CN103130673B - Preparation method of agomelatine crystal type I - Google Patents
Preparation method of agomelatine crystal type I Download PDFInfo
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- CN103130673B CN103130673B CN201110381749.1A CN201110381749A CN103130673B CN 103130673 B CN103130673 B CN 103130673B CN 201110381749 A CN201110381749 A CN 201110381749A CN 103130673 B CN103130673 B CN 103130673B
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- organic solvent
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- agomelatine
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Abstract
The invention discloses a preparation method of agomelatine crystal type I which is an antidepressant drug. The preparation of the agomelatine crystal type I comprises the following steps: dissolving the agomelatine in at least a hydrophilic organic solvent; dropping in at least a hydrophilic organic solvent, at least a non-water-solubility solvent and an ice-water mixed system along with stirring; adding at least a low-polarity organic solvent after dropping, and separating crystals. The agomelatine crystal type I prepared with the method has the advantages of being good in quality and reproducibility, and applicable to large-scale industrial production.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis field and field of medicaments, and in particular to the brilliant preparation side of agomelatine I type
Method, the crystal formation I purity obtained by the method is high, favorable reproducibility.
Background technology
Agomelatine (Agomelatine), chemistry is entitled：N- [2- (7- methoxy-1-naphthyls) ethyl] acetamide,
Structure shown in formula I, can be prepared by the method disclosed in EP0447285,
Agomelatine is melatonin 1,2（MT1, MT2）Receptor stimulating agent, while being also five hydroxytryptamine 2c（5HT2C）Receive
Body antagonist, can directly with the 5HT2C receptor bindings of nerve synapse caudacoria, so as to play its antidepressant curative effect, and do not increase prominent
5HT concentration between touching, hence without five hydroxytryptamine reuptake inhibitor class medicine and the suppression of five hydroxytryptamine norepinephrine reuptake
The common adverse effect of preparation class medicine.Another unique effect target spot of the medicine in MT receptors, by swashing to MT1 and MT2 receptors
Action is used, tired, sleep disordered and anxiety for example nervous to following disease, severe depression, seasonal affective disorder, cardiovascular
Disease, digestive system disease, by caused by the time difference insomnia and fatigue, schizophrenia, panic attack, melancholia, appetite disorder,
Obesity, insomnia, pain, abalienation, epilepsy, diabetes, parkinson disease, alzheimer disease and normal or pathologic are aging
Relevant various disorders, migraine, the loss of memory, Alzheimer and cerebral circulation disorder have improvement or therapeutical effect.
Another active field can be additionally used in the treatment of sexual dysfunction, suppress with ovulation and immunoregulatory property, and also can use
In treating cancer.
Agomelatine belongs to slightly water-soluble compound, typically uses in solid form in the formulation, therefore to its crystal formation
Research tool is of great significance.
In view of the medical value of this compound, if I type crystalline substance can be successfully prepared, and by I type crystalline substance stable preparation process,
It is critically important to carry out industrialization production.
Agomelatine I type crystalline substance is earliest by Tinant et al.（Actacryst, 1994, c50,907-910）Disclose and right
I type crystalline substance is described in detail.China Patent Publication No. CN1017046763 describes to prepare the brilliant side of agomelatine I type
Method, it is that agomelatine crude product is dissolved in hydrophilic organic solvent, is filtered, and filtrate is instilled under agitation in water, is separated out solid
Body, is dried.CN101781226 is that agomelatine crude product is dissolved in DMF, is filtered, and filtrate pours the distilled water of quick stirring into
In, 15-45 minutes are maintained, filter, it is dried.CN101921205 is agomelatine to be added in the mixed solvent of amide and water,
Heating dissolves it, then lowers the temperature, and separates out crystal, is dried gained solid.WO2011054917 discloses one kind and prepares the U.S. drawing of algebraic oriented language
The method of spit of fland crystal formation I, agomelatine crude product is dissolved in hydrophilic organic solvent, is filtered, in filtrate added drop-wise to frozen water system,
Solid is separated out, is dried.
