CN114957230A - Novel crystal form of brexpiprazole and preparation method thereof - Google Patents
Novel crystal form of brexpiprazole and preparation method thereof Download PDFInfo
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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Abstract
Provides a novel crystal form of brexpiprazole and a preparation method thereof. The novel crystal form of brexpiprazole is named as a crystal form II, and has characteristic peaks at positions of about 5.2 degrees, 7.4 degrees, 9.8 degrees, 10.5 degrees, 14.3 degrees, 14.8 degrees, 18.6 degrees, 19.7 degrees, 23.6 degrees (2 theta) in an X-ray powder diffraction pattern detected by Cu-Kalpha radiation. The method is simple and convenient, has good reproducibility, and the crystal form II of the obtained epipiprazole has high purity and good stability, and is suitable for industrial production.
Description
The application is a divisional application of Chinese patent application with the application date of 2017, 10 and 09, and the application number of 201780047454.6, namely a new crystal form of ipiprazole and a preparation method thereof.
Technical Field
The invention relates to a novel crystal form of Brexpiprazole (Brexpiprazole) and a preparation method thereof.
Background
The chemical name of the brexpiprazole is (7- (4- (4-benzothiophen-4-yl) piperazine-1-yl) butoxy) -1H-quinoline-2-ketone), and the structural formula is shown as the following formula I:
in dopamine D2 receptors, partial D2 receptor agonists can generate functional antagonism on the limbic pathway of the brain, and can effectively improve the positive symptoms of schizophrenia caused by D2 overactivity; can produce functional excitation effect on the middle cerebral cortex channel, and can improve negative symptoms and cognitive impairment caused by D2 hypofunction. The ipiprazole jointly developed by the Lingbei pharmacy and the Tsukamur pharmacy is an experimental serotonin-dopamine activity modifier (SDAM) and is a novel multi-target action mechanism medicine for treating mental disorder diseases. The brexpiprazole has partial dopamine D3 receptor agonism, 5-HT1A partial receptor agonism and 5-HT2A partial receptor antagonism besides partial dopamine D2 receptor agonism, and is a novel drug which is developed aiming at multiple targets of monoamine neurotransmitters and has anti-schizophrenia and anti-depression effects.
In recent years, polymorphism of drug molecules has attracted much attention. Methods for preparing the crystal forms of ipiprazole dihydrate and the crystal forms of ipiprazole anhydrate are reported in patent documents CN104254530A and WO 2013/162046; a process for the preparation of amorphous ipiprazole is reported in CN 104844586A; however, in the reported crystal forms of brexpiprazole, the stability still needs to be improved.
Disclosure of Invention
The inventor unexpectedly obtains a new crystal form of the brexpiprazole through deep research, the new crystal form is named as a crystal form II in the text, the new crystal form is different from an anhydrous crystal form and a dihydrate crystal form, the stability is better, and the wide application prospect is realized; and based on this, the present invention has been completed.
The invention aims to provide a new crystal form II of brexpiprazole with good stability and a preparation method thereof, and the specific scheme is as follows:
the invention firstly provides a novel crystal form II of brexpiprazole shown as a formula I,
in an X-ray powder diffraction pattern measured using Cu-ka radiation, it has the following characteristic peaks, whose values of 2 θ angle (± 0.2 °) and relative intensities are shown in table 1 below:
TABLE 1
| 2θ/(°) | Relative strength |
| 5.2 | 100.0 |
| 7.4 | 54.4 |
| 9.8 | 58.7 |
| 10.5 | 53.2 |
| 14.3 | 34.6 |
| 14.8 | 74.6 |
| 18.6 | 45.5 |
| 19.7 | 45.6 |
| 23.6 | 32.3 |
In one embodiment of the present invention, the EPI novel crystalline form II has a differential scanning calorimetry analysis spectrum showing an endothermic peak at about 80-91 ℃ with crystal water, an endothermic peak at 130-150 ℃ with solvent, an exothermic peak at 176-186 ℃ with crystal, and an endothermic peak at 212-223 ℃ with melting. It is noted that, in the present context, the term "about" generally means within a tolerance allowed in the art, such as ± 10%, such as ± 5%, such as ± 2%, such as ± 1%.
The invention also provides a method for preparing the novel crystal form II of the brexpiprazole, which comprises the following steps:
(a) mixing the brexpiprazole and the ethanol-water mixed solvent at room temperature to prepare a suspension;
(b) adding organic acid into the suspension in the step (a), and heating until the organic acid is completely dissolved to obtain a clear solution;
(c) cooling the clarified liquid of step (b);
(d) adjusting the pH of the clear liquid cooled in the step (c) to be alkaline by using alkaline liquid, and separating out solids;
(e) keeping the temperature of the solid precipitated in the step (d) and continuously stirring for 0.5-2 hours, preferably 1 hour, filtering, washing the filter cake with water until the washing liquid is neutral, and drying to obtain the new crystal form II of the ipiprazole.
