CN104725470B - Novel taltirelin crystal form and preparation method and application thereof - Google Patents
Novel taltirelin crystal form and preparation method and application thereof Download PDFInfo
- Publication number
- CN104725470B CN104725470B CN201310699696.7A CN201310699696A CN104725470B CN 104725470 B CN104725470 B CN 104725470B CN 201310699696 A CN201310699696 A CN 201310699696A CN 104725470 B CN104725470 B CN 104725470B
- Authority
- CN
- China
- Prior art keywords
- minus
- plus
- taltirelin
- new
- crystal form
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of medicinal chemistry, in particular to a novel crystal form of taltirelin and a preparation method thereof, wherein the crystal of the novel crystal form I is subjected to X-ray powder diffraction, the position 2theta of a diffraction peak is taken as a characteristic parameter of a spectrogram, and the 2theta sequentially comprises the following components: 8.17 plus or minus 0.2, 11.32 plus or minus 0.2, 15.33 plus or minus 0.2, 15.86 plus or minus 0.2, 18.49 plus or minus 0.2, 19.43 plus or minus 0.2, 20.93 plus or minus 0.2, 23.76 plus or minus 0.2, 26.15 plus or minus 0.2 and 32.40 plus or minus 0.2; the preparation method comprises the following steps: mixing the taltirelin and an alcohol solvent, and fully dissolving to obtain a taltirelin alcohol solution; and crystallizing the taltirelin alcohol solution by using a temperature difference method, carrying out solid-liquid separation and drying the solid to obtain the crystal of the new crystal form I. The novel taltirelin crystal form I provided by the invention has the advantages of high melting point, good stability, storage and transportation, and great convenience for industrial production.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a novel crystal form of a medicament taltirelin for improving dyskinesia of a patient with spinocerebellar degeneration and a preparation method thereof.
Background
Spinocerebellar ataxia (SCAs), old known as autosomal dominant ataxia, is a group of chronic degenerative diseases of the central nervous system with ataxia and dysdiscrimination as the main clinical manifestations. Since the disease is a genetic disease, there is no effective treatment so far. The only approved drug for ataxia is TRH. However, clinical studies show that because TRH is rapidly metabolized and degraded in vivo, the half-life period is only 4-5min, and the action time is too short, therefore, people can enhance the biological activity of TRH by modifying or changing the molecular structure of TRH, and prolong the half-life period, and nearly hundred TRH derivatives are artificially synthesized in sequence, wherein, taltirelin is the TRH derivative which is most effective in treating the spinocerebellar degeneration.
Taltirelin (Taltirelin) with the chemical name of (4S) -N- [ (2S) -2-1- [ (2S) -2-carbamoylpyrrolidin-1-yl ] -3- (1H-imidazol-4-yl) -1-oxoprop-2-yl ] -1-methyl-2, 6-dioxo-1, 3-diazahexane-4-carboxamide (shown in formula I) was developed by Mitsubishi pharmaceutical corporation, and was first marketed in Japan in 2000-9 months, the marketed dosage form and specification are 5mg tablets, and the Taltirelin tetrahydrate (α crystal form) is an effective component, and α metastable crystal form (triclinic P1) is a crystal form, has a melting point of 65-70 ℃, has good solid-liquid separation property and high solubility.
The literature Chemical Engineering Journal (Lausane) (1999),75(3), 193-.
It is worth mentioning that both the two crystal forms belong to the tetrahydrate, the melting points are very low, and the drying process can only be carried out at a lower temperature, generally not more than 40 ℃. Although the lower temperature can ensure that the crystal water in the molecule is kept stable, the drying is time-consuming and troublesome, and more importantly, the melting point is too low, so that the processing, storage and transportation of the preparation are more strict, and finally, the manufacturing cost and the use cost of the product are high.