CN1017046763, CN101781226 are to be dissolved in hydrophilic organic solvent using agomelatine, water insoluble
Property, first agomelatine is dissolved in hydrophilic organic solvent, in being then added dropwise to substantial amounts of water, make hydrophilic organic molten
Agent moment is diluted by a large amount of water, separates out agomelatine I type brilliant；WO2011054917 is dissolved in hydrophilic also with agomelatine
Property organic solvent, water-fast property is first dissolved in agomelatine in hydrophilic organic solvent, and difference is that and is added drop-wise to
In frozen water, agomelatine I type is separated out brilliant；CN101921205 using crystallization by the way of, with specific solvent, temperature, quantity of solvent
It is brilliant that direct crystallization obtains agomelatine I type.But the present inventor has found under study for action, using CN1017046763,
The method that CN101781226, WO2011054917, CN101921205 are disclosed, it is difficult to obtain single agomelatine crystal form I,
Highly purified agomelatine I type can not be obtained brilliant, and poor reproducibility, it is impossible to amplify, therefore, be not suitable for large-scale industry
Metaplasia is produced.Therefore, finding one kind can obtain highly purified agomelatine I type crystalline substance, or the extraordinary preparation of industrialization of repeatability
Method is very important, and the present inventor have developed for this and a kind of overcome prior art not enough and and different from existing method
The brilliant method of agomelatine I type is prepared, and is succeeded.
The content of the invention
It is an object of the invention to provide a kind of method for preparing agomelatine crystal form I, the method overcomes and prepares algebraic oriented language
The prior art poor reproducibility of Mei Lating crystal formations I, purity is not high, the problems such as be not suitable for industrialized production, the method for the present invention is obtained
The agomelatine I type crystalline substance that arrives is superior in quality, purity is high, unicity good, technique favorable reproducibility.
To realize the purpose of the invention described above, there is provided following technical scheme.
A kind of method for preparing agomelatine crystal form I, comprises the following steps：
A, agomelatine is dissolved at least one hydrophilic organic solvent forms solution；
B, solution is instilled under agitation in the mixed solvent system containing at least one water-insoluble solvent and frozen water；
After c, completion of dropping, at least one low polar organic solvent is added, isolate solid crystal.
The method of the invention described above, at least one hydrophilic is further comprised in the mixed solvent system of step b to be had
Machine solvent.
The method of the invention described above, the temperature of the mixed solvent system of step b is 2 DEG C～-12 DEG C, preferably 0～-12 DEG C
In one embodiment, the method for preparing agomelatine crystal form I of the invention, comprises the following steps：
A, agomelatine is dissolved at least one hydrophilic organic solvent forms solution；
B, solution is instilled under agitation containing at least one hydrophilic organic solvent, at least one water-insoluble solvent and
In the mixed solvent system of frozen water；
After c, completion of dropping, at least one low polar organic solvent is added, isolate solid crystal.
In a preferred version, the method for preparing agomelatine crystal form I of the invention described above, described hydrophilic is organic
Solvent includes：Alcohols, amide-type, ketone, nitrile, acids etc., wherein step a and hydrophilic organic solvent described in step b
Be able to can also be differed with identical；Described water-insoluble solvent referred to after mixing with water at normal temperatures, can stratification have
Machine solvent, preferred water-insoluble solvent includes esters, arene, ethers etc., wherein, alcohols include methanol, ethanol, third
Alcohol, isopropanol, ethylene glycol, glycol monoethyl ether, ethylene glycol monoethyl ether etc.；Amide-type includes N,N-dimethylformamide, N, N-
Dimethyl acetylamide, Methanamide, N-METHYLFORMAMIDE etc.；Ketone includes acetone, 2-butanone etc., and nitrile includes acetonitrile, succinonitrile
Deng；Acids includes formic acid, glacial acetic acid etc.；Described low polar organic solvent including alkane etc., described alkane include hexamethylene,
Normal hexane, Pentamethylene., normal heptane or petroleum ether；Described water-insoluble solvent includes：Esters, arene, ethers etc., its
Middle esters include methyl acetate, ethyl acetate, isopropyl acetate etc., wherein, arene is including benzene,toluene,xylene etc.；Its
Middle ethers includes ether, diisopropyl ether, methyl tertiary butyl ether(MTBE) etc..
