CN104341397A - Eletriptan free base with crystal forms, preparing method thereof and applications of the eletriptan free base - Google Patents
Eletriptan free base with crystal forms, preparing method thereof and applications of the eletriptan free base Download PDFInfo
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- CN104341397A CN104341397A CN201310330052.0A CN201310330052A CN104341397A CN 104341397 A CN104341397 A CN 104341397A CN 201310330052 A CN201310330052 A CN 201310330052A CN 104341397 A CN104341397 A CN 104341397A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
Eletriptan free base with crystal forms, a preparing method thereof and applications of the eletriptan free base are disclosed. The eletriptan free base with the crystal forms is characterized by an XRD spectrum and a DSC trace. The preparing method includes: 1) adding a first solvent into oily eletriptan free base, and stirring to obtain solid; 2) dissolving the solid obtained in the step 1) into a second solvent, stirring, adding water dropwise, stirring and precipitating solid to obtain the eletriptan free base with a crystal form a; or dissolving the solid obtained in the step 1) into a third solvent, allowing the mixture to stand, and precipitating solid to obtain the eletriptan free base with a crystal form b. The eletriptan free base with the crystal forms has advantages of high purity, good stability, and the like, and can be salified to obtain eletriptan hydrobromide with a high yield and high purity.
Description
Technical field
The present invention relates to a kind of Eletriptan free alkali and method for making thereof and application, particularly relate to a kind of Eletriptan free alkali of tool crystal formation and method for making thereof and application.
Background technology
Eletriptan (eletriptan) is the migrainous medicine for the treatment of, chemical name is (R)-3-[(1-methylpyrrolidin-2-yl) methyl]-5-(2-phenylSulphon ethyl)-1H-indoles, and its molecular structural formula is as follows:
US5607951A discloses Eletriptan and preparation method thereof, and US5545644A, WO2005/007649A1, US2009/0299077A1, WO2010/121673A1, US2005020663A1 etc. patent discloses the preparation technology of Eletriptan and the improvement of technique.Usual Eletriptan free alkali is oily matter, and purity is lower, salify productive rate afterwards and the purity of salt also lower.
It is solid that US005545644A and WO2005/007649A1 these two sections patent discloses Eletriptan free alkali, but finds through experiment, when repeating above two sections of patented methods, is still oily matter after this solid filtering.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of Eletriptan free alkali of tool crystal formation and method for making thereof and application.By Eletriptan free alkali is converted into crystal, solve that its purity is not high, the purity of productive rate and salt is not high after salify problem.
For solving the problems of the technologies described above, the Eletriptan free alkali (Eletriptan free alkali crystal formation) of tool crystal formation of the present invention, is selected from the one in following manner:
1) the Eletriptan free alkali of described tool crystal formation is characterized by the X-ray diffraction pattern comprising two or more X-ray diffraction peak, wherein, described two or more X-ray diffraction peak, being selected from 2 θ values is 8.84 °, 11.09 °, 12.18 °, 14.39 °, 16.36 °, 16.10 °, 16.76 °, 17.74 °, 18.97 °, 19.64 °, 20.43 °, 20.86 °, 21.59 °, 22.30 °, 23.53 °, 24.49 °, 26.72 °, 27.22 °, 28.11 °, 28.52 °, 31.01 °, 31.74 °, 32.27 °, 32.98 °, the X-ray diffraction peak at 33.93 ° and 35.09 ° ± 0.2 ° places,
2) the Eletriptan free alkali of described tool crystal formation is characterized by the X-ray diffraction pattern comprising two or more X-ray diffraction peak, wherein, described two or more X-ray diffraction peak, being selected from 2 θ values is 5.18 °, 8.79 °, 10.32 °, 11.05 °, 12.17 °, 13.47 °, 14.33 °, 15.31 °, 15.47 °, 16.11 °, 16.73 °, 17.68 °, 18.43 °, 18.94 °, 19.64 °, 20.82 °, 21.57 °, 22.28 °, 22.86 °, 23.35 °, 23.50 °, 24.43 °, 26.70 °, 27.19 °, 28.02 °, 28.64 °, 31.12 °, 31.69 °, 32.11 °, 32.94 °, 33.87 °, 35.15 °, the X-ray diffraction peak at 36.92 ° and 38.03 ° ± 0.2 ° places.