In one embodiment of the present invention, the volume percentage of ethanol in the ethanol-water mixed solvent used in step (a) is 10 to 50%, preferably 20 to 40%, and more preferably 30%. In practical applications, for example, 30% by volume of the ethanol-water mixed solvent can be prepared by mixing 3: 7 volume ratio of ethanol to water.
In one embodiment of the present invention, the organic acid used in step (b) is selected from formic acid, acetic acid, and/or propionic acid. In one embodiment of the present invention, the mass ratio of the organic acid to the brexpiprazole in the step (b) is: 1 (1.5-3), preferably 1: 2. In another embodiment of the present invention, when the organic acid is acetic acid, the mass ratio of the acetic acid to the ipiprazole in step (b) may be 1: 2.
In one embodiment of the present invention, the cooling temperature of the clarified liquid of step (c) is: -10 to 5 ℃.
In one embodiment of the present invention, the lye of step (d) may be: a monobasic aqueous strong base solution. In another embodiment of the present invention, the aqueous monobasic strong base solution may be an aqueous sodium hydroxide solution and/or an aqueous potassium hydroxide solution. In a further embodiment of the invention, the sodium hydroxide solution is present in an amount of 10 to 40% by weight, preferably 20 to 30% by weight, more preferably 25% by weight, of sodium hydroxide, based on the sodium hydroxide solution.
In one embodiment of the present invention, the alkalinity in step (d) is specifically: the pH range is as follows: 10 to 11.
In one embodiment of the present invention, the holding temperature in step (e) is: 0 to 5 ℃.
In one embodiment of the present invention, the neutralization of step (e) may be pH 7.
The novel crystal form II of brexpiprazole provided by the invention has good stability; the method for preparing the novel crystal form II of the brexpiprazole has the advantages of simple operation, good reproducibility and high purity of the obtained product, and is suitable for large-scale industrial production.
Drawings
In order to more clearly illustrate the embodiments of the present invention and the technical solutions of the prior art, the following briefly introduces the drawings required for the embodiments and the prior art, and obviously, the drawings in the following description are only some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 shows an X-ray powder diffraction (XRPD) pattern of new crystalline form II of brexpiprazole obtained according to example 1 of the present invention.
FIG. 2 is a Differential Scanning Calorimetry (DSC) profile of the novel crystalline form II of brexpiprazole obtained in example 1 according to the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail below with reference to the accompanying drawings and examples. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The following examples are intended to illustrate the invention in detail, but are not intended to limit the invention.
The analytical test conditions of the following examples of the invention are as follows:
1. x-ray powder diffraction data were measured using BRUKER D8 Advance, brueck, germany, voltage current: 40kV and 40 mA; an angle gauge: a vertical goniometer with a radius of 280 mm; slit: DS 2 °, SS 1/2 °, mask 15mm, RS 5.0 mm; a detector: a LYNXEYE detector; scanning mode: continuous scanning; scanning range: 3 to 40 ° (2 θ); counting time per step: 0.2 s; total time of scanning: 390 s.
2. DSC is measured by NETZSCH 200F3 Maia of Nachi company of Germany, and the test condition is 120 ml/min N 2 The temperature rise rate is 10 ℃/min.
Example 1
Weighing 0.5g of brexpiprazole at room temperature, adding the brexpiprazole into 50ml of 30% ethanol-water mixed solvent, adding 0.25g of acetic acid, and heating to 70-75 ℃ to completely dissolve the brexpiprazole to obtain clear liquid. Cooling the clear liquid to-10-5 ℃, dropwise adding 25% sodium hydroxide aqueous solution to the clear liquid to adjust the pH value to 11, and separating out solids. Stirring for 1 hour at the temperature of 0-5 ℃, then performing suction filtration, and washing a filter cake with water until the pH value of a washing liquid is 7. The filter cake is dried to obtain the new crystal form II of the lopiperazol with white color (purity: 98.7%, KF: 0.89%, EtOH <500ppm, HAc <400ppm, MS: 433).