In view of the above difficulties, it is an urgent problem to provide a new crystalline form which has a high pharmaceutical value and a high stability and is convenient for the preparation process, manufacture, storage and transportation.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a new crystal form of taltirelin, which has a high melting point.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the novel crystal form I of the taltirelin, wherein the crystal of the novel crystal form I is subjected to X-ray powder diffraction, and the novel crystal form I is characterized in that the position 2theta of a diffraction peak is taken as a characteristic parameter of a spectrogram, and the 2theta sequentially comprises the following components: 8.17 +/-0.2, 11.32 +/-0.2, 15.33 +/-0.2, 15.86 +/-0.2, 18.49 +/-0.2, 19.43 +/-0.2, 20.93 +/-0.2, 23.76 +/-0.2, 26.15 +/-0.2 and 32.40 +/-0.2, wherein the types and the test conditions of an X-ray powder diffraction instrument are as follows:
the name of the experimental instrument is an X-ray diffractometer (Empyrean) with sharp shadow of Dutch Pasnake company, an X-ray tube is a Cu target and a Ni filter monochromatic mark, the wavelength of the X-ray is 1.54051 Å, the shape of a test sample is powder, the test temperature is room temperature, the test angle is 5-50 degrees, the scanning speed is 4 degrees/min, the scanning mode is theta/2theta linkage, the scanning mode is continuee, the tube pressure is 40KV, and the tube current is 16 mA.
Further, the diffraction peak positions 2theta of the new taltirelin crystal form I are sequentially as follows according to the I/IO value from large to small: 20.93 plus or minus 0.2, 23.76 plus or minus 0.2, 18.49 plus or minus 0.2, 19.43 plus or minus 0.2 and 15.86 plus or minus 0.2; or see examples tables 1-6.
Further, the novel crystal form I of taltirelin is characterized in that the position 2theta of the diffraction peak is according to I/IOThe values of (A) are as follows from big to small: 20.93 plus or minus 0.2, 23.76 plus or minus 0.2, 18.49 plus or minus 0.2, 19.43 plus or minus 0.2, 15.86 plus or minus 0.2, 8.17 plus or minus 0.2, 15.33 plus or minus 0.2, 26.15 plus or minus 0.2, 32.40 plus or minus 0.2 and 11.32 plus or minus 0.2; or see tables 1-6 in the examples.
As a person skilled in the art, in the X-ray powder diffraction pattern, the diffraction peaks listed in the first 5-10 of the new crystal form I intensity position have the same peak position and peak intensity within the error range, namely, the fingerprint of the new crystal form I can be represented.
Furthermore, the X-ray powder diffraction of the new taltirelin crystal form I is shown in figure 1 and/or 3 and/or 5 and/or 7 and/or 9 and/or 11.
Further, the melting point of the new taltirelin crystal form I is 212-217 ℃.
Further, the new crystalline form I of taltirelin does not contain water of crystallization.
The technical problem to be solved by the invention is to provide a preparation method of the new crystal form I, which has simple process and stable method.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the preparation method of the new crystal form I of the taltirelin with high melting point is prepared according to the following steps:
dissolution of a taltirelin
Mixing taltirelin and an alcohol solvent, and fully dissolving to obtain a taltirelin alcohol solution, wherein the alcohol solvent contains no water;
b crystallization
And (3) crystallizing the taltirelin alcohol solution by using a temperature difference method, and then carrying out solid-liquid separation and drying the solid to obtain the crystal of the new crystal form I.
Preferably, in the preparation method, in the step A, the taltirelin and the alcohol solvent are mixed and heated to 30-80 ℃ to be fully dissolved.
Preferably, in the preparation method, step a, the alcoholic solvent includes methanol and/or ethanol and/or isopropanol.
Preferably, in the preparation method, in the step a, the dissolving temperature of the taltirelin in the alcohol solvent is 40-60 ℃, and stirring is carried out during the dissolving process.
In a preferable scheme, in the preparation method, in the step A, the amount of the alcohol solvent is 3-25 times that of taltirelin; the alcohol solvent is calculated by V/M, and the taltirelin is calculated by ml/g.
Preferably, in the preparation method, under the condition that the constant temperature of the taltirelin alcohol solution obtained in the step A is ensured, an aprotic organic solvent is dropwise added, wherein the aprotic organic solvent is tetrahydrofuran and/or acetonitrile. The experiments in the examples confirm that: the addition of the aprotic organic solvent and the control step are added, so that the dosage of the corresponding alcohol solvent can be reduced, the dissolving temperature can be reduced, and the product yield can be further obviously improved by reducing the solubility of the taltirelin in the mixed solvent.
