CN105315203A - V-type elvitegravir crystal and preparation method thereof - Google Patents
V-type elvitegravir crystal and preparation method thereof Download PDFInfo
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- CN105315203A CN105315203A CN201410250880.8A CN201410250880A CN105315203A CN 105315203 A CN105315203 A CN 105315203A CN 201410250880 A CN201410250880 A CN 201410250880A CN 105315203 A CN105315203 A CN 105315203A
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Abstract
The invention discloses a V-type elvitegravir crystal and a preparation method thereof. An X-ray powder diffraction spectrogram of the V-type elvitegravir crystal has main characteristic peaks at the 2[theta] of 9.65 degrees, 10.22 degrees, 11.92 degrees, 17.12 degrees, 17.42 degrees, 19.31 degrees, 23.59 degrees, 23.96 degrees and 26.65 degrees. The preparation method includes the steps of adding an elvitegravir raw material to a proper amount of methanol, increasing the temperature until the solution is clear, reducing the temperature to not more than 0 DEG C, stirring the solution to separate out the crystal, collecting the crystal and drying the crystal. The V-type elvitegravir crystal is high in purity, has better solubility and stability when compared with the crystal forms in the prior art, and is more beneficial to preparation production. The preparation method is simple, has good repeatability, is low in cost and is easy to achieve large-scale production.
Description
Technical field
The present invention relates to dust for a kind of new crystal drawing Wei and preparation method thereof, specifically, relating to a kind of V-type dust for drawing Wei Jingti and preparation method thereof, belonging to field of pharmaceutical chemistry technology.
Background technology
Dust is by Gilid Science Co. (GileadSciences for drawing Wei (elvitegravir), Inc.) the new class integrase inhibitor developed, it is mainly used for stoping HIV virus by chromosomal integration to the medicine in host cell DNA, now be in pre-registration stage, its chemical structural formula is as follows:
At present, dust is synthesized several as follows for drawing the method for Wei to mainly contain:
1., following route disclosed in international application WO2004046115:
2., following route is disclosed in U.S. Patent application US2009036684:
About dust for the crystal formation drawing Wei, report has at present:
Dust is disclosed for crystal formation I, II and III of drawing Wei in international patent application WO2005113508A, it is reported, described crystallized form has excellent physics and chemistry stability compared with other physical form of this compound, especially crystal form II is relative to crystal formation I and III, has the physicochemical property being more suitable for preparation and preparing.
Disclose unformed and II type, type III that dust replaces La Wei and sodium salt thereof in international patent application WO2010137032A, the acquisition of described crystal formation just changes recrystallisation solvent gained on the basis of international application WO2005113508A.
Summary of the invention
The present invention is to provide dust for a kind of new crystal (referred to as V-type) drawing Wei and preparation method thereof.
V-type dust of the present invention has main characteristic peak for drawing the X-ray powder diffractogram of Wei Jingti at following 2 θ: 9.65 °, 10.22 °, 11.92 °, 17.12 °, 17.42 °, 19.31 °, 23.59 °, 23.96 °, 26.65 ° places, and test error is ± 0.2 °.
Furtherly, the X-ray powder diffractogram of described crystal has characteristic peak at following 2 θ: 9.65 °, 10.22 °, 10.76 °, 11.92 °, 14.80 °, 16.33 °, 17.12 °, 17.42 °, 19.31 °, 20.57 °, 23.59 °, 23.96 °, 25.01 °, 26.31 °, 26.65 ° places, and test error is ± 0.2 °.
Prepare above-mentioned V-type dust for a method of drawing Wei Jingti, comprise the steps:
A) dust being added in proper amount of methanol for drawing Wei raw material, being warming up to clearly molten;
B) be cooled to≤0 DEG C, stir and make crystallization;
C) crystal is collected, dry.
The above-mentioned V-type dust of another kind of preparation, for the method for drawing Wei Jingti, comprises the steps:
1) dust being added in proper amount of methanol for drawing Wei raw material, being warming up to clearly molten;
2) drip anti-solvent, the anti-solvent volume of dropping and the volume ratio of methyl alcohol are 1:1; Described anti-solvent is selected from least one in normal hexane, normal heptane, ether, isopropyl ether, methyl tertiary butyl ether;
3) drip and finish, to be cooled to≤0 DEG C, to stir and make crystallization;
4) crystal is collected, dry.
Another prepares above-mentioned V-type dust for the method for drawing Wei Jingti, comprises the steps:
I) dust being added in proper amount of methanol for drawing Wei raw material, being warming up to clearly molten;
Ii) 15 ~ 30% of original volume is evaporated to;
Iii) be cooled to≤0 DEG C, stir and make crystallization;
Iv) crystal is collected, dry.