The Eletriptan free alkali of described tool crystal formation, has the X-ray diffractogram substantially as shown in Fig. 3 or Fig. 5.
The Eletriptan free alkali of tool crystal formation of the present invention, also by DSC(differential scanning calorimetry, dsc) trace characterizes, wherein, described DSC trace is included in the endotherm(ic)peak at 98.78 ~ 110.42 DEG C of (as 100.78 ± 2 ~ 108.42 ± 2 DEG C) places, preferably in the endotherm(ic)peak at 104.67 ± 2 DEG C of places; Or described DSC trace is included in the endotherm(ic)peak of 104.27 ~ 118.15 DEG C of places's (as 106.27 ± 2 ~ 116.15 ± 2 DEG C), preferably in the endotherm(ic)peak at 111.96 ± 2 DEG C of places.In addition, described DSC trace is included in the enthalpy of phase change at-91.84 ± 2J/g or-96.27 ± 2J/g place.
The Eletriptan free alkali of described tool crystal formation, has DSC trace as illustrated in fig. 4 or 6 substantially.
In addition, the invention also discloses the preparation method of the Eletriptan free alkali of above-mentioned tool crystal formation, comprise step:
(1) in the Eletriptan free alkali shown in the structural formula I of oily, add the first solvent, stir, obtain solid;
(2) solid that step (1) obtains is dissolved in the second solvent, stirs, drip water, stir, separate out solid, obtain the Eletriptan free alkali of tool crystal formation (crystal formation a);
Or the solid that step (1) obtains is dissolved in the 3rd solvent, leave standstill, separate out solid, obtain the Eletriptan free alkali (crystal formation b) of tool crystal formation.
In described step (1), the first solvent comprises: one or more in normal hexane, normal heptane, sherwood oil, dimethylbenzene; The amount ratio of the Eletriptan free alkali shown in structural formula I of the first solvent and oily is Eletriptan free alkali/12 milliliter the first solvent shown in the structural formula I of milliliter the first solvent ~ 1 gram oily of Eletriptan free alkali/8 shown in the structural formula I of 1 gram of oily; The method stirred is: be warming up to 110 ~ 140 DEG C and stir after 1 ~ 5 hour, be cooled to 0 DEG C, stir 1 ~ 5h, and wherein, the time of stirring is respectively preferably 2 ~ 3h.
In described step (2), the second solvent comprises: the one in acetone, acetonitrile or its mixture; The amount ratio of the Eletriptan free alkali shown in structural formula I of the second solvent and oily is Eletriptan free alkali/5 milliliter the second solvent shown in the structural formula I of milliliter the second solvent ~ 1 gram oily of Eletriptan free alkali/3 shown in the structural formula I of 1 gram of oily; The volume ratio of water and the second solvent is 3 ~ 5:1; In step (2), the solid that step (1) obtains is dissolved in the second solvent, namely stirring at room temperature 0.2 ~ 1h(is stirred to molten clear), drip water, stir 2 ~ 5h, separate out solid, obtain the Eletriptan free alkali of tool crystal formation.
In described step (2), the 3rd solvent comprises: ethyl acetate; The amount ratio of the Eletriptan free alkali shown in structural formula I of the 3rd solvent and oily is Eletriptan free alkali/3 milliliter the 3rd solvent shown in the structural formula I of milliliter the 3rd solvent ~ 1 gram oily of Eletriptan free alkali/1 shown in the structural formula I of 1 gram of oily; The time left standstill is 2 ~ 12h.
