CN101870662A - Crystalline Agomelatine solvate and preparation method thereof - Google Patents
Crystalline Agomelatine solvate and preparation method thereof Download PDFInfo
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- CN101870662A CN101870662A CN201010187158A CN201010187158A CN101870662A CN 101870662 A CN101870662 A CN 101870662A CN 201010187158 A CN201010187158 A CN 201010187158A CN 201010187158 A CN201010187158 A CN 201010187158A CN 101870662 A CN101870662 A CN 101870662A
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- ethylene glycol
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- 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 100
- 229960002629 agomelatine Drugs 0.000 title claims abstract description 100
- 239000012453 solvate Substances 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 105
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 44
- 239000013078 crystal Substances 0.000 claims abstract description 36
- 239000002904 solvent Substances 0.000 claims abstract description 29
- 238000003756 stirring Methods 0.000 claims abstract description 13
- 239000012296 anti-solvent Substances 0.000 claims abstract description 7
- 238000001816 cooling Methods 0.000 claims abstract description 3
- 238000001704 evaporation Methods 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 30
- 239000000126 substance Substances 0.000 claims description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 3
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 3
- 230000004927 fusion Effects 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 15
- 238000002425 crystallisation Methods 0.000 abstract description 14
- 230000008025 crystallization Effects 0.000 abstract description 14
- 239000007787 solid Substances 0.000 abstract description 11
- 238000010438 heat treatment Methods 0.000 abstract description 7
- 238000002844 melting Methods 0.000 abstract description 5
- 230000008018 melting Effects 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 2
- 239000011261 inert gas Substances 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 abstract description 2
- 239000011874 heated mixture Substances 0.000 abstract 1
- 238000002156 mixing Methods 0.000 abstract 1
- 239000000843 powder Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 16
- 229960000583 acetic acid Drugs 0.000 description 13
- 238000010586 diagram Methods 0.000 description 12
- 239000012362 glacial acetic acid Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000005755 formation reaction Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000001069 Raman spectroscopy Methods 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 238000007789 sealing Methods 0.000 description 4
- 238000010257 thawing Methods 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 238000000634 powder X-ray diffraction Methods 0.000 description 3
- 150000001793 charged compounds Chemical class 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004088 simulation Methods 0.000 description 2
- 125000006850 spacer group Chemical group 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000001419 Melatonin receptor Human genes 0.000 description 1
- 108050009605 Melatonin receptor Proteins 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000005260 alpha ray Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
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- 238000002050 diffraction method Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 208000024732 dysthymic disease Diseases 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 238000000713 high-energy ball milling Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical class COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- 230000036299 sexual function Effects 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000001519 thymoleptic effect Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000004304 visual acuity Effects 0.000 description 1
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Abstract
The invention discloses a crystalline Agomelatine ethylene glycol, acetic acid solvate and a preparation method thereof. The preparation method of the crystalline Agomelatine ethylene glycol solvate comprises the steps of: mixing Agomelatine with ethylene glycol according to the proportion of 1:2-5, heating the mixture to 100 to 130 DEG C, and melting and cooling the heated mixture to result in solids. The preparation method of the crystalline Agomelatine ethylene glycol solvate further comprises the steps of: dissolving Agomelatine in acetic acid to result in solution, and adding the solution into antisolvent, followed by standing still or constantly stirring or evaporating the solvent below 50 DEG C to result in crystal. The crystalline Agomelatine ethylene glycol, acetic acid solvate prepared according to the method has the advantages of: obviously reduced melting point of the solvate, high crystallization purity, good reproducibility, less amount of the solvent used, no need of protection from inert gas, low production cost, simple operation, mild reaction condition and easy control.
Description
Technical field
The present invention relates to two kinds of Agomelatine solvate crystal formations and preparation method thereof.
Background technology
Agomelatine (agomelatine), chemistry N-[2-(7-methoxyl group-1-naphthyl) ethyl by name] ethanamide, its commodity are called Valdoxan, be first melatonin class thymoleptic of Servier company research and development, obtain listing approval in European Union in February, 2009, can effectively treat dysthymia disorders, improve sleep parameters and do not influence characteristics such as sexual function.
