CN101870662B - Crystalline Agomelatine solvate and preparation method thereof - Google Patents
Crystalline Agomelatine solvate and preparation method thereof Download PDFInfo
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- CN101870662B CN101870662B CN 201010187158 CN201010187158A CN101870662B CN 101870662 B CN101870662 B CN 101870662B CN 201010187158 CN201010187158 CN 201010187158 CN 201010187158 A CN201010187158 A CN 201010187158A CN 101870662 B CN101870662 B CN 101870662B
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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-methoxy-1-naphthyl) ethyl by name] ethanamide, its commodity are called Valdoxan, first melatonin class thymoleptic of Servier company research and development, obtain listing approval in European Union in February, 2009, effectively Cure of depression improves sleep parameters and does not affect the 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 central nervous system activity, especially make its have treatment Serious 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: heat Agomelatines until melt fully at 110 ℃, then Slow cooling is until obtain crystallization.
Reported the preparation method of form IV in the Chinese patent CN200610108394.8 specification sheets: heat Agomelatines until melt fully at 110 ℃, then temperature is cooled to rapidly between 50 to 70 ℃, and keeps about 5 hours until crystallization at 70 ℃.
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 melt fully at 110 ℃, then place immediately and also add simultaneously a small amount of freshly prepd crystal form V Agomelatine crystal seed under the room temperature, 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 the method for preparing agomelatine crystal form V with spray-drying process 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, 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 VI is disclosed in the Chinese patent CN200910047329.2 specification sheets: Agomelatine is dissolved in acetic acid, this solution slowly added do not stop to stir in 0-25 ℃ the water and make crystallization, gained solid purity is 99.6%, and fusing point is 97-98 ℃.
It is harsh that patent CN200610108395.2 prepares the method condition of agomelatine crystal form, can't promote the use of in industrial production.Patent CN200610108394.8 method prepares the form IV Agomelatine need to be cooled to rapidly 50-70 ℃ and kept 5 hours at 70 ℃, and the method circulation ratio is bad, generates easily the Agomelatine that is mixed with crystal form II I.Patent CN200910160307.7 spray-drying process prepares the crystal form V Agomelatine need to pass into rare gas element, and production cost is high, 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 compound, its chemical formula shown in formula I,
Described ethylene glycol solvent compound 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 ratio of Agomelatine and ethylene glycol 1: 2 in molar ratio～5 is mixed, and is heated to 100～130 ℃ of meltings, obtains crystal after the cooling.。
Crystalline Agomelatine spit of fland acetate solvate compound, its chemical formula shown in formula II,
Described acetate solvate compound 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 lower 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 of the present invention's preparation is high, and it is few to introduce impurity.
The quantity of solvent that the method that the present invention uses needs is few, need not to pass into protection of inert gas, low production cost.
The method that the present invention uses is simple to operate, and reaction conditions is gentle, and easily control need not the high-energy ball milling, strictly controls the operation such as temperature.
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 compound;
Fig. 2 is the crystalline structure figure that resolves the crystalline Agomelatine spit of fland ethylene glycol solvent compound that obtains by powder diagram;
Fig. 3 is the structure cell accumulation graph of crystalline Agomelatine spit of fland ethylene glycol solvent compound;
Fig. 4 is differential scanning calorimeter (DSC) figure of crystalline Agomelatine spit of fland ethylene glycol solvent compound;
Fig. 5 is infrared spectra (IR) figure of crystalline Agomelatine spit of fland ethylene glycol solvent compound;
Fig. 6 is the mass spectrum of crystalline Agomelatine spit of fland ethylene glycol solvent compound;
Fig. 7 is the Raman spectrogram of crystalline Agomelatine spit of fland ethylene glycol solvent compound;
Fig. 8 is the powder diagram of crystalline Agomelatine spit of fland acetate solvate compound;
Fig. 9 is that crystalline Agomelatine spit of fland acetate solvate compound is from the powder diagram of single crystal structure digital simulation;
Figure 10 is the single crystal structure figure of crystalline Agomelatine spit of fland acetate solvate compound;
Figure 11 is the structure cell accumulation graph of crystalline Agomelatine spit of fland acetate solvate compound;
Figure 12 is differential scanning calorimeter (DSC) figure of crystalline Agomelatine spit of fland acetate solvate compound;
Figure 13 is infrared spectra (IR) figure of crystalline Agomelatine spit of fland acetate solvate compound;
Figure 14 is the mass spectrum of crystalline Agomelatine spit of fland acetate solvate compound;
Figure 15 is crystalline Agomelatine spit of fland acetate solvate compound 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 compound
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 ℃.