Moreover the invention also discloses a kind of hydrobromate of Eletriptan free alkali of tool crystal formation, even if the Eletriptan free alkali of apparatus crystal formation is hydrobromate prepared by raw material, its structural formula is as follows:
The invention also discloses the preparation method of hydrobromate (formula II shown in) of Eletriptan free alkali of tool crystal formation of high HPLC purity, high-optical-purity, comprise step:
1), after the Eletriptan free alkali (shown in structural formula I) of the tool crystal formation of above-mentioned preparation being dissolved in the 4th solvent, at 20 ~ 30 DEG C, in this system, dripping the mixing solutions of hydrobromic acid aqueous solution and butanone, stir;
2) filter, with the 4th solvent cleaning, obtain the hydrobromate (formula II shown) of Eletriptan free alkali of tool crystal formation of high HPLC purity, high-optical-purity.
In described step 1), the 4th solvent comprises: butanone; The amount ratio of the Eletriptan free alkali of the 4th solvent and tool crystal formation is: Eletriptan free alkali/1 milliliter the 4th solvent of Eletriptan free alkali/0.6 milliliter the 4th solvent ~ 1st gram tool crystal formation of 1 gram of tool crystal formation; ; The massfraction of hydrobromic acid aqueous solution is 40 ~ 48%, and the mol ratio of the Eletriptan free alkali of Hydrogen bromide and tool crystal formation is 1.01 ~ 1.20:1; In the mixing solutions of hydrobromic acid aqueous solution and butanone, the mass ratio of butanone and hydrobromic acid aqueous solution is 4 ~ 6:1, preferred 5.5:1; The time of stirring is 2h ~ 12h.
Described step 2) in, the amount ratio of the Eletriptan free alkali of the 4th solvent and tool crystal formation is: Eletriptan free alkali/4 milliliter the 4th solvent of Eletriptan free alkali/2 milliliter the 4th solvent ~ 1st gram tool crystal formation of 1 gram of tool crystal formation.
The invention also discloses the application of Eletriptan free alkali in preparation treatment migraine remedy of above-mentioned tool crystal formation.
The invention also discloses a kind of pharmaceutical composition, it contains the Eletriptan free alkali of the tool crystal formation as above of significant quantity and pharmaceutically acceptable carrier.
Wherein, pharmaceutically acceptable carrier refers to the pharmaceutical carrier of pharmaceutical field routine, as water, starch, gelatin, spices, calcium carbonate, quaternary ammonium compound, cetyl alcohol, talcum powder etc.
This pharmaceutical composition can administration in a convenient way, as by the route of administration such as in local, intravenously, intramuscular, subcutaneous, intracutaneous, nose.
This pharmaceutical composition can adopt ordinary method to be prepared into corresponding preparations, as can be made into injection, tablet, capsule, etc. form.
The amount of the Eletriptan free alkali of the tool crystal formation in pharmaceutical composition of the present invention can change in the four corner that those skilled in the art are used.Usually, (wt%) note by weight percentage, containing the Eletriptan free alkali accounting for total formulation and be about the tool crystal formation of 0.1-99.5wt% in pharmaceutical composition (formulation), the ratio being preferably 0.5-95wt% exists.
The consumption of pharmaceutical composition of the present invention and the course for the treatment of can appropriately adjust according to the light and heavy degree of the age of formulation, patient, disease, namely concrete application dosage depends on many factors, as factors such as administering mode, medication person's healthy state, these are all in skilled practitioners skill.Specifically can be, about per daily dose is 0.01-10mg/kg body weight, and preferably about 0.1-5mg/kg body weight, can use by one or many.