1 H-NMR(DMSO-d 6 ，400M):1.57～1.64(m，2H)；1.73～1.82(m，2H)；2.39～2.43(t，2H)；2.58(m，4H)；3.03(m，4H)；4.01～4.04(t，2H)；6.25～6.28(d，1H)；6.76～6.78(m，2H)；6.84～6.86(d，1H)；7.22～7.26(t，1H)；7.36～7.37(d，1H)；7.51～7.53(d，1H)；7.57～7.59(d，1H)；7.65～7.67(d，1H)；7.76～7.78(d，1H)；11.55(s，1H))。
The new crystalline form II of brexpiprazole prepared in example 1 was subjected to X-ray powder diffraction, and the results are shown in FIG. 1. As can be seen from fig. 1, the novel crystalline form ii of ipiprazole prepared in example 1 has the following characteristic peaks, and the values of 2 θ angle and relative intensities are shown in table 2 below:
TABLE 2
| 2θ/(°) | Relative strength |
| 5.2 | 100.0 |
| 7.4 | 54.4 |
| 9.8 | 58.7 |
| 10.5 | 53.2 |
| 14.3 | 34.6 |
| 14.8 | 74.6 |
| 18.6 | 45.5 |
| 19.7 | 45.6 |
| 23.6 | 32.3 |
DSC detection is carried out on the new crystal form II of the brexpiprazole prepared in the example 1, and the result is shown in figure 2, and as can be seen from figure 2, the new crystal form II of the brexpiprazole has a crystal water endothermic peak at about 80-91 ℃, a solvent endothermic peak at 130-150 ℃, a crystal exothermic peak at 176-186 ℃ and a melting endothermic peak at 212-223 ℃.
Example 2
Weighing 5g of brexpiprazole at room temperature, adding the brexpiprazole into 500ml of 50% ethanol-water mixed solvent, adding 2.5g of acetic acid, and heating to 70-75 ℃ to completely dissolve the brexpiprazole to obtain clear liquid. And cooling the clarified liquid to-10-5 ℃, dropwise adding 25% sodium hydroxide aqueous solution to the clarified liquid to adjust the pH to 10, and separating out solids. Stirring for 2 hours at the temperature of 0-5 ℃, then performing suction filtration, and washing a filter cake with water until the pH value of a washing liquid is 7. Drying the filter cake to obtain the white-like new crystal form II of the brexpiprazole.
Example 3
Example 3 differs from example 1 in that: example 3 the ethanol water mixed solvent is 10% ethanol water mixed solvent.
Example 4
Example 4 differs from example 1 in that: the stirring time in example 4 was 0.5 hour, and the alkali solution used was 30% aqueous potassium hydroxide solution.
Example 5
Example 5 differs from example 1 in that: the organic acid of example 5 was formic acid, which was used in an amount of 0.17 g.
Example 6
Example 6 differs from example 1 in that: the organic acid of example 6 was propionic acid, used in an amount of 0.33 g.
Example 7
Example 7 differs from example 1 in that: the amount of acetic acid used in example 7 was 0.17 g.
Example 8
Example 8 differs from example 1 in that: the amount of acetic acid used in example 8 was 0.33 g.
It should be noted that the characterization results of examples 2 to 8 are consistent with example 1, confirming that the materials prepared in examples 2 to 8 are consistent with example 1. Therefore, the characterization results of embodiments 2 to 8 are not described herein again.
Stability and solubility test
Stability and solubility tests were performed on the new crystalline form ii of ipiprazole prepared by the method of example 1, the crystalline form of ipiprazole dihydrate prepared according to the description of example 1 in CN104254530a and the anhydrous crystalline form of ipiprazole prepared according to comparative example 1, and the amorphous ipiprazole prepared according to the method of example 1 in CN104844586A, and the test results are shown in tables 3 and 4. The test conditions were as follows:
stability test conditions
A10.00 g sample was weighed and tested at 25 ℃ and 60% ambient humidity.
Solubility test conditions
A sample (2.00 g) was weighed, 100.00mL of a solvent was added, and the mixture was stirred under heating to reflux. Keeping the temperature for 50-60 minutes in a reflux state, not completely dissolving the solid, slowly cooling (the cooling rate is 10 ℃/h) to 20 ℃, standing after the temperature is reduced and kept for 5-6 hours, and taking the supernatant to check the solubility.
The comparison of the stability results of the crystal form II, the crystal form II dihydrate, the crystal form Anhydrous and the amorphous form of Epipprazole is shown in Table 3.
TABLE 3
The solubility results of the crystal form II, the crystal form dihydrate, the crystal form anhydrous and the amorphous brexpiprazole are shown in Table 4.