Agomelatine has dual nature, is the agonist of melatonin receptor on the one hand, and on the other hand, it is again 5-HT
2CThe antagonist of acceptor.These character make it have the central nervous system activity, especially make its have treatment severe depression, seasonal emotion barrier, somnopathy, cardiovascular pathologies, Digestive tract symptom, because the insomnia that causes of the time difference and fatigue, limited appetite and fat activity etc.
The preparation method of Agomelatine and the application in treatment are described in European patent EP 0447285 and EP1564202.So far, existing result of study shows that there are six kinds of different crystal forms in this compound.
Reported in the Chinese patent CN200510071611.6 specification sheets Agomelatine has been carried out the method that recrystallization makes the crystal form II Agomelatine with 35/65 ethanol/water mixed solution, productive rate 92.5%, chemical purity surpasses 99%, fusing point is 108 ℃, use high resolving power powder diffractometer record data, this compound unit cell parameters is defined as: oblique system, a=20.0903
B=9.3194
C=15.4796
β=108.667 °, unit cell volume=2746.742
Reported the preparation method of crystal form II I in the Chinese patent CN200610108396.7 specification sheets: until melting fully, slowly cool off then until obtaining crystallization at 110 ℃ of heating Agomelatines.
Reported the preparation method of form IV in the Chinese patent CN200610108394.8 specification sheets: until melting fully, then temperature is cooled to rapidly between 50 to 70 ℃, and keeps about 5 hours until crystallization at 70 ℃ at 110 ℃ of heating Agomelatines.
Reported the preparation method of crystal form V in the Chinese patent CN200610108395.2 specification sheets: place the mechanical grinder of speed change high-energy planetary mill (vario-planetary mill) type to grind Agomelatine and made in about 6 hours.Perhaps heat Agomelatines until melting fully at 110 ℃, place immediately then and also add a small amount of freshly prepd crystal form V Agomelatine crystal seed under the room temperature simultaneously, decrease temperature crystalline makes, the amount of the crystal form V Agomelatine crystal seed of adding preferably Agomelatine weight 1/100 and 1/50 between.Reported method in the Chinese patent CN200910160307.7 specification sheets: Agomelatine is dissolved in ethanol/isopropyl ether mixture (50/50:v/v) makes the solution that concentration is 10g/L with spray drying method for preparation Agomelatine crystal form V, this solution is incorporated in the spraying gun of spray-dryer, the temperature in of kiln is 90 ℃, temperature out is 66 ℃, reclaim the powder that has been atomized and identify with powder diffraction method in collecting bowl: crystal form V belongs to oblique system, a=11.967
B=17.902
C=15.423
β=124.5 °, unit cell volume=2720.0
The method of Agomelatine crystal form V I is disclosed in the Chinese patent CN200910047329.2 specification sheets: Agomelatine is dissolved in acetic acid, this solution slowly being added do not stop to stir in 0-25 ℃ the water separates out crystallization, gained solid purity is 99.6%, and fusing point is 97-98 ℃.
Patent CN200610108395.2 prepares the method condition harshness of Agomelatine crystal formation, can't promote the use of in industrial production.Patent CN200610108394.8 method prepares the form IV Agomelatine need be cooled to 50-70 ℃ and kept 5 hours at 70 ℃ rapidly, and the method circulation ratio is bad, generates the Agomelatine that is mixed with crystal form II I easily.Patent CN200910160307.7 spray drying method for preparation crystal form V Agomelatine need feed rare gas element, production cost height, complex operation.
Summary of the invention
The object of the present invention is to provide two kinds of solvate crystal formations of Agomelatine and preparation method thereof.
The technical solution used in the present invention is:
Crystalline Agomelatine spit of fland ethylene glycol solvent thing, its chemical formula shown in formula I,
Described ethylene glycol solvent thing is that 10.125,12.705,13.836,15.754,16.238,17.536,18.21,20.262,20.48,20.859,21.476,22.042,23.715,23.822,25.191,27.422 degree places have diffraction peak at angle of diffraction 2 θ, and its X-ray powder diffraction figure as shown in Figure 1.