In a preferable scheme, in the preparation method, the temperature of the aprotic organic solvent is 40-60 ℃, and the dosage of the aprotic organic solvent is 10-30 times of that of the taltirelin. The aprotic organic solvent is calculated by V/M, and the taltirelin is calculated by ml/g.
In a preferable scheme, in the preparation method, in the step A, the dissolving temperature of the taltirelin in the alcohol solvent is 40-60 ℃, and stirring is carried out in the dissolving process; and in the step B, cooling to-10 ℃ for crystallization, wherein the crystallization time is 1-24 hours. Or in the step A, the dissolving temperature of the taltirelin in the alcohol solvent is 30-80 ℃ so as to fully dissolve the taltirelin; and in the step B, cooling to-10 ℃ for crystallization, wherein the crystallization time is 1-24 hours.
Preferably, in the preparation method, in the step B, the drying temperature is 25 to 75 ℃, and the crystal does not contain crystal water.
The technical problem to be solved by the invention is also that the invention provides a preparation and a composition of taltirelin, which can be used for clinical application.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the novel crystal form I of the taltirelin and a pharmaceutically acceptable carrier.
The fourth purpose of the invention is to provide an application of the new crystal form I, and the application provides a new idea for treating spinocerebellar ataxia.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the new crystal form I of the taltirelin is applied to the preparation of the drugs for treating spinocerebellar ataxia.
The invention has the beneficial effects that: the novel taltirelin crystal form I provided by the invention has the advantages of high melting point, good stability, storage and transportation, and great convenience for industrial production. Compared with the known crystal form, the melting point of the crystal form I is improved by about 150 ℃, so that wider drying conditions are provided for a drying procedure, and the drying time is greatly shortened by increasing the drying temperature, so that the production efficiency of raw materials or preparations is improved; the defects of low melting point, high preparation cost, complicated drying process and poor controllability of large-scale production of the known crystal form reported in the prior art are overcome. Moreover, the method for preparing the new taltirelin crystal form I provided by the invention adopts alcohols as solvents, so that the process steps are short, the product yield is high, and the post-treatment is simple and convenient; the addition of the aprotic organic solvent and the control step are added, so that the dosage of the corresponding alcohol solvent can be reduced, the dissolving temperature can be reduced, and the product yield can be further obviously improved by reducing the solubility of the taltirelin in the mixed solvent.
In conclusion, the invention provides a new taltirelin crystal form I and a preparation method thereof. Under the condition of short and easy-to-implement process, the novel taltirelin crystal form I with many advantages of good stability, high melting point, convenience for processing, storage, transportation and the like is obtained, and the defects of over-low melting point, high preparation cost, complicated drying procedure and poor controllability of large-scale production of the known crystal form reported in the prior art are overcome.
Drawings
The invention is further described below with reference to the figures and examples.
Figure 1 example an X-ray powder diffraction pattern of the obtained new form I of taltirelin.
FIG. 2 is a differential scanning calorimetry and thermogravimetric analysis pattern of the obtained new crystalline form I of taltirelin.
FIG. 3X-ray powder diffraction pattern of new crystalline form I of taltirelin obtained in example two.
FIG. 4 is a differential scanning calorimetry and thermogravimetric analysis chart of the new taltirelin crystal form I obtained in example two.
FIG. 5X-ray powder diffraction pattern of new crystalline form I of taltirelin obtained in example III.
FIG. 6 is a differential scanning calorimetry and thermogravimetric analysis chart of the new taltirelin crystal form I obtained in the third embodiment.
FIG. 7X-ray powder diffraction pattern of the new crystalline form I of taltirelin obtained in example four.
FIG. 8 is a differential scanning calorimetry and thermogravimetric analysis chart of the new crystalline form I of taltirelin obtained in example four.
FIG. 9X-ray powder diffraction pattern of the new crystalline form I of taltirelin obtained in example five.
FIG. 10 is a differential scanning calorimetry and thermogravimetric analysis chart of the new crystalline form I of taltirelin obtained in example five.
FIG. 11X-ray powder diffraction pattern of the new crystalline form I of taltirelin obtained in example six.