It is highly preferred that the method for preparing agomelatine crystal form I of the invention described above, described hydrophilic organic solvent bag
Include methanol, ethanol, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, Methanamide, N-METHYLFORMAMIDE, acetonitrile, acetone or
Glacial acetic acid, wherein step a be able to can also be differed with hydrophilic organic solvent described in step b with identical；Described is non-aqueous
Soluble solvent includes ether, diisopropyl ether, methyl tertiary butyl ether(MTBE), toluene or isopropyl acetate, described low polar organic solvent bag
Include hexamethylene, normal hexane, Pentamethylene., normal heptane or petroleum ether.
In a preferred version, the method for preparing agomelatine crystal form I of the invention described above, wherein, hydrophilic is organic
The cumulative volume of solvent is 1 with the volume ratio of frozen water：3～1：12；The ratio of the volume of water-insoluble solvent and low polar organic solvent
No more than 1：2, preferably 1：3～1：5；The temperature of the mixed solvent system of step b is 2 DEG C～-12 DEG C, preferably 0～-12 DEG C.
The method for preparing agomelatine crystal form I of the present invention, it is that agomelatine is dissolved in at least one parent
In aqueous organic solvent, filter, then filtrate is added dropwise under agitation containing at least one hydrophilic organic solvent, at least one
In the mixed solvent system of kind of water-insoluble solvent and frozen water, the temperature of mixed solvent system is 2 DEG C～-12 DEG C, preferably 0～-
12 DEG C, after completion of dropping, a large amount of solid crystals are separated out, be subsequently adding at least one low polar organic solvent and filter, isolated solid
Body is crystallized, and is dried.
It is of the present invention dissolving agomelatine hydrophilic organic solvent amount, it can be understood as not less than dissolving Ah
The minimum amount of Ge Meilating（Can with due regard to heating for dissolving factor）.Described hydrophilic organic solvent includes：Alcohols,
Amide-type, ketone, nitrile, acids, alcohols therein includes methanol, ethanol, propanol, isopropanol, ethylene glycol, ethylene glycol list first
Ether, ethylene glycol monoethyl ether etc.；Amide-type includes N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, Methanamide, N- methyl first
Amide etc.；Ketone includes acetone, 2-butanone etc., and nitrile includes acetonitrile, succinonitrile etc.；Acids includes formic acid, glacial acetic acid etc..
Water-insoluble solvent of the present invention includes：Esters, arene, ethers etc., wherein esters include acetic acid first
Ester, ethyl acetate, isopropyl acetate etc.；Wherein arene is including benzene,toluene,xylene etc.；Wherein ethers includes ether, different
Propyl ether, methyl tertiary butyl ether(MTBE) etc..
Frozen water of the present invention can be common ordinary water, medicinal purified water, water for injection, deionized water or distilled water,
Preferably use deionized water.
Including alkane etc., wherein alkane includes hexamethylene, normal hexane, ring penta to low polar organic solvent of the present invention
Alkane, normal heptane, petroleum ether etc..
The method of the invention described above, the total volume of hydrophilic organic solvent is 1 with the volume ratio of frozen water：3～1：12, preferably
1：4～1：6.
The method of the invention described above, water-insoluble solvent is not more than 1 with the volume ratio of low polar organic solvent：2, preferably
1：3～1：5.
Agomelatine I crystal form obtained by this law be Jing XRD-6000 type x-ray diffractometers CuK α sources (α=
1.5406) determine what is completed, specific XRPD collection of illustrative plates is shown in Fig. 1.
Agomelatine I crystal form obtained by this law is measured using METTLER.1100LF DSC testers, and heat up speed
Spend for 10 DEG C/min, specific DSC collection of illustrative plates is shown in Fig. 2.
Description of the drawings
Fig. 1 is the x-ray diffraction pattern of agomelatine I crystal form.
Fig. 2 is the DSC figures of agomelatine I crystal form.
Specific embodiment
Below in conjunction with embodiment, the invention will be further described, can make professional and technical personnel in the field more fully
Understand the present invention, but limit the scope of the present invention never in any form.Wherein the preparation method of agomelatine, refers to
The preparation method of EP0447285, and introduce reference in full.