Its preparation method comprises the mixed of Agomelatine and ethylene glycol 1: 2 in molar ratio～5, is heated to 100～130 ℃ of fusions, obtains crystal after the cooling.。
Crystalline Agomelatine spit of fland acetate solvate thing, its chemical formula shown in formula II,
Described acetate solvate thing is that 11.62,14.255,16.338,17.646,19.181,20.141,20.656,21.742,22.829,23.362,23.857,24.158,25.029,25.918,27.045,27.214,28.765 degree places have diffraction peak at angle of diffraction 2 θ, and its X-ray powder diffraction figure as shown in Figure 8.
Its preparation method comprises Agomelatine is dissolved in and obtains solution in the acetic acid, and solution is joined in the anti-solvent, leaves standstill or continues to stir or obtain crystal being lower than 50 ℃ of following evaporating solvents, and described anti-solvent is the alkane of sherwood oil and carbonatoms 〉=5.
Preferred anti-solvent adding amount is 6～10 times of acetic acid.
The Agomelatine solvate crystal formation purity height of the present invention's preparation, it is few to introduce impurity.
The quantity of solvent that the method that the present invention uses needs is few, need not to feed protection of inert gas, low production cost.
The method that the present invention uses is simple to operate, the reaction conditions gentleness, and control need not operations such as high-energy ball milling, strict controlled temperature easily.
The method that the present invention uses can acquisition target product crystal formation very definite, favorable reproducibility.
Description of drawings
Fig. 1 is the powder diagram of crystalline Agomelatine spit of fland ethylene glycol solvent thing;
Fig. 2 is the crystalline structure figure that resolves the crystalline Agomelatine spit of fland ethylene glycol solvent thing that obtains by powder diagram;
Fig. 3 is the structure cell accumulation graph of crystalline Agomelatine spit of fland ethylene glycol solvent thing;
Fig. 4 is differential scanning calorimeter (DSC) figure of crystalline Agomelatine spit of fland ethylene glycol solvent thing;
Fig. 5 is infrared spectra (IR) figure of crystalline Agomelatine spit of fland ethylene glycol solvent thing;
Fig. 6 is the mass spectrum of crystalline Agomelatine spit of fland ethylene glycol solvent thing;
Fig. 7 is the Raman spectrogram of crystalline Agomelatine spit of fland ethylene glycol solvent thing;
Fig. 8 is the powder diagram of crystalline Agomelatine spit of fland acetate solvate thing;
Fig. 9 is the powder diagram of crystalline Agomelatine spit of fland acetate solvate thing from the single crystal structure digital simulation;
Figure 10 is the single crystal structure figure of crystalline Agomelatine spit of fland acetate solvate thing;
Figure 11 is the structure cell accumulation graph of crystalline Agomelatine spit of fland acetate solvate thing;
Figure 12 is differential scanning calorimeter (DSC) figure of crystalline Agomelatine spit of fland acetate solvate thing;
Figure 13 is infrared spectra (IR) figure of crystalline Agomelatine spit of fland acetate solvate thing;
Figure 14 is the mass spectrum of crystalline Agomelatine spit of fland acetate solvate thing;
Figure 15 is a crystalline Agomelatine spit of fland acetate solvate thing Raman spectrogram.
Embodiment
Below in conjunction with example, further specify the present invention.Following examples are exemplary illustration only, do not limit the present invention in any way.
The preparation of crystalline Agomelatine spit of fland ethylene glycol solvent thing
Embodiment 1
The 1g Agomelatine is placed test tube, add 0.51g ethylene glycol (mol ratio 1: 2), sealing makes its thawing 100 ℃ of heating, behind the stirring 2h, maintains 0 ℃ and makes its sufficient crystallising, obtains white solid 1.23g.Productive rate: 98%, fusing point: 67.6 ℃.