FIG. 12 is a differential scanning calorimetry and thermogravimetric analysis pattern of the new crystalline form I of taltirelin obtained in example six.
Detailed Description
The taltirelin raw material used in the crystallization of the invention is prepared by a reference (EP 0168042A 2), but the crystal form of the adopted crystallization raw material is not limited at all.
Dissolving 30.0 g of 1-methyl-L-4, 5-dihydroorotic acid and 22.2 g of N-hydroxysuccinimide in 600 ml of anhydrous N, N-dimethylformamide at normal temperature, uniformly stirring, cooling to 0 ℃, adding 40.8 g of N, N-dicyclohexylcarbodiimide, stirring at the temperature for reaction for 1.5 hours, continuously cooling to-15 ℃, adding L-histamine acyl prolinamide dihydrobromide (prepared from 75 g of benzyloxycarbonyl-L-histamine acyl prolinamide), dropwise adding 60ml of anhydrous triethylamine, continuously reacting for 1 hour, naturally heating to 0-15 ℃, and reacting at the temperature for about 40 hours. Filtering, and concentrating the filtrate to dryness. The residue was dissolved in water and the pH was adjusted to 7.0-8.5 with sodium bicarbonate. Insoluble matter was filtered off, the filtrate was passed through a macroporous resin column (HP20,4CM 60CM), rinsed with water,then eluting with mixed solvent of methanol/water =30/70, collecting PAULY reaction positive component, concentrating, recrystallizing with water to obtain product 25.5 g. [ α ]]D 25= 22.0(c =2, 1mol/LHCl), yield 30.6%.1H-NMR （D2O) analysis is shown in the following figures and tables:
1H-NMR nuclear magnetic resonance spectrum detection data and analysis
The following specific examples are intended to further illustrate the invention and should not be construed as limiting the invention.
In the X-ray powder diffraction, differential scanning calorimetry and thermogravimetric analysis test instrument models and test conditions related in the examples, the X-ray powder diffraction instrument models and test conditions are as follows:
the name of the experimental instrument is an X-ray diffractometer (Empyrean) with sharp shadow of Dutch Pasnake company, an X-ray tube is a Cu target and a Ni filter monochromatic mark, the wavelength of the X-ray is 1.54051 Å, the shape of a test sample is powder, the test temperature is room temperature, the test angle is 5-50 degrees, the scanning speed is 4 degrees/min, the scanning mode is theta/2theta linkage, the scanning mode is continuee, the tube pressure is 40KV, and the tube current is 16 mA.
The types and test conditions of Differential Scanning Calorimetry (DSC) and thermogravimetric analysis (TG) instruments are as follows:
name of experimental instrument: METTLER TOLEDO1100LF
And (3) testing conditions are as follows: the upper limit temperature is 350 ℃;
the lower limit temperature is 20 ℃;
the heating rate is 10 ℃/min.
Example 1
Adding 3.0g of taltirelin and 45ml of ethanol into a reaction bottle, heating to 40 +/-2 ℃, and stirring to dissolve. After the solution is dissolved and clarified, 45ml of tetrahydrofuran is slowly and uniformly added dropwise for about 1.5 hours, and the temperature is kept at 40 +/-2 ℃. After the tetrahydrofuran is dripped, the mixture is cooled by ice water bath, the temperature is controlled to be 0 +/-2 ℃ for crystallization for 13 hours, the mixture is filtered, and the mixture is decompressed and dried at 50 ℃ to obtain 2.74g of white solid. The yield is 91.2 percent, the melting point is 215-217 ℃, and the moisture content is 0.3 percent. X-ray powder diffraction, differential scanning calorimetry and thermogravimetric analysis are shown in figure 1 and figure 2 respectively.