Beneficial effect of the present invention is as follows:
The Eletriptan free alkali of the tool crystal formation 1, prepared has the advantages such as purity is high, good stability, and as its HPLC purity can obtain more than 99.1%, and existing patented method can only obtain the compound that purity is less than 99.0% usually;
2, by the Eletriptan free alkali of tool crystal formation of the present invention as lower step salify raw material, disposablely can obtain high yield, HPLC purity is high, Eletriptan hydrobromate that optical purity is high, productive rate as the Eletriptan hydrobromate (shown in formula II) obtained can reach more than 90%, the HPLC purity of Eletriptan hydrobromate (shown in formula II) can reach more than 99.5%, ee value and can reach more than 99.5%.
Accompanying drawing explanation
Below in conjunction with accompanying drawing and embodiment, the present invention is further detailed explanation:
Fig. 1 is the X-ray diffractogram (XRD figure) of a kind of Eletriptan free alkali crystal formation containing part amorphous of the present invention;
Fig. 2 is the differential scanning calorimetric thermogram (DSC trace) of a kind of Eletriptan free alkali crystalline forms containing part amorphous of the present invention;
Fig. 3 is Eletriptan free alkali (crystal formation X-ray diffractogram a) of a kind of tool crystal formation of the present invention.
Fig. 4 is Eletriptan free alkali (crystal formation differential scanning calorimetric thermogram a) of a kind of tool crystal formation of the present invention;
Fig. 5 is the XRD figure of the Eletriptan free alkali (crystal formation b) of a kind of tool crystal formation of the present invention;
Fig. 6 is the differential scanning calorimetric thermogram of the Eletriptan free alkali (crystal formation b) of a kind of tool crystal formation of the present invention.
Embodiment
The compound below related to if not otherwise specified, equal available from commercial product.
In addition, the testing conditions of XRD, DSC and HPLC of relating in following examples can carry out according to as follows:
1.XRD
Instrument Bruker D8Advance XRD;
Method:
1) scanning angle: 3 °-40 °;
2) scanning step: 0.02 °;
3) sweep velocity: 0.2 second/step.
2、DSC
Instrument company: Mei Tele company of Switzerland (Mettler), instrument title: differential scanning calorimeter (DSC), INSTRUMENT MODEL: DSC1;
Testing method: 20 DEG C ~ 250 DEG C, 5 DEG C/min or 25 DEG C ~ 180 DEG C, 5 DEG C/min.
3、HPLC
Chromatographic instrument: Agilent1260(quaternary pump), VWD
Chromatographic column: Phenomex Luna5u C18(2), 4.6*250mm, 5um
Moving phase: volume ratio=75/25 of damping fluid/acetonitrile, add triethylamine 4ml in 1000ml after mixing, then adjust PH=3.8 with phosphoric acid, wherein, damping fluid is: take 4.0827g potassium primary phosphate and be dissolved in 1000ml pure water.
Flow velocity: 1.0ml/min
Determined wavelength: 220nm
Column temperature: 30 DEG C
Sample size: 5 μ l
Wherein, Chiral HPLC conditions is as follows:
Instrument: U.S. Dionex UltiMate3000 analytical system, DAD detector;
Chromatographic column: CHIRALCEL OD-H4.6 × 250mm particle diameter 5 μm;
Column temperature: 30 DEG C;
Moving phase: normal hexane: the volume ratio=70:30 of dehydrated alcohol;
Flow velocity: 1.0 ml/min;
Determined wavelength: 220nm UV.
Embodiment 1
In Eletriptan free alkali (preparing gained according to the patent US2005020663A1) 50g shown in the structural formula I of oily, add 500mL dimethylbenzene, be warming up to 130 DEG C to stir 2 hours, be slow cooling to 0 DEG C, stir 2h, filter, obtain product (white powdery solids shown in structural formula I), be dried to 45g after constant weight, yield 90%.HPLC purity 99.2%, the ee value 99.5% of obtained product.