TABLE 4
| Epipiprazole crystal form | Crystal form II | Crystal form | Anhydrous crystal form | Amorphous form |
| Solubility (Water) | 0.001％ | 0.001％ | 0.001％ | 0.001％ |
| Solubility (ethanol) | 0.192％ | 0.197％ | 0.200％ | 0.186％ |
As can be seen from the above tables 3 and 4, the novel crystalline form ii of ipiprazole prepared by the present invention has a far better stability than other crystalline forms, such as the dihydrate form of ipiprazole, the anhydrous form of ipiprazole and amorphous form of ipiprazole, while maintaining excellent solubility (e.g., water or ethanol as a solvent). The experimental results are unexpected in advance, and obviously, the novel crystal form II of the brexpiprazole prepared by the invention has more extensive application prospect due to more excellent stability and solubility.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. A crystal form II of brexpiprazole shown in a formula I, which is characterized in that an X-ray powder diffraction pattern of the crystal form II comprises characteristic peaks (+ -0.2 degree) shown in the following 2 theta angles:
5.2°，7.4°，9.8°，10.5°，14.3°，14.8°，18.6°，19.7°，23.6°；
2. the crystalline form II of brexpiprazole according to claim 1, wherein the differential scanning calorimetry analysis of the crystalline form II shows an endothermic peak with water of crystallization at 80-91 ℃, an endothermic peak with solvent at 130-150 ℃, an exothermic peak with crystallization at 176-186 ℃, and/or an endothermic peak with melting at 212-223 ℃.
3. A process for preparing the crystalline form II of brexpiprazole of claim 1 or 2, comprising the steps of:
(a) mixing the brexpiprazole and the mixed solvent of ethanol and water at room temperature to prepare suspension;
(b) adding an organic acid into the suspension obtained in the step (a), and heating until the organic acid is completely dissolved to obtain a clear solution;
(c) cooling the clarified liquid of step (b);
(d) adjusting the pH of the clear liquid cooled in the step (c) to be alkaline by using alkaline liquid, and separating out solids;
(e) keeping the temperature of the solid precipitated in the step (d) and continuously stirring for 0.5-2 hours, preferably 1 hour, filtering, washing the filter cake with water until the washing liquid is neutral, and drying to obtain the crystal form II of the ipiprazole.
4. The method according to claim 3, wherein the volume percentage of ethanol in the ethanol-water mixed solvent used in step (a) is 10-50%, preferably 20-40%, and more preferably 30%.
5. The process as claimed in claim 3 or 4, wherein the organic acid used in step (b) is selected from formic acid, acetic acid and/or propionic acid.
6. The method according to any one of claims 3 to 5, wherein the mass ratio of the organic acid to the brexpiprazole in the step (b) is: 1 (1.5-3), preferably 1: 2.
7. The method according to any one of claims 3 to 6, wherein the cooling temperature of the clarified liquid in the step (c) is: -10 to 5 ℃.
8. The method of any one of claims 3 to 7, wherein the lye of step (d) is: the sodium hydroxide aqueous solution and/or the potassium hydroxide aqueous solution are preferably sodium hydroxide aqueous solutions with the mass fraction of sodium hydroxide of 10-40%, more preferably 20-30%, and most preferably 25%.
9. The process according to any one of claims 3 to 8, wherein the alkalinity of step (d) is in particular: the pH range is as follows: 10 to 11.
10. The method of any one of claims 3 to 9, wherein the incubation temperature of step (e) is: 0 to 5 ℃.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610891725.3A CN107936005A (en) | 2016-10-13 | 2016-10-13 | One kind is according to piperazine azoles novel crystal forms II and preparation method thereof |
| CN2016108917253 | 2016-10-13 | ||
| CN201780047454.6A CN109863149A (en) | 2016-10-13 | 2017-10-09 | One kind is according to piperazine azoles novel crystal forms and preparation method thereof |
| PCT/CN2017/105367 WO2018068690A1 (en) | 2016-10-13 | 2017-10-09 | New crystal form of brexpiprazole and preparation method thereof |
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| CN202210780490.6A Pending CN114957230A (en) | 2016-10-13 | 2017-10-09 | Novel crystal form of brexpiprazole and preparation method thereof |
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- 2016-10-13 CN CN201610891725.3A patent/CN107936005A/en active Pending
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- 2017-10-09 CN CN202210780490.6A patent/CN114957230A/en active Pending
- 2017-10-09 WO PCT/CN2017/105367 patent/WO2018068690A1/en active Application Filing
- 2017-10-09 CN CN201780047454.6A patent/CN109863149A/en active Pending
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| CN109863149A (en) | 2019-06-07 |
| CN107936005A (en) | 2018-04-20 |
| WO2018068690A1 (en) | 2018-04-19 |
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