characterised in that：The algebraic oriented language
50-80 DEG C of Mei Lating finished product synthetic reactions temperature control.
7. it is according to claim 1 it is a kind of synthesize II crystal formation agomelatine new method, it is characterised in that：The algebraic oriented language
The reaction solution of the synthesis of Mei Lating finished products need to be poured into saturated sodium bicarbonate aqueous solution.
8. it is according to claim 1 it is a kind of synthesize II crystal formation agomelatine new method, it is characterised in that：The algebraic oriented language
The drip washing solvent of Mei Lating crude products is water.
9. it is according to claim 1 it is a kind of synthesize II crystal formation agomelatine new method, it is characterised in that：The finished product
Crystallization solvent is absolute ethyl alcohol/ethyl acetate (v/v is 4/6-7/3) system.
10. it is according to claim 1 it is a kind of synthesize II crystal formation agomelatine new method, it is characterised in that：It is described into
Product recrystallization temperature is room temperature.
A kind of new method of the 11. crystal formation agomelatine of synthesis II according to claim 1-10, it is characterised in that：It is described
Finished product is II crystal formation.
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|---|---|---|---|---|
| CN101041629A (en) * | 2004-02-13 | 2007-09-26 | 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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| CN101041629A (en) * | 2004-02-13 | 2007-09-26 | 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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| CN116947673A (en) * | 2023-07-19 | 2023-10-27 | 常州瑞明药业有限公司 | Synthesis method of agomelatine |
| CN116947673B (en) * | 2023-07-19 | 2025-07-22 | 常州瑞明药业有限公司 | Agomela Synthesis method of statin |
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