Wherein, obtained product is a kind of Eletriptan free alkali crystal formation containing part amorphous, and its X-ray diffraction as shown in Figure 1.Fig. 1 provides obtained product has corresponding diffraction peak in the position that 2 θ values are 8.86 °, 11.15 °, 15.40 °, 16.15 °, 16.83 °, 17.78 °, 19.01 °, 20.51 °, 20.82 °, 22.38 °, 23.59 °, 24.55 °, 25.51 °, 26.82 °, 27.22 °, 28.58 °, 30.16 °, 31.01 °, 31.82 °, 33.04 °, 35.27 °, 36.20 ° and 38.47 ° places.
Means of differential scanning calorimetry thermogram (DSC trace) feature of obtained product as shown in Figure 2, has endotherm(ic)peak in the scope of 89.66 ~ 99.43 DEG C, and the DSC trace of enthalpy of phase change that Fig. 2 obtained product of additionally providing the present embodiment 1 is located at-63.93J/g.
Embodiment 2
In 500mL there-necked flask, add product (the Eletriptan free alkali white powdery solids namely shown in structure above I) prepared by 10g embodiment 1, acetone 40mL, stir 0.5h to clearly molten, dripping 120mL deionized water, there is white opacity in system, stirs 2h, filter, 20mL deionized water filter wash cake, forced air drying, to constant weight, obtains Eletriptan free alkali product (white powdery solids) 7.8g of tool crystal formation, i.e. crystal formation a, yield 78%.Fusing point 103-105 DEG C of obtained product, HPLC purity 99.2%, ee value 99.5%.
Wherein, (crystal formation X-ray diffractogram a) as shown in Figure 3 for the Eletriptan free alkali of the tool crystal formation of gained.Fig. 3 provides the diffraction peak that crystal formation I is 8.84 °, 11.09 °, 12.18 °, 14.39 °, 16.36 °, 16.10 °, 16.76 °, 17.74 °, 18.97 °, 19.64 °, 20.43 °, 20.86 °, 21.59 °, 22.30 °, 23.53 °, 24.49 °, 26.72 °, 27.22 °, 28.11 °, 28.52 °, 31.01 °, 31.74 °, 32.27 °, 32.98 °, 33.93 and 35.09 ± 0.2 ° places in 2 θ values.
(feature as shown in Figure 4 for crystal formation means of differential scanning calorimetry thermogram a) (DSC trace) for the Eletriptan free alkali of tool crystal formation, endotherm(ic)peak is had in the scope of 100.78 ~ 108.42 DEG C, and the DSC trace of enthalpy of phase change that Fig. 4 Eletriptan free alkali of additionally providing the tool crystal formation of the present embodiment 2 is located at-91.84J/g.
Embodiment 3
2L there-necked flask, add the tool crystal formation that 19.0g is obtained by embodiment 2 Eletriptan free alkali (crystal formation a), adds butanone (12.1g), system stir clearly molten.In addition, in lucifuge situation, preparation hydrogen bromide butanone solution (9.2g massfraction is that 48% hydrobromic acid solution mixes with 45g butanone).At 25 DEG C, by under Hydrogen bromide butanone solution lucifuge condition, be added dropwise in the butanone solution of Eletriptan free alkali of tool crystal formation, continue to stir 2h, filter, with 50mL butanone drip washing filter cake, obtain the hydrobromate 20.7g of the Eletriptan free alkali of the tool crystal formation shown in formula II, yield is 90%, and the HPLC purity of this hydrobromate be 99.5%, ee value is 99.5%.
Embodiment 4
2L there-necked flask, add the compound (the white powdery solids product that embodiment 1 is obtained) shown in 19.0g structural formula I, add butanone (12.1g), system stirs clearly molten.In addition, in lucifuge situation, preparation hydrogen bromide butanone solution (9.2g massfraction is that 48% hydrobromic acid solution mixes with 45g butanone).At 25 DEG C, by under Hydrogen bromide butanone solution lucifuge condition, be added dropwise in the butanone solution of Compound I, continue to stir 2h, filter, with 50mL butanone drip washing filter cake, obtain the hydrobromate 17.4g of the Eletriptan free alkali of the tool crystal formation shown in formula II, yield 75%, and the HPLC purity of this hydrobromate is 98.8%, ee value is 99.2%.