Table 1 example one X-ray powder diffraction characteristic absorption peak of the new crystalline form I of taltirelin obtained
| 2θ | d-value | I/IO（%） |
| 8.17 | 10.8193 | 25.5（6） |
| 11.32 | 7.8133 | 11.9（10） |
| 15.33 | 5.7740 | 15.3（7） |
| 15.86 | 5.5839 | 28.0（5） |
| 18.49 | 4.7959 | 32.2（3） |
| 19.43 | 4.5647 | 30.9（4） |
| 20.93 | 4.2414 | 100.0（1） |
| 23.76 | 3.7411 | 45.8（2） |
| 26.15 | 3.4046 | 14.5（8） |
| 32.40 | 2.7606 | 13.7（9） |
Example 2
Adding 3.0g of taltirelin and 54.0ml of isopropanol into a reaction bottle, heating to 70 +/-2 ℃, and stirring to dissolve. After dissolution and clarification, the mixture is cooled by ice water bath, and is crystallized for 16 hours at the temperature of minus 3 +/-2 ℃. Filtering, drying under reduced pressure at 60 ℃ to obtain 2.7g of white solid, wherein the yield is 90.0%, the melting point is 215-217 ℃ and the water content is 0.4%. X-ray powder diffraction, differential scanning calorimetry and thermogravimetric analysis are shown in figure 3 and figure 4 respectively.
TABLE 2 characteristic absorption peaks of X-ray powder diffraction of the new taltirelin form I obtained in example two
| 2θ | d-value | I/IO（%） |
| 8.09 | 10.9260 | 23.5（6） |
| 11.24 | 7.8683 | 13.5（10） |
| 15.25 | 5.8036 | 17.4（7） |
| 15.76 | 5.6201 | 27.3（5） |
| 18.41 | 4.8164 | 33.2（3） |
| 19.35 | 4.5830 | 31.7（4） |
| 20.82 | 4.2625 | 100.0（1） |
| 23.69 | 3.7534 | 46.3（2） |
| 26.08 | 3.4146 | 15.2（8） |
| 32.33 | 2.7672 | 14.7（9） |
EXAMPLE III
Adding 2.0g of taltirelin and 32ml of isopropanol into a reaction bottle, heating to 60 +/-2 ℃, and stirring to dissolve. After dissolution and clarification, keeping the temperature at 60 +/-2 ℃, slowly and uniformly dripping 36ml of tetrahydrofuran for about 2.5 hours, cooling by using an ice water bath after dripping is finished, and controlling the temperature at 3 +/-2 ℃ for crystallization for 9 hours. Filtering, drying under reduced pressure at 55 ℃ to obtain 1.86g of white solid, wherein the yield is 93.0%, the melting point is 212 ℃ and 214 ℃, and the water content is 1.0%. The X-ray powder diffraction, differential scanning calorimetry and thermogravimetric analysis test patterns are shown in figure 5 and figure 6 respectively.
TABLE 3 characteristic absorption peaks of X-ray powder diffraction of the new taltirelin crystal form I obtained in example III
| 2θ | d-value | I/IO（%） |
| 8.09 | 10.9179 | 24.7（6） |
| 11.24 | 7.8640 | 10.5（10） |
| 15.29 | 5.7917 | 18.0（7） |
| 15.81 | 5.6003 | 28.1（5） |
| 18.44 | 4.8083 | 34.2（3） |
| 19.38 | 4.5758 | 30.7（4） |
| 20.88 | 4.2510 | 100.0（1） |
| 23.74 | 3.7447 | 48.0（2） |
| 26.08 | 3.4140 | 12.5（8） |
| 32.36 | 2.7646 | 11.1（9） |
Example four
4.0g of taltirelin and 32ml of methanol are added into a reaction bottle, the temperature is raised to 35 +/-2 ℃, and the mixture is stirred and dissolved. After dissolution and clarification, 120ml of acetonitrile is slowly dripped at a constant speed at the temperature of 35 +/-2 ℃, the time for dripping the acetonitrile is about 1.5 hours, and after the dripping is finished, the temperature is reduced by using an ice water bath, and the temperature is controlled to be minus 6 +/-2 ℃ for crystallization for 19 hours. Filtered and dried under reduced pressure at 40 ℃ to obtain 3.42g of white solid. The yield is 85.5 percent, the melting point is 212 ℃ and 215 ℃, and the moisture content is 0.8 percent. X-ray powder diffraction, differential scanning calorimetry and thermogravimetric analysis are shown in figure 7 and figure 8 respectively.