The 2g Agomelatine is placed test tube, add 1.53g ethylene glycol (mol ratio 1: 3), sealing makes its thawing 110 ℃ of heating, behind the stirring 2h, maintains 0 ℃ and makes its sufficient crystallising, obtains white solid 2.46g.Productive rate: 98%, fusing point: 67.6 ℃.
The 5g Agomelatine is placed test tube, add 3.825g ethylene glycol (mol ratio 1: 3), sealing makes its thawing 120 ℃ of heating, behind the stirring 2h, maintains 0 ℃ and makes its sufficient crystallising, obtains white solid 6.15g.Productive rate: 98%, fusing point: 67.6 ℃.
Embodiment 4
The 5g Agomelatine is placed test tube, add 6.375g ethylene glycol (mol ratio 1: 5), sealing makes its thawing 130 ℃ of heating, behind the stirring 2h, maintains 0 ℃ and makes its sufficient crystallising, obtains white solid 6.15g.Productive rate: 98%, fusing point: 67.6 ℃.
The preparation of crystalline Agomelatine spit of fland acetate solvate thing
The 1g Agomelatine is dissolved in about 4mL glacial acetic acid, this solution is slowly joined in the 24mL Skellysolve A, leave standstill crystallization.Obtain the 1.20g crystal.Productive rate: 96%, fusing point: 76.0 ℃.
The 2g Agomelatine is dissolved in about 8mL glacial acetic acid, this solution is slowly joined in the 56mL normal hexane, leave standstill crystallization.Obtain the 2.35g crystal.Productive rate: 94%, fusing point: 76.0 ℃.
Embodiment 7
The 5g Agomelatine is dissolved in about 20mL glacial acetic acid, this solution is slowly joined in the 160mL hexanaphthene, leave standstill crystallization.Obtain the 6.10g crystal.Productive rate: 97%, fusing point: 76.0 ℃.
The 10g Agomelatine is dissolved in about 40mL glacial acetic acid, this solution is slowly joined in the 360mL normal heptane, leave standstill crystallization.Obtain the 11.85g crystal.Productive rate: 95%, fusing point: 76.0 ℃.
Embodiment 9
The 10g Agomelatine is dissolved in about 40mL glacial acetic acid, this solution is slowly joined in the 400mL sherwood oil, leave standstill crystallization.Obtain the 12.10g crystal.Productive rate: 97%, fusing point: 76.0 ℃.
The 1g Agomelatine is dissolved in about 4mL glacial acetic acid, this solution is joined in the 24mL Skellysolve A, continue to stir crystallization in 4 hours, filter, obtain white solid 0.95g.Productive rate: 76%, fusing point: 76.0 ℃.
Embodiment 11
The 2g Agomelatine is dissolved in about 8mL glacial acetic acid, this solution is joined in the 56mL normal hexane, continue to stir crystallization in 4 hours, filter, obtain white solid 1.87g.Productive rate: 75%, fusing point: 76.0 ℃.
The 5g Agomelatine is dissolved in about 20mL glacial acetic acid, this solution is joined in the 160mL hexanaphthene, continue to stir crystallization in 4 hours, filter, obtain white solid 4.74g.Productive rate: 76%, fusing point: 76.0 ℃.
Embodiment 13
The 10g Agomelatine is dissolved in about 40mL glacial acetic acid, this solution is joined in the 360mL normal heptane, continue to stir crystallization in 4 hours, filter, obtain white solid 9.85g.Productive rate: 79%, fusing point: 76.0 ℃.
Embodiment 14
The 10g Agomelatine is dissolved in about 40mL glacial acetic acid, this solution is joined in the 400mL sherwood oil, continue to stir crystallization in 4 hours, filter, obtain white solid 9.45g.Productive rate: 76%, fusing point: 76.0 ℃.