Embodiment 5
2L there-necked flask, adds the compound (preparing gained according to patent US2005020663A1) shown in 19.0g structure above I, adds butanone (12.1g), and system stirs clearly molten.In addition, in lucifuge situation, preparation hydrogen bromide butanone solution (9.2g massfraction is that 48% hydrobromic acid solution mixes with 45g butanone).At 25 DEG C, by under Hydrogen bromide butanone solution lucifuge condition, be added dropwise in the butanone solution of Compound I, continue to stir 2h, filter, with 50mL butanone drip washing filter cake, obtain the hydrobromate 15.0g of the Eletriptan free alkali of the tool crystal formation shown in structure above II, yield 75%, and the HPLC purity of this hydrobromate is 97.8%, ee value is 98.8%.
From embodiment 3-5, the Eletriptan free alkali salify of the tool crystal formation using method of the present invention to prepare can obtain the Eletriptan hydrobromate of high HPLC purity, high-optical-purity.
Embodiment 6
In 50mL there-necked flask, add product (white powdery solids shown in structure above I) prepared by 2g embodiment 1, ethyl acetate 5mL, stirs 1h to clearly molten, leaves standstill after 6 hours, separate out solid, filter, forced air drying, to constant weight, obtains Eletriptan free alkali product (White crystalline solid shown in the structure above I) 1.8g of tool crystal formation, i.e. crystal formation b, yield 90%.Fusing point 103-105 DEG C of obtained product, HPLC purity 99.8%, ee value 99.9%.
Wherein, the X-ray diffractogram of the Eletriptan free alkali (crystal formation b) of tool crystal formation as shown in Figure 5.It is 5.18 ° that Fig. 5 provides Compound I in 2 θ values, 8.79 °, 10.32 °, 11.05 °, 12.17 °, 13.47 °, 14.33 °, 15.31 °, 15.47 °, 16.11 °, 16.73 °, 17.68 °, 18.43 °, 18.94 °, 19.64 °, 20.82 °, 21.57 °, 22.28 °, 22.86 °, 23.35 °, 23.50 °, 24.43 °, 26.70 °, 27.19 °, 28.02 °, 28.64 °, 31.12 °, 31.69 °, 32.11 °, 32.94 °, 33.87 °, 35.15 °, the diffraction peak at 36.92 ° and 38.03 ° ± 0.2 ° places.
Feature as shown in Figure 6 for the means of differential scanning calorimetry thermogram (DSC trace) of the Eletriptan free alkali (crystal formation b) of tool crystal formation, endotherm(ic)peak is had in the scope of 106.27 ~ 116.15 DEG C, and the DSC trace of enthalpy of phase change that Fig. 6 Eletriptan free alkali (crystal formation b) of additionally providing the tool crystal formation of the present embodiment 5 is located at-96.27J/g.
Embodiment 7
In 500mL there-necked flask, add product (10g, the white powdery solids shown in structure above I) prepared by embodiment 1, acetone 50mL, stirs 1h to clearly molten, drips 250mL deionized water, there is white opacity in system, stir 5h, filter, 20mL deionized water filter wash cake, forced air drying is to constant weight, obtain Eletriptan free alkali (white powdery solids) 8.3g of tool crystal formation, i.e. crystal formation a, yield 83%.Fusing point 103-105 DEG C, HPLC purity 99.1%, ee value 99.5% of the Eletriptan free alkali of obtained tool crystal formation.
X-ray diffraction spectrogram and the DSC trace of the Eletriptan free alkali of the tool crystal formation prepared in embodiment 7 are similar to embodiment 2.