Above-mentioned dust for draw Wei raw material can for amorphous dust for any one dust in La Wei or known crystal formation (as: I type, II type, III type, IV type) for drawing Wei Jingti, also can be any mixture in them.
Furtherly, 1g dust is recommended to add 1 ~ 10mL methyl alcohol for drawing Wei raw material.
Furtherly, above-mentioned methyl alcohol is preferably anhydrous methanol.
Furtherly, dust is recommended as reflux temperature for the molten clear temperature of drawing Wei raw material in methyl alcohol.
Furtherly, above-mentioned drying is vacuum-drying, warm air drying or fluidised bed drying.
Compared with prior art, the present invention has following beneficial effect:
V-type dust provided by the invention, for drawing Wei crystal purity high, has more excellent solubleness and excellent stability relative to existing crystal formation, is more conducive to the preparation of preparation; Especially, preparation method of the present invention is simple, favorable reproducibility, cost are low, be easy to large-scale production.
Accompanying drawing explanation
Fig. 1 is that the V-type dust that obtains of the embodiment of the present invention 1 is for the X-ray powder diffractogram drawing Wei Jingti.
Fig. 2 is that the V-type dust that obtains of the embodiment of the present invention 1 is for the DSC-TGA spectrogram drawing Wei Jingti.
Specific implementation method
Below in conjunction with embodiment, the present invention is described in further detail and completely.
Unformed dust used in embodiment is obtain with reference to the preparation of method described in WO2010137032A2 for drawing Wei.
The test condition of carrying out X-ray powder diffraction analysis is as follows: Cu-K α 1 ray, 40kV tube voltage, 40mA tube current, and sweep velocity is 0.1 second/step, and walking wide is 0.02 °/sec, and sweep limit is 2.0000 ° ~ 50.0000 °; Test error is ± 0.2 °.
Carry out the test condition that differential thermal-thermogravimetric (DSC-TGA) analyzes as follows: Range of measuring temp is 30 ~ 300 DEG C, and temperature rise rate is 10 DEG C/min.
The condition of carrying out the analysis of HPLC purity test is as follows:
Embodiment 1
Add in 20mL anhydrous methanol by 10gI type dust for drawing Wei Jingti, it is clearly molten that stirring is warming up to backflow; Be cooled to 0 DEG C, stir and make crystallization 2 ~ 6 hours; Collect crystal, dry, obtain V-type dust for drawing Wei Jingti 8g; HPLC purity is 99.76%.
Fig. 1 is for obtained V-type dust is for the X-ray powder diffractogram drawing Wei Jingti, as seen from Figure 1: the X-ray powder diffractogram of described crystal is at following 2 θ: 9.65 °, 10.22 °, 11.92 °, 17.12 °, 17.42 °, 19.31 °, 23.59 °, 23.96 °, 26.65 ° of places have main characteristic peak, at following 2 θ: 9.65 °, 10.22 °, 10.76 °, 11.92 °, 14.80 °, 16.33 °, 17.12 °, 17.42 °, 19.31 °, 20.57 °, 23.59 °, 23.96 °, 25.01 °, 26.31 °, 26.65 ° of places have characteristic peak.
Fig. 2 for obtained V-type dust is for the DSC-TGA spectrogram drawing Wei Jingti, as seen from Figure 2: described crystal rate of weight loss in the thermogravimetric analysis within the scope of room temperature to 200 DEG C is 6.75 ± 0.25%.
Embodiment 2
Add in 20mL anhydrous methanol by amorphous for 10g dust for drawing Wei, it is clearly molten that stirring is warming up to backflow; Be cooled to 0 DEG C, stir and make crystallization 2 ~ 6 hours; Collect crystal, dry, obtain V-type dust for drawing Wei Jingti 8.1g; HPLC purity is 99.78%.
The V-type dust that the present embodiment obtains also has the DSC-TGA chromatogram characteristic shown in the X-ray powder diffractogram characteristic sum Fig. 2 shown in Fig. 1 for drawing Wei Jingti.
Embodiment 3
Add in 100mL anhydrous methanol by 10gII type dust for drawing Wei Jingti, it is clearly molten that stirring is warming up to backflow; About 20mL is evaporated at 50 DEG C; Be cooled to 0 DEG C, stir and make crystallization 2 ~ 6 hours; Collect crystal, dry, obtain V-type dust for drawing Wei Jingti 9.0g; HPLC purity is 99.79%.