Crystalline Agomelatine spit of fland ethylene glycol solvent thing crystal parameter is measured
Adopt Bruker D8 Advance diffractometer to measure the powder diagram of the crystalline Agomelatine spit of fland ethylene glycol solvent thing that obtains among the embodiment 1, condition determination is as follows: Cu K α, 40kV, 40mV is a light source, 0.018 ° of step-length, 4 °/min of sweep velocity, 5～40 ° of sweep limits, room temperature, in its x-ray diffractogram of powder, at angle of diffraction 2 θ is 10.125,12.705,13.836,15.754,16.238,17.536,18.21,20.262,20.48,20.859,21.476,22.042,23.715,23.822,25.191,27.422 there is diffraction peak at the degree place, powder diagram as shown in Figure 1.
Crystalline Agomelatine of the present invention spit of fland ethylene glycol solvent thing, its x-ray diffractogram of powder is expressed with the per-cent I of spacing d, Bragg angle (2 θ) and relative intensity, and is as follows:
Data according to powder diagram are resolved the structure of crystalline Agomelatine spit of fland ethylene glycol solvent thing, and its structure cell is an oblique system, and spacer is P2
1, a=13.054 (1)
B=7.347 (1)
C=8.766 (1)
β=95.177 (2) °, unit cell volume V=837.3 (2)
Its crystalline structure as shown in Figure 2, structure cell is piled up as shown in Figure 3.
The crystallographic parameter of crystalline Agomelatine spit of fland ethylene glycol solvent thing is as shown in the table.
The crystallographic parameter table of crystalline Agomelatine spit of fland ethylene glycol solvent thing
*R
wp＝[w(cY
sim(2θ
i)-I
exp(2
i)+Y
back(2θ
i))
2/∑w(I
exp(2θ
i))
2]
1/2，
R
wp(without?background)＝[∑w(cY
sim(2θ
i)-I
exp(2θ
i)+Y
back(2θ
i))
2/w(I
exp(2θ
i)-Y
back(2θ
i))
2]
1/2，w＝1/I
exp(2θ
i)，
R
p＝∑|cY
sim(2θ
i)-I
exp(2θ
i)+Y
back(2θ
i)|/∑|I
exp(2θ
i)|
The differential scanning calorimeter (DSC) of crystalline Agomelatine spit of fland ethylene glycol solvent thing is schemed as shown in Figure 4, and its endothermic transition temperature is at 67.6 ℃.
The infrared spectrogram of crystalline Agomelatine spit of fland ethylene glycol solvent thing is that 3258,3083,2997,2971,2939,2864,1917,1636,1598,1563,1509,1469,1441,1372,1343,1306,1253,1215,1182,1161,1132,1096,1060,1029,906,891,866,833,758,735,698,648,610,591,552,473,450,433 places have absorption peak in wave number as shown in Figure 5.
The mass spectrum of crystalline Agomelatine spit of fland ethylene glycol solvent thing as shown in Figure 6, m/z=243 is molecular ion peak.
Crystalline Agomelatine spit of fland ethylene glycol solvent thing Raman spectrogram as shown in Figure 7.
After testing, the crystalline structure of embodiment 2～4 is identical with the crystalline structure of embodiment 1.As seen, the inventive method repeated fine can obtain stable crystalline Agomelatine spit of fland ethylene glycol solvent thing.
Crystalline Agomelatine spit of fland acetate solvate thing crystal parameter is measured
Adopt Bruker D8 Advance diffractometer to measure the powder diagram of the crystalline Agomelatine spit of fland acetate solvate thing of embodiment 5 acquisitions, condition determination is as follows: Cu K α, 40kV, the 40mV light source, 0.018 ° of step-length, 4 °/min of sweep velocity, 5～40 ° of sweep limits, room temperature, in its x-ray diffractogram of powder, at angle of diffraction 2 θ is 11.62,14.255,16.338,17.646,19.181,20.141,20.656,21.742,22.829,23.362,23.857,24.158,25.029,25.918,27.045,27.214,28.765 there is diffraction peak at the degree place, its powder diagram as shown in Figure 8.