Claims (13)
1. an Eletriptan free alkali for tool crystal formation, is characterized in that, is selected from the one in following manner:
1) the Eletriptan free alkali of described tool crystal formation is characterized by the X-ray diffraction pattern comprising two or more X-ray diffraction peak, wherein, described two or more X-ray diffraction peak, being selected from 2 θ values is 8.84 °, 11.09 °, 12.18 °, 14.39 °, 16.36 °, 16.10 °, 16.76 °, 17.74 °, 18.97 °, 19.64 °, 20.43 °, 20.86 °, 21.59 °, 22.30 °, 23.53 °, 24.49 °, 26.72 °, 27.22 °, 28.11 °, 28.52 °, 31.01 °, 31.74 °, 32.27 °, 32.98 °, the X-ray diffraction peak at 33.93 ° and 35.09 ° ± 0.2 ° places,
2) the Eletriptan free alkali of described tool crystal formation is characterized by the X-ray diffraction pattern comprising two or more X-ray diffraction peak, wherein, described two or more X-ray diffraction peak, being selected from 2 θ values is 5.18 °, 8.79 °, 10.32 °, 11.05 °, 12.17 °, 13.47 °, 14.33 °, 15.31 °, 15.47 °, 16.11 °, 16.73 °, 17.68 °, 18.43 °, 18.94 °, 19.64 °, 20.82 °, 21.57 °, 22.28 °, 22.86 °, 23.35 °, 23.50 °, 24.43 °, 26.70 °, 27.19 °, 28.02 °, 28.64 °, 31.12 °, 31.69 °, 32.11 °, 32.94 °, 33.87 °, 35.15 °, the X-ray diffraction peak at 36.92 ° and 38.03 ° ± 0.2 ° places.
2. the Eletriptan free alkali of tool crystal formation as claimed in claim 1, is characterized in that: the Eletriptan free alkali of described tool crystal formation, has the X-ray diffractogram substantially as shown in Fig. 3 or Fig. 5.
3. the Eletriptan free alkali of tool crystal formation as claimed in claim 1, it is characterized in that: the Eletriptan free alkali of described tool crystal formation is also characterized by DSC trace, wherein, described DSC trace be included in 98.78 ~ 110.42 DEG C place endotherm(ic)peaks or described DSC trace be included in 104.27 ~ 118.15 DEG C place endotherm(ic)peaks.
4. the Eletriptan free alkali of tool crystal formation as claimed in claim 3, is characterized in that: described DSC trace is included in 104.67 ± 2 DEG C of endotherm(ic)peaks located or described DSC trace is included in 111.96 ± 2 DEG C of endotherm(ic)peaks located.
5. the Eletriptan free alkali of tool crystal formation as claimed in claim 1, it is characterized in that: the Eletriptan free alkali of described tool crystal formation is also characterized by DSC trace, wherein, described DSC trace is included in the enthalpy of phase change at-91.84 ± 2J/g or-96.27 ± 2J/g place.
6. the Eletriptan free alkali of tool crystal formation as claimed in claim 1, is characterized in that: the Eletriptan free alkali of described tool crystal formation, has DSC trace as illustrated in fig. 4 or 6 substantially.
7. a preparation method for the Eletriptan free alkali of the tool crystal formation as described in any one of claim 1-6, is characterized in that, comprise step:
(1) in the Eletriptan free alkali shown in the structural formula I of oily, add the first solvent, stir, obtain solid;
(2) solid that step (1) obtains is dissolved in the second solvent, stirs, drip water, stir, separate out solid, obtain the Eletriptan free alkali of tool crystal formation;
Or the solid that step (1) obtains is dissolved in the 3rd solvent, leave standstill, separate out solid, obtain the Eletriptan free alkali of tool crystal formation.