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 compound
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 ℃.
Embodiment 8
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 ℃.
Embodiment 12
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 compound crystal parameter is measured
Adopt Bruker D8 Advance diffractometer to measure the powder diagram of the crystalline Agomelatine spit of fland ethylene glycol solvent compound that obtains among the embodiment 1, condition determination is as follows: Cu K α, 40kV, 40mV is 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, be 10.125 at angle of diffraction 2 θ, 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 compound, 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 compound, and its structure cell is 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 compound is as shown in the table.
The crystallographic parameter table of crystalline Agomelatine spit of fland ethylene glycol solvent compound
*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 compound 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 compound 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 compound as shown in Figure 6, m/z=243 is molecular ion peak.
Crystalline Agomelatine spit of fland ethylene glycol solvent compound 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 compound.
Crystalline Agomelatine spit of fland acetate solvate compound crystal parameter is measured
Adopt Bruker D8 Advance diffractometer to measure the powder diagram of the crystalline Agomelatine spit of fland acetate solvate compound 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, be 11.62 at angle of diffraction 2 θ, 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 compound, 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 crystalline structure of the crystalline Agomelatine spit of fland acetate solvate compound of the embodiment of the invention 5 acquisitions is measured in use under 150 (2) K with the Rigaku RAXIS-SPIDER IP single crystal diffractometer of graphite monochromator.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 compound
*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 be crystalline Agomelatine spit of fland acetate solvate compound from the powder diagram of single crystal structure digital simulation, the peak of Fig. 8 and Fig. 9 overlaps, and prove that the crystalline Agomelatine spit of fland acetate solvate compound for preparing is pure single crystal form;
The single crystal structure figure of crystalline Agomelatine spit of fland acetate solvate compound as shown in figure 10;
The structure cell accumulation graph of crystalline Agomelatine spit of fland acetate solvate compound as shown in figure 11;
The differential scanning calorimeter (DSC) of crystalline Agomelatine spit of fland acetate solvate compound 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 compound 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 compound as shown in figure 14, m/z=243 is molecular ion peak.
Crystalline Agomelatine spit of fland acetate solvate compound 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 compound.
Claims (6)
1. crystalline Agomelatine spit of fland ethylene glycol solvent compound, its chemical formula as shown in the formula (I),
Described crystalline Agomelatine spit of fland ethylene glycol solvent compound 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 compound comprises Agomelatine and the in molar ratio ratio mixing of 1:2～5 of ethylene glycol, is heated to 100～130 ℃ of meltings, obtains crystal after the cooling.
3. crystalline Agomelatine spit of fland acetate solvate compound, its chemical formula shown in formula II,
Described crystalline Agomelatine spit of fland acetate solvate compound 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 compound, 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 lower evaporating solvents, described anti-solvent is selected from the alkane of sherwood oil, carbonatoms 〉=5.
5. the preparation method of crystalline Agomelatine according to claim 4 spit of fland acetate solvate compound, it 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 compound, it is characterized in that: the alkane of carbonatoms 〉=5 is selected from Skellysolve A, normal hexane, hexanaphthene, normal heptane.
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| CN102452952A (en) * | 2010-11-03 | 2012-05-16 | 天津药物研究院 | Preparation method of high-purity I-type agomelatine crystal |
| PH12012000132A1 (en) * | 2011-06-09 | 2014-10-20 | Servier Lab | New co-crystals of agomelatine, a process for their preparation and pharmaceutical compositions containing them |
| FR2978916B1 (en) | 2011-08-10 | 2013-07-26 | Servier Lab | SOLID PHARMACEUTICAL COMPOSITION FOR BUCCAL ADMINISTRATION OF AGOMELATIN |
| CN102503886B (en) * | 2011-10-11 | 2013-09-11 | 中山大学 | Agomelatine-isonicotine eutectic crystal and compound and preparation method thereof |
| CN102718675B (en) * | 2012-06-07 | 2015-03-25 | 上海右手医药科技开发有限公司 | Agomelatine methanesulfonic acid complex and preparation method thereof |
| FR3001894A1 (en) | 2013-02-08 | 2014-08-15 | Servier Lab | SOLID PHARMACEUTICAL COMPOSITION FOR BUCCAL ADMINISTRATION OF AGOMELATIN |
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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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| Publication number | Priority date | Publication date | Assignee | Title |
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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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