The V-type dust that the present embodiment obtains also has the DSC-TGA chromatogram characteristic shown in the X-ray powder diffractogram characteristic sum Fig. 2 shown in Fig. 1 for drawing Wei Jingti.
Embodiment 4
Add in 20mL anhydrous methanol by 10gIV type dust for drawing Wei Jingti, it is clearly molten that stirring is warming up to backflow; Be cooled to 50 DEG C, drip 20mL normal heptane; Be cooled to 0 DEG C, stir and make crystallization 2 ~ 6 hours; Collect crystal, dry, obtain V-type dust for drawing Wei Jingti 9.2g; HPLC purity is 99.77%.
The V-type dust that the present embodiment obtains also has the DSC-TGA chromatogram characteristic shown in the X-ray powder diffractogram characteristic sum Fig. 2 shown in Fig. 1 for drawing Wei Jingti.
Embodiment 5
Add in 20mL anhydrous methanol by 10gI type dust for drawing Wei Jingti, it is clearly molten that stirring is warming up to backflow; Be cooled to 50 DEG C, drip 20mL methyl tertiary butyl ether; Be cooled to 0 DEG C, stir and make crystallization 2 ~ 6 hours; Collect crystal, dry, obtain V-type dust for drawing Wei Jingti 9.1g; HPLC purity is 99.79%.
The V-type dust that the present embodiment obtains also has the DSC-TGA chromatogram characteristic shown in the X-ray powder diffractogram characteristic sum Fig. 2 shown in Fig. 1 for drawing Wei Jingti.
Solubleness is tested
Because solubleness characterizes one of crystal stability index, and can be used as the reference index absorbed by living body biological.Therefore this test purpose compares gained V-type crystal and the solubleness of existing known crystal in various test soln.Testing method is as follows:
Will often kind of sample (V-type crystal, IV N-type waferN and II N-type waferN, all about 0.5 ~ 5g) be placed in 10mL centrifuge tube and after (XW-80A) vibrate about 0.5 hour with eddy mixer, filter the tetrafluoroethylene disc type strainer of 0.22 micron by mixture standing sedimentation and by supernatant together with following test soln (5mL).Content measurement is carried out by high performance liquid chromatography (HPLC).Test result is as shown in Table 1 below.
Table 1 solubleness test result
From table 1 result: V-type crystal provided by the present invention has better solubleness relative to existing crystal.
Stability test
Test and comparison is carried out according to the stability of condition of storage shown in table 2 to V-type crystal, IV N-type waferN and II N-type waferN.DCO the results are shown in Table shown in 2.
Table 2 stability test condition and result
To sum up experiment is visible: V-type dust provided by the invention, for drawing Wei crystal purity high, has more excellent solubleness and excellent stability relative to existing crystal formation, is more conducive to the preparation of preparation.
Finally be necessary described hereinly be, above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted the present invention, those of ordinary skill in the art is to be understood that, can modify to the technical scheme of invention or equivalent replacement, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed in right of the present invention.
Claims (10)
1. a V-type dust is for drawing Wei Jingti, it is characterized in that, the X-ray powder diffractogram of described crystal has main characteristic peak at following 2 θ: 9.65 °, 10.22 °, 11.92 °, 17.12 °, 17.42 °, 19.31 °, 23.59 °, 23.96 °, 26.65 ° places, and test error is ± 0.2 °.
2. V-type dust as claimed in claim 1 is for drawing Wei Jingti, it is characterized in that, the X-ray powder diffractogram of described crystal has characteristic peak at following 2 θ: 9.65 °, 10.22 °, 10.76 °, 11.92 °, 14.80 °, 16.33 °, 17.12 °, 17.42 °, 19.31 °, 20.57 °, 23.59 °, 23.96 °, 25.01 °, 26.31 °, 26.65 ° places, and test error is ± 0.2 °.
3. prepare V-type dust described in claim 1 or 2 for a method of drawing Wei Jingti, it is characterized in that, comprise the steps:
A) dust being added in proper amount of methanol for drawing Wei raw material, being warming up to clearly molten;
B) be cooled to≤0 DEG C, stir and make crystallization;
C) crystal is collected, dry.
4. prepare V-type dust described in claim 1 or 2 for a method of drawing Wei Jingti, it is characterized in that, comprise the steps:
1) dust being added in proper amount of methanol for drawing Wei raw material, being warming up to clearly molten;
2) drip anti-solvent, the anti-solvent volume of dropping and the volume ratio of methyl alcohol are 1:1; Described anti-solvent is selected from least one in normal hexane, normal heptane, ether, isopropyl ether, methyl tertiary butyl ether;
3) drip and finish, to be cooled to≤0 DEG C, to stir and make crystallization;
4) crystal is collected, dry.