8. method as claimed in claim 7, is characterized in that: in described step (1), the first solvent comprises: one or more in normal hexane, normal heptane, sherwood oil, dimethylbenzene; The amount ratio of the Eletriptan free alkali shown in structural formula I of the first solvent and oily is Eletriptan free alkali/12 milliliter the first solvent shown in the structural formula I of milliliter the first solvent ~ 1 gram oily of Eletriptan free alkali/8 shown in the structural formula I of 1 gram of oily; The method stirred is: be warming up to 110 ~ 140 DEG C and stir after 1 ~ 5 hour, be cooled to 0 DEG C, stir 1 ~ 5h;
In step (2), the second solvent comprises: the one in acetone, acetonitrile or its mixture; The amount ratio of the Eletriptan free alkali shown in structural formula I of the second solvent and oily is Eletriptan free alkali/5 milliliter the second solvent shown in the structural formula I of milliliter the second solvent ~ 1 gram oily of Eletriptan free alkali/3 shown in the structural formula I of 1 gram of oily; The volume ratio of water and the second solvent is 3 ~ 5:1; In step (2), the solid that step (1) obtains is dissolved in the second solvent, stirring at room temperature 0.2 ~ 1h, drips water, stir 2 ~ 5h, separate out solid, obtain the Eletriptan free alkali of tool crystal formation;
In step (2), the 3rd solvent comprises: ethyl acetate; The amount ratio of the Eletriptan free alkali shown in structural formula I of the 3rd solvent and oily is Eletriptan free alkali/3 milliliter the 3rd solvent shown in the structural formula I of milliliter the 3rd solvent ~ 1 gram oily of Eletriptan free alkali/1 shown in the structural formula I of 1 gram of oily; The time left standstill is 2 ~ 12h.
9. an application for the Eletriptan free alkali of the tool crystal formation as described in any one of claim 1-6, is characterized in that: the application of Eletriptan free alkali in preparation treatment migraine remedy of described tool crystal formation.
10. a pharmaceutical composition, is characterized in that: it contains the Eletriptan free alkali of the tool crystal formation as described in any one of claim 1-6 of significant quantity and pharmaceutically acceptable carrier.
The hydrobromate of the Eletriptan free alkali of 11. 1 kinds of tool crystal formations as described in any one of claim 1-6, is characterized in that, its structural formula is as follows:
The preparation method of the hydrobromate of the Eletriptan free alkali of 12. 1 kinds of tool crystal formations as claimed in claim 11, is characterized in that, comprise step:
1) after the Eletriptan free alkali of the tool crystal formation as described in any one of claim 1-6 being dissolved in the 4th solvent, at 20 ~ 30 DEG C, in this system, drip the mixing solutions of hydrobromic acid aqueous solution and butanone, stir;
2) filter, by the 4th solvent cleaning, obtain the hydrobromate of the Eletriptan free alkali of tool crystal formation.
13. methods as claimed in claim 12, it is characterized in that: in described step 1), the 4th solvent comprises: butanone; The amount ratio of the Eletriptan free alkali of the 4th solvent and tool crystal formation is: Eletriptan free alkali/1 milliliter the 4th solvent of Eletriptan free alkali/0.6 milliliter the 4th solvent ~ 1st gram tool crystal formation of 1 gram of tool crystal formation; The massfraction of hydrobromic acid aqueous solution is 40 ~ 48%, and the mol ratio of the Eletriptan free alkali of Hydrogen bromide and tool crystal formation is 1.01 ~ 1.20:1; In the mixing solutions of hydrobromic acid aqueous solution and butanone, the mass ratio of butanone and hydrobromic acid aqueous solution is 4 ~ 6:1; The time of stirring is 2h ~ 12h;
Step 2) in, the amount ratio of the Eletriptan free alkali of the 4th solvent and tool crystal formation is: Eletriptan free alkali/4 milliliter the 4th solvent of Eletriptan free alkali/2 milliliter the 4th solvent ~ 1st gram tool crystal formation of 1 gram of tool crystal formation.
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| US5545644A (en) * | 1990-10-15 | 1996-08-13 | Pfizer Inc. | Indole derivatives |
| CN1823060A (en) * | 2003-07-23 | 2006-08-23 | 辉瑞大药厂 | Improved process for preparing alpha-polymorphic eletriptan hydrobromide |
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