Table 4 characteristic absorption peaks of X-ray powder diffraction of the new crystalline form I of taltirelin obtained in example four
| 2θ | d-value | I/IO（%） |
| 8.07 | 10.9548 | 25.8（6） |
| 11.19 | 7.9011 | 13.0（10） |
| 15.23 | 5.8113 | 19.9（7） |
| 15.76 | 5.6191 | 26.7（5） |
| 18.38 | 4.8219 | 29.4（3） |
| 19.33 | 4.5881 | 29.3（4） |
| 20.80 | 4.2667 | 100.0（1） |
| 23.69 | 3.7528 | 48.1（2） |
| 26.00 | 3.4242 | 16.0（8） |
| 32.303 | 2.7690 | 14.6（9） |
EXAMPLE five
Adding 5.0g of taltirelin and 75.0ml of absolute ethyl alcohol into a reaction bottle, heating to 45 +/-2 ℃, and stirring to dissolve. After dissolution and clarification, 100ml of acetonitrile is slowly dripped at a constant speed at the temperature of 45 +/-2 ℃, the time for dripping the acetonitrile is about 2.0 hours, and after the dripping is finished, the temperature is reduced by using an ice water bath, and the temperature is controlled to be minus 2 +/-2 ℃ for crystallization for 15 hours. Filtered and dried under reduced pressure at 55 ℃ to obtain 4.5g of white solid. The yield is 90.0 percent, the melting point is 214 ℃ and 216 ℃, and the moisture content is 0.5 percent. X-ray powder diffraction, differential scanning calorimetry and thermogravimetric analysis are shown in figure 9 and figure 10 respectively.
TABLE 5 characteristic absorption peaks of X-ray powder diffraction of the new taltirelin form I obtained in example five
| 2θ | d-value | I/IO（%） |
| 8.12 | 10.8827 | 25.9（6） |
| 11.27 | 7.8461 | 13.4（10） |
| 15.29 | 5.7918 | 17.4（7） |
| 15.81 | 5.6004 | 29.5（5） |
| 18.44 | 4.8081 | 33.2（3） |
| 19.38 | 4.5757 | 31.1（4） |
| 20.88 | 4.2509 | 100.0（1） |
| 23.72 | 3.7485 | 47.4（2） |
| 26.08 | 3.4139 | 14.9（8） |
| 32.36 | 2.7646 | 13.7（9） |
EXAMPLE six
4.0g of taltirelin and 72ml of isopropanol are added into a reaction bottle, the temperature is raised to 60 +/-2 ℃, and the mixture is stirred and dissolved. After dissolution and clarification, keeping the temperature at 60 +/-2 ℃, slowly dripping 60ml of acetonitrile at a constant speed for 2.5 hours, cooling by using an ice water bath after dripping is finished, and controlling the temperature to be 3 +/-2 ℃ for crystallization for 12 hours. Filtering, drying under reduced pressure at 60 ℃ to obtain 3.66g of white solid, wherein the yield is 91.5%, the melting point is 213-215 ℃, and the water content is 0.7%. X-ray powder diffraction, differential scanning calorimetry and thermogravimetric analysis are shown in figure 11 and figure 12 respectively.
Table 6X-ray powder diffraction characteristic absorption peaks of the new crystalline form I of taltirelin obtained in example six
| 2θ | d-value | I/IO（%） |
| 8.07 | 10.9552 | 26.5（6） |
| 11.22 | 7.8832 | 13.0（10） |
| 15.23 | 5.8118 | 18.0（7） |
| 15.73 | 5.6277 | 27.7（5） |
| 18.38 | 4.8221 | 34.4（3） |
| 19.33 | 4.5881 | 32.5（4） |
| 20.80 | 4.2667 | 100.0（1） |
| 23.66 | 3.7567 | 48.5（2） |
| 26.05 | 3.4174 | 15.3（8） |
| 32.30 | 2.7690 | 13.5（9） |
EXAMPLE seven
Adding 3.0g of taltirelin and 36.0ml of absolute ethyl alcohol into a reaction bottle, heating to 55 +/-2 ℃, and stirring to dissolve. After dissolution and clarification, the mixture is cooled by ice water bath, and is crystallized for 10 hours at the temperature of minus 2 +/-2 ℃. Filtering, and drying at 45 ℃ under reduced pressure. 2.53g of white solid is obtained with a yield of 84.3%, a melting point of 214 ℃ and a moisture content of 0.6%.