5. prepare V-type dust described in claim 1 or 2 for a method of drawing Wei Jingti, it is characterized in that, comprise the steps:
I) dust being added in proper amount of methanol for drawing Wei raw material, being warming up to clearly molten;
Ii) 15 ~ 30% of original volume is evaporated to;
Iii) be cooled to≤0 DEG C, stir and make crystallization;
Iv) crystal is collected, dry.
6. the method as described in claim 3 or 4 or 5, is characterized in that: described dust is for drawing Wei raw material to be amorphous dust for any one dust in La Wei or known crystal formation for drawing Wei Jingti or any mixture between it.
7. the method as described in claim 3 or 4 or 5, is characterized in that: 1g dust adds 1 ~ 10mL methyl alcohol for drawing Wei raw material.
8. the method as described in claim 3 or 4 or 5, is characterized in that: described methyl alcohol is anhydrous methanol.
9. the method as described in claim 3 or 4 or 5, is characterized in that: dust is reflux temperature for the molten clear temperature of drawing Wei raw material in methyl alcohol.
10. the method as described in claim 3 or 4 or 5, is characterized in that: described drying is vacuum-drying, warm air drying or fluidised bed drying.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410250880.8A CN105315203A (en) | 2014-06-06 | 2014-06-06 | V-type elvitegravir crystal and preparation method thereof |
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| CN201410250880.8A CN105315203A (en) | 2014-06-06 | 2014-06-06 | V-type elvitegravir crystal and preparation method thereof |
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Citations (8)
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| CN1692101A (en) * | 2002-11-20 | 2005-11-02 | 日本烟草产业株式会社 | 4-oxoquinoline compounds and utilization thereof as HIV integrase inhibitors |
| CN1956961A (en) * | 2004-05-20 | 2007-05-02 | 日本烟草产业株式会社 | Stable crystal form of 4-oxoquinoline compound |
| CN101437801A (en) * | 2006-03-06 | 2009-05-20 | 日本烟草产业株式会社 | Process for production of 4-oxoquinoline compound |
| CN101437785A (en) * | 2006-03-06 | 2009-05-20 | 日本烟草产业株式会社 | Method for producing 4-oxoquinoline compound |
| WO2011004389A2 (en) * | 2009-06-18 | 2011-01-13 | Matrix Laboratories Ltd | An improved process for the preparation of elvitegravir |
| WO2014056464A1 (en) * | 2012-10-12 | 2014-04-17 | Zentiva, K.S. | A new production method and new intermediates of synthesis of elvitegravir |
| WO2014056465A1 (en) * | 2012-10-12 | 2014-04-17 | Zentiva, K.S. | An improved production method and new intermediates of synthesis of elvitegravir |
| CN105377818A (en) * | 2013-07-11 | 2016-03-02 | 赞蒂瓦有限合伙公司 | A new process for the preparation of elvitegravir |
-
2014
- 2014-06-06 CN CN201410250880.8A patent/CN105315203A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1692101A (en) * | 2002-11-20 | 2005-11-02 | 日本烟草产业株式会社 | 4-oxoquinoline compounds and utilization thereof as HIV integrase inhibitors |
| CN1956961A (en) * | 2004-05-20 | 2007-05-02 | 日本烟草产业株式会社 | Stable crystal form of 4-oxoquinoline compound |
| CN101437801A (en) * | 2006-03-06 | 2009-05-20 | 日本烟草产业株式会社 | Process for production of 4-oxoquinoline compound |
| CN101437785A (en) * | 2006-03-06 | 2009-05-20 | 日本烟草产业株式会社 | Method for producing 4-oxoquinoline compound |
| WO2011004389A2 (en) * | 2009-06-18 | 2011-01-13 | Matrix Laboratories Ltd | An improved process for the preparation of elvitegravir |
| WO2014056464A1 (en) * | 2012-10-12 | 2014-04-17 | Zentiva, K.S. | A new production method and new intermediates of synthesis of elvitegravir |
| WO2014056465A1 (en) * | 2012-10-12 | 2014-04-17 | Zentiva, K.S. | An improved production method and new intermediates of synthesis of elvitegravir |
| CN105377818A (en) * | 2013-07-11 | 2016-03-02 | 赞蒂瓦有限合伙公司 | A new process for the preparation of elvitegravir |
Non-Patent Citations (1)
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| 马帅等: "埃替格韦的合成", 《中国医药工业杂志》 * |
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Application publication date: 20160210 |