Embodiment 1
6g agomelatines are dissolved in 30ml DMFs, it is stand-by after filtration, then by 12ml N, N- bis-
In methylformamide, 30ml diisopropyl ethers, the there-necked flask of 250ml water input 500ml, stirring under ice salt bath is cooled to system and produces ice
Bits, Deca filtrate after completion of dropping, adds 90ml petroleum ether, then removes ice salt bath, when system temperature rises to -2 DEG C, takes out
Filter, with 10ml water washing solids, 40 DEG C of drying under reduced pressure 40h obtain solid, yield：93.5%, fusing point：98.1-99.2℃.This is consolidated
Body Jing XRPD tests are crystal formation I.Crystal formation Jing XRPD tests are crystal formation I, see Fig. 1, and its DSC is shown in Fig. 2.
Embodiment 2
500g agomelatines are dissolved in 2.5L ethanol, then 1L ethanol, 2.5L ether, 14L water are put into into the reaction of 50L
In bottle, stirring under ice salt bath is cooled to system and produces ice bits, and Deca filtrate after completion of dropping, adds 7.5L hexamethylene, then removes
Deicing salt bath, when system temperature rises to -5 DEG C, sucking filtration, with 5L water washing solids, 40 DEG C of drying under reduced pressure 40h obtain solid, receive
Rate：96.8%, fusing point：98.2-99.0℃.Solid Jing XRPD tests are crystal formation I.
Embodiment 3
6g agomelatines are dissolved in 30ml methanol, it is stand-by after filtration, then by 12ml DMFs,
In 30ml methyl tertiary butyl ether(MTBE)s, the there-necked flask of 258ml water input 500ml, stirring under ice salt bath is cooled to system and produces ice bits, drop
Plus filtrate, after completion of dropping, 90ml hexamethylene is added, ice salt bath is then removed, when system temperature rises to 0 DEG C, sucking filtration is used
10ml water washing solids, 40 DEG C of drying under reduced pressure 40h obtain solid, yield：95.1%, fusing point：97.9-99.3℃.Solid Jing
XRPD tests are crystal formation I.
Embodiment 4
6g agomelatines are dissolved in 30ml glacial acetic acid, it is stand-by after filtration, then by 12ml glacial acetic acid, 150ml ether,
In the there-necked flask of 84ml water input 2L, stirring cooling under ice salt bath drops to 2 DEG C etc. interior temperature, adds 42g ice cubes, Deca filtrate, drop
Plus after finishing, 200ml petroleum ether and 300ml normal hexane are added, and ice salt bath is then removed, to be risen again to 10 DEG C with ordinary water, sucking filtration is used
10ml water washing solids, 40 DEG C of drying under reduced pressure 40h obtain crystal formation, yield：90.5%, fusing point：97.9-99.1℃.
Embodiment 5
6g agomelatines are dissolved in 30ml methanol, it is stand-by after filtration, then by 12ml ethanol, 30ml isopropyl acetates,
In the there-necked flask of 108ml water input 1L, stirring cooling under ice salt bath drops to -12 DEG C etc. interior temperature, adds 396g ice cubes, Deca filter
Liquid, after completion of dropping, adds 90ml hexamethylene, then removes ice salt bath, is risen again to -5 DEG C with ordinary water, and sucking filtration is washed with 10ml
Solid is washed, 40 DEG C of drying under reduced pressure 40h obtain solid, yield：96.2%, fusing point：98.0-99.2℃.Solid Jing XRPD are tested
Crystal formation I.
Embodiment 6
6g agomelatines are dissolved in 30ml acetone, it is stand-by after filtration, then by 12ml acetone, 30ml diisopropyl ethers, 180ml
In the there-necked flask of water input 500ml, stirring under ice salt bath is cooled to system and produces ice bits, and Deca filtrate after completion of dropping, adds
150ml hexamethylene, then removes ice salt bath, is risen again to 2 DEG C with ordinary water, sucking filtration, with 10ml water washing solids, 40 DEG C of drying under reduced pressure
40h obtains solid, yield：94.6%, fusing point：98.2-99.3℃.Solid Jing XRPD tests are crystal formation I.
Embodiment 7
6g agomelatines are dissolved in 30ml acetonitriles, it is stand-by after filtration, then by 12ml acetonitriles, 30ml diisopropyl ethers, 258ml
In the there-necked flask of water input 500ml, stirring under ice salt bath is cooled to system and produces ice bits, and Deca filtrate after completion of dropping, adds
70ml hexamethylene, then removes ice salt bath, is risen again to -5 DEG C with ordinary water, sucking filtration, with 10ml water washing solids, 40 DEG C of drying under reduced pressure
40h obtains solid, yield：93.4%, fusing point：97.8-99.0℃.Solid Jing XRPD tests are crystal formation I.
Embodiment 8
6g agomelatines are dissolved in 30ml ethylene glycol, it is stand-by after filtration, then by 12ml ethylene glycol, 30ml toluene,
In the there-necked flask of 168ml water input 500ml, stirring under ice salt bath is cooled to system and produces ice bits, Deca filtrate, completion of dropping
Afterwards, 90ml hexamethylene is added, then removes ice salt bath, risen again to -5 DEG C with ordinary water, sucking filtration, with 10ml water washing solids, 40 DEG C
Drying under reduced pressure 40h obtains solid, yield：95.5%, fusing point：98.2-99.0℃.Solid Jing XRPD tests are crystal formation I.
Embodiment 9
6g agomelatines are dissolved in 42ml methanol, it is stand-by after filtration, then 30ml ether, 168ml water are put into into 500ml
There-necked flask in, under ice salt bath stirring cooling, etc. system produce ice bits, Deca filtrate, after completion of dropping, add 90ml oil
Ether, then removes ice salt bath, is risen again to -4 DEG C with ordinary water, sucking filtration, and with 10ml water washing solids, 40 DEG C of drying under reduced pressure 40h are obtained
Solid, yield：95.2%, fusing point：98.2-99.0℃.Solid Jing XRPD tests are crystal formation I.
Claims (8)
1. a kind of method for preparing agomelatine crystal form I, comprises the following steps：
A. agomelatine is dissolved in at least one hydrophilic organic solvent and forms solution；
B. solution is instilled under agitation in the mixed solvent system containing at least one water-insoluble organic solvent and frozen water, institute
State water-insoluble organic solvent to be selected from：Methyl acetate, ethyl acetate, isopropyl acetate, ether, diisopropyl ether, methyl tertiary butyl ether(MTBE),
Benzene, toluene or dimethylbenzene；
C. after completion of dropping, at least one low polar organic solvent is added, isolates solid crystal, the low polarity is organic molten
Agent is selected from：Hexamethylene, normal hexane, Pentamethylene., normal heptane or petroleum ether,
Wherein, the water-insoluble organic solvent and the volume ratio of low polar organic solvent are 1:2 ~ 5, the agomelatine is brilliant
The X-ray diffractogram of type I is as shown in Figure 1.
2. the method for claim 1, further includes in the mixed solvent system of step b also containing at least one parent
Aqueous organic solvent.
3. method as claimed in claim 1 or 2, step a can be with identical with hydrophilic organic solvent described in step b
To differ.
4. method as claimed in claim 1 or 2, described hydrophilic organic solvent be alcohols, amide-type, ketone, nitrile,
Acids or their mixture.
5. method as claimed in claim 4, wherein, alcohols is methanol, ethanol, propanol, isopropanol, ethylene glycol, ethylene glycol list
Methyl ether or ethylene glycol monoethyl ether, or amide-type is DMF, N,N-dimethylacetamide, Methanamide or N- methyl
Methanamide, or ketone is acetone or 2-butanone, or nitrile is acetonitrile or succinonitrile, or acids is formic acid or glacial acetic acid.
6. method as claimed in claim 1 or 2, wherein, total hydrophilic organic solvent and the volume ratio of frozen water is 1: 3~1:
12。
7. the method for claim 1, wherein the volume ratio of water-insoluble organic solvent and low polar organic solvent is 1:
3~1:5。
8. method as claimed in claim 1 or 2, the temperature of mixed solvent system is 2 °C ~ -12 °C.
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| CN103130673A (en) | 2013-06-05 |
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