The yields in the following tables are based on the charge substrate for each particular step as the calculation denominator. The solvent is calculated by V/M, and the taltirelin is calculated by ml/g.
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.
Claims (7)
1. The method for improving the melting point of taltirelin is characterized by being prepared according to the following method:
dissolution of a taltirelin
Mixing taltirelin and an alcohol solvent, wherein the alcohol solvent is methanol and/or ethanol and/or isopropanol, heating to 30-80 ℃, fully dissolving, the using amount of the alcohol solvent is 3-25 times of that of the taltirelin, the dissolving temperature in the alcohol solvent is 40-60 ℃, and stirring during dissolving to obtain a taltirelin alcohol solution; under the condition of ensuring the constant temperature of the obtained taltirelin alcohol solution, dropwise adding an aprotic organic solvent, wherein the aprotic organic solvent is tetrahydrofuran and/or acetonitrile; the temperature of the aprotic organic solvent is 40-60 ℃, and the dosage of the aprotic organic solvent is 10-30 times of that of taltirelin;
b crystallization
Crystallizing the taltirelin alcohol solution by using a temperature difference method, cooling to-10 ℃ for crystallization, wherein the crystallization time is 1-24 hours, carrying out solid-liquid separation, and drying the solid to obtain a crystal of a new crystal form I, wherein the drying temperature is 25-75 ℃.
2. The method of claim 1, wherein: the crystal of the new crystal form I is subjected to X-ray powder diffraction, the position 2theta of a diffraction peak is taken as a characteristic parameter of a spectrogram, and the 2theta sequentially comprises the following components: 8.17 plus or minus 0.2, 11.32 plus or minus 0.2, 15.33 plus or minus 0.2, 15.86 plus or minus 0.2, 18.49 plus or minus 0.2, 19.43 plus or minus 0.2, 20.93 plus or minus 0.2, 23.76 plus or minus 0.2, 26.15 plus or minus 0.2 and 32.40 plus or minus 0.2.
3. The method according to claim 1, wherein the diffraction peak positions 2 θ of the crystal of the new form I are, in order of magnitude I/IO: 20.93 plus or minus 0.2, 23.76 plus or minus 0.2, 18.49 plus or minus 0.2, 19.43 plus or minus 0.2 and 15.86 plus or minus 0.2.
4. The method according to claim 1, wherein the diffraction peak positions 2 θ of the crystal of the new form I are, in order of magnitude I/IO: 20.93 plus or minus 0.2, 23.76 plus or minus 0.2, 18.49 plus or minus 0.2, 19.43 plus or minus 0.2, 15.86 plus or minus 0.2, 8.17 plus or minus 0.2, 15.33 plus or minus 0.2, 26.15 plus or minus 0.2, 32.40 plus or minus 0.2 and 11.32 plus or minus 0.2.
5. The process according to claim 1, characterized in that the X-ray powder diffraction pattern of the new form I is as shown in figure 1 and/or 3 and/or 5 and/or 7 and/or 9 and/or 11.
6. The process according to claim 1, characterized in that the melting point of the new taltirelin form I is between 212 and 217 ℃.