Crystalline Agomelatine of the present invention spit of fland acetate solvate thing, its X-ray powder diffraction figure expresses with the per-cent I of spacing d, Bragg angle (2 θ) and relative intensity, and is as follows:
The Rigaku RAXIS-SPIDER IP single crystal diffractometer that use has a graphite monochromator is measured the crystalline structure of the crystalline Agomelatine spit of fland acetate solvate thing that the embodiment of the invention 5 obtains under 150 (2) K.With Mo K alpha-ray (0.071073nm), collect data with ω/2 θ scan modes.The reduction of data and absorption correction use Rigaku RAPID AUTO (Rigaku, 1998, Ver2.30) routine package.Spacer is definite according to the delustring rule of system, and by the refine result verification.All crystalline structure all use the SHELXS-97 program, are solved by direct method, and with complete matrix least-squares refinement structure, the hydrogen atom coordinate is added by Theoretical Calculation with the SHELXL-97 program.Its crystallographic parameter is as shown in the table:
The crystallographic parameter table of crystalline Agomelatine spit of fland acetate solvate thing
*R
1＝∑||F
o|-|F
c||/∑|F
o|，wR
2＝[∑w(F
o 2-F
c 2)
2/∑w(F
o 2)
2]
1/2，w＝[σ
2(F
o)
2+(0.1(max(0，F
o 2)+2F
c 2)/3)
2]
-1
Fig. 9 is the powder diagram of crystalline Agomelatine spit of fland acetate solvate thing from the single crystal structure digital simulation, and the peak of Fig. 8 and Fig. 9 overlaps, and proves that the crystalline Agomelatine spit of fland acetate solvate thing of preparation is pure single crystal form;
The single crystal structure figure of crystalline Agomelatine spit of fland acetate solvate thing as shown in figure 10;
The structure cell accumulation graph of crystalline Agomelatine spit of fland acetate solvate thing as shown in figure 11;
The differential scanning calorimeter (DSC) of crystalline Agomelatine spit of fland acetate solvate thing is schemed as shown in figure 12, and its endothermic transition temperature is at 76 ℃;
The infrared spectrogram of crystalline Agomelatine spit of fland acetate solvate thing is that 3252,3079,2998,2973,2936,2865,2837,1918,1637,1599,1562,1510,1471,1437,1371,1345,1299,1253,1215,1183,1160,1132,1098,1031,907,864,834,755,733,698,644,612,589,550,473,450,432 places have absorption peak in wave number as shown in figure 13.
The mass spectrum of crystalline Agomelatine spit of fland acetate solvate thing as shown in figure 14, m/z=243 is molecular ion peak.
Crystalline Agomelatine spit of fland acetate solvate thing Raman spectrogram as shown in figure 15.
After testing, the powder diagram of embodiment 6～14 is identical with the powder diagram of embodiment 5.As seen, the good reproducibility of the inventive method can obtain stable crystalline Agomelatine spit of fland acetate solvate thing.
Claims (6)
1. crystalline Agomelatine spit of fland ethylene glycol solvent thing, its chemical formula shown in formula I,
Described crystalline Agomelatine spit of fland ethylene glycol solvent thing is that 10.125,12.705,13.836,15.754,16.238,17.536,18.21,20.262,20.48,20.859,21.476,22.042,23.715,23.822,25.191,27.422 degree places have diffraction peak at angle of diffraction 2 θ, and its X-ray diffractogram as shown in Figure 1.
2. the preparation method of the described crystalline Agomelatine of claim 1 spit of fland ethylene glycol solvent thing comprises the mixed of Agomelatine and ethylene glycol 1: 2 in molar ratio～5, is heated to 100～130 ℃ of fusions, obtains crystal after the cooling.
3. crystalline Agomelatine spit of fland acetate solvate thing, its chemical formula shown in formula II,
Described crystalline Agomelatine spit of fland acetate solvate thing is that 11.62,14.255,16.338,17.646,19.181,20.141,20.656,21.742,22.829,23.362,23.857,24.158,25.029,25.918,27.045,27.214,28.765 degree places have diffraction peak at angle of diffraction 2 θ, and its X-ray diffractogram as shown in Figure 8.
4. the preparation method of the described crystalline Agomelatine of claim 3 spit of fland acetate solvate thing, comprise Agomelatine is dissolved in and obtain solution in the acetic acid, solution is joined in the anti-solvent, leave standstill or continue to stir or obtain crystal being lower than 50 ℃ of following evaporating solvents, described anti-solvent comprises the alkane of sherwood oil, carbonatoms 〉=5.
5. the preparation method of crystalline Agomelatine according to claim 4 spit of fland acetate solvate thing is characterized in that: the add-on of anti-solvent is 6～10 times of acetic acid volume.
6. the preparation method of crystalline Agomelatine according to claim 4 spit of fland acetate solvate thing, it is characterized in that: the alkane of carbonatoms 〉=5 comprises Skellysolve A, normal hexane, hexanaphthene, normal heptane.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102452952A (en) * | 2010-11-03 | 2012-05-16 | 天津药物研究院 | Preparation method of high-purity I-type agomelatine crystal |
| CN102503886A (en) * | 2011-10-11 | 2012-06-20 | 中山大学 | Agomelatine-isonicotine eutectic crystal and compound and preparation method thereof |
| CN102718675A (en) * | 2012-06-07 | 2012-10-10 | 上海右手医药科技开发有限公司 | Agomelatine methanesulfonic acid complex and preparation method thereof |
| WO2013021139A1 (en) | 2011-08-10 | 2013-02-14 | Les Laboratoires Servier | Solid pharmaceutical composition for orally delivering agomelatine |
| WO2014122405A1 (en) | 2013-02-08 | 2014-08-14 | Les Laboratoires Servier | Solid pharmaceutical composition for oral delivery of agomelatine |
| MD4308C1 (en) * | 2011-06-09 | 2015-05-31 | Les Laboratoires Servier | New cocrystals of agomelatine, process for their preparation and pharmaceutical compositions containing them |
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| CN1680284A (en) * | 2004-02-13 | 2005-10-12 | 瑟维尔实验室 | New process for the synthesis and new crystalline form of agomelatine and pharmaceutical compositions containing it |
| CN1907957A (en) * | 2005-08-03 | 2007-02-07 | 瑟维尔实验室 | Crystalline form iv of agomelatine, a process for its preparation and pharmaceutical compositions containing it |
| CN101481321A (en) * | 2009-02-27 | 2009-07-15 | 上海医药工业研究院 | Agomelatine halogen hydride complex and preparation thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1680284A (en) * | 2004-02-13 | 2005-10-12 | 瑟维尔实验室 | New process for the synthesis and new crystalline form of agomelatine and pharmaceutical compositions containing it |
| CN1907957A (en) * | 2005-08-03 | 2007-02-07 | 瑟维尔实验室 | Crystalline form iv of agomelatine, a process for its preparation and pharmaceutical compositions containing it |
| CN101481321A (en) * | 2009-02-27 | 2009-07-15 | 上海医药工业研究院 | Agomelatine halogen hydride complex and preparation thereof |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102452952A (en) * | 2010-11-03 | 2012-05-16 | 天津药物研究院 | Preparation method of high-purity I-type agomelatine crystal |
| MD4308C1 (en) * | 2011-06-09 | 2015-05-31 | Les Laboratoires Servier | New cocrystals of agomelatine, process for their preparation and pharmaceutical compositions containing them |
| WO2013021139A1 (en) | 2011-08-10 | 2013-02-14 | Les Laboratoires Servier | Solid pharmaceutical composition for orally delivering agomelatine |
| CN102503886A (en) * | 2011-10-11 | 2012-06-20 | 中山大学 | Agomelatine-isonicotine eutectic crystal and compound and preparation method thereof |
| CN102718675A (en) * | 2012-06-07 | 2012-10-10 | 上海右手医药科技开发有限公司 | Agomelatine methanesulfonic acid complex and preparation method thereof |
| WO2014122405A1 (en) | 2013-02-08 | 2014-08-14 | Les Laboratoires Servier | Solid pharmaceutical composition for oral delivery of agomelatine |
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