7. The process according to claim 1, characterized in that the new crystalline form I of taltirelin is free of water of crystallization.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310699696.7A CN104725470B (en) | 2013-12-18 | 2013-12-18 | Novel taltirelin crystal form and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310699696.7A CN104725470B (en) | 2013-12-18 | 2013-12-18 | Novel taltirelin crystal form and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104725470A CN104725470A (en) | 2015-06-24 |
| CN104725470B true CN104725470B (en) | 2020-03-27 |
Family
ID=53449946
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310699696.7A Active CN104725470B (en) | 2013-12-18 | 2013-12-18 | Novel taltirelin crystal form and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104725470B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114516898A (en) * | 2020-11-20 | 2022-05-20 | 上海丽珠制药有限公司 | Preparation method and application of thyrotropin releasing hormone |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101330905A (en) * | 2005-11-18 | 2008-12-24 | 赛多斯有限责任公司 | Lyophilization process and products obtained thereby |
| CN101544596A (en) * | 2008-03-25 | 2009-09-30 | 中国医学科学院药物研究所 | Preferred crystal-form substance of nitrendipine and preparation method, pharmaceutical composition and application thereof |
| CN102002004A (en) * | 2010-10-15 | 2011-04-06 | 深圳翰宇药业股份有限公司 | Taltirelin intermediate and synchronizing method of taltirelin |
-
2013
- 2013-12-18 CN CN201310699696.7A patent/CN104725470B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101330905A (en) * | 2005-11-18 | 2008-12-24 | 赛多斯有限责任公司 | Lyophilization process and products obtained thereby |
| CN101544596A (en) * | 2008-03-25 | 2009-09-30 | 中国医学科学院药物研究所 | Preferred crystal-form substance of nitrendipine and preparation method, pharmaceutical composition and application thereof |
| CN102002004A (en) * | 2010-10-15 | 2011-04-06 | 深圳翰宇药业股份有限公司 | Taltirelin intermediate and synchronizing method of taltirelin |
Non-Patent Citations (3)
| Title |
|---|
| Crystal structures and solvent-mediated transformation of Taltireline polymorphs;Shoji Maruyama;《Chemical Engineering Journal》;19991215;第75卷(第3期);193–200 * |
| Crystallization behavior of taltirelin polymorphs in a mixture of water and methanol;Shoji Maruyama;《Journal of Crystal Growth》;20001231;第212卷(第1-2期);239-245 * |
| Mechanism of the solvent-mediated transformation of taltirelin polymorphs promoted by methanol;Shoji Maruyama;《Chemical Engineering Journal》;20010101(第81期);第1-7页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104725470A (en) | 2015-06-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3797795A1 (en) | Preparation process of antibody drug conjugate intermediate | |
| JP2021530565A (en) | Salt of LSD1 inhibitor and its crystalline form | |
| CN107286220B (en) | 1,2, 4-triazole coupled dihydromyricetin derivative and preparation method and application thereof | |
| CN103059074B (en) | Glucosamine peptidomimetic compound as well as preparation method and application thereof | |
| CN102485723A (en) | Semi-synthesis of vinpocetine through one kettle way and preparation of water-soluble vinpocetine salt | |
| CN104725470B (en) | Novel taltirelin crystal form and preparation method and application thereof | |
| CN105646446B (en) | A method of purifying Egelieting | |
| CN117164662A (en) | Production process of acetyl hexapeptide-1 | |
| JPS6289695A (en) | Glutathione monoalkyl ester sulfate and production thereof | |
| CN101735220B (en) | Crystal form of 6, 7-dihydro-6-mercapto-5H-pyrazolo[1,2-alpha][1,2,4] triazoliumchloride and preparation method thereof | |
| CN104530112A (en) | Method for preparing everolimus intermediate and ethylated impurities thereof | |
| CN102702039A (en) | Process for synthesizing beta-alanyl-taurine | |
| CN107629115A (en) | A kind of purification process of Te Lawan stars | |
| CN109053808B (en) | Industrial preparation method of high-purity dicycloplatin needle crystal | |
| CN114163348A (en) | Synthesis method of aminoacyl-substituted L-phenylalanine | |
| CN113956266A (en) | Method for synthesizing tetrodotoxin on large scale | |
| CN113563401A (en) | Novel cordycepin alkanamide derivative and preparation method and application thereof | |
| CN106117075B (en) | Novel ubenimex recrystallization method | |
| JP2022074008A (en) | Treprostinil monohydrate crystals and methods for preparation thereof | |
| CN113493467B (en) | Improved preparation method of penethamate hydroiodide | |
| CN102432532B (en) | High-purity torasemide compound | |
| CN110003210B (en) | Synthesis and application of ester bond linked naphthalimide macrocyclic polyamine compound | |
| WO2015180549A1 (en) | I-type crystal of l-alanine-(14-oridonin) ester trifluoroacetate and preparation method therefor | |
| CN107043405B (en) | Crystal form of polycyclic heterocyclic compound, preparation method, application and composition thereof | |
| CN115403476A (en) | Citrate and tartrate salts of 5-aminolevulinic acid and methods for making the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |