CN102850339B - New neurokinin (NK-1) receptor antagonist crystal form and preparation method thereof - Google Patents
New neurokinin (NK-1) receptor antagonist crystal form and preparation method thereof Download PDFInfo
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Abstract
The invention provides a new neurokinin (NK-1) receptor antagonist aprepitant crystal form V. The new aprepitant crystal form V powder has characteristic X diffraction ray peaks at the wavelengths of 12.08 degrees +/-0.2, 15.31 degrees +/-0.2, 17.61 degrees +/-0.2, 20.62 degrees +/-0.2 and 24.76 degrees +/-0.2 2 theta in an X-ray diffraction pattern. The invention also provides a preparation method of the aprepitant new crystal form V.
Description
Technical field
The invention belongs to field of medicine and chemical technology, relate in particular to a kind of neurokinin (NK-1) receptor antagonist aprepitant crystal formation preparation method.
Background technology
Aprepitant (aprepitant), chemistry 5-[2 (R)-[1 (R)-[3 by name, 5-bis-(trifluoromethyl) phenyl] oxyethyl group]-3 (S)-(4-fluorophenyl) morpholine-4-ylmethyl]-3,4-dihydro-2H-1,2,4-triazole-3-ketone, structure is as shown below:
Aprepitant is neurokinine-1 (NK-1) receptor antagonist of Merck & Co company of U.S. research and development, and 2003 through U.S. FDA approval listing, trade(brand)name Emend.Clinical its tablet of using of this product, be used for preventing highly causing acute due to telling property antineoplastic chemotherapy medicine (comprising High-dose Cisplatin Chemotherapy treatment plan) and Delayed onset is felt sick, vomiting, can see through hemato encephalic barrier, be combined with brain NK-1 receptor-selective and bring into play antiemetic effect, but 5-HT3, Dopamine HCL and glucocorticoid receptor are not had to avidity substantially.
Application number is 98806703.X, Granted publication number is that the Chinese patent literature of CN1106390C discloses aprepitant crystalline form I and crystal form II, and crystalline form I x-ray diffractogram of powder shows to have located crucial reflection at 12.0,15.3,16.6,17.0,17.6,19.4,20.0,21.9,23.6,23.8 and 24.8 ° (2 θ).Crystal form II x-ray diffractogram of powder shows to have located crucial reflection at 12.6,16.7,17.1,17.2,18.0,20.1,20.6,21.1,22.8,23.9 and 24.8 ° (2 θ).
US Patent No. 20110015191 discloses aprepitant crystalline form III, crystalline form III X-ray diffractogram shows at 6.8 ± 0.2 °, 7.4 ± 0.2 °, and 11.9 ± 0.2 °, 12.6 ± 0.2 °, 17.1 ± 0.2 °, 18.3 ± 0.2 °, 18.7 ± 0.2 °, 19.3 ± 0.2 °, 19.7 ± 0.2 °, 20.2 ± 0.2 °, 20.6 ± 0.2 ° and 21.0 ± 0.2 ° (2 θ) have located absorption peak.
Patent WO2010092591 discloses aprepitant crystalline form IV, and crystalline form IV X-ray diffractogram shows 12.41,20.14, and 23.69,24.03,24.89,25.43,25.82,27.70,29.39 ° (2 θ) located absorption peak.
Summary of the invention
The invention provides a kind of preparation method of aprepitant crystal formation.
Aprepitant crystal formation provided by the present invention, adopt Dutch PANalytical X ' the Pert PRO 40KV 40mA of company model x-ray powder diffraction instrument to analyze, in its x-ray diffractogram of powder, there is distinctive X diffraction ray peak at 12.08 ° ± 0.2,15.31 ° ± 0.2,17.61 ° ± 0.2,20.62 ° ± 0.2 and 24.76 ° ± 0.2 2 θ.
Above-mentioned aprepitant crystal formation, also has X-ray diffraction peak at 8.17 ° ± 0.2,13.40 ° ± 0.2,16.61 ° ± 0.2,16.99 ° ± 0.2,17.17 ° ± 0.2,18.43 ° ± 0.2,18.69 ° ± 0.2,19.44 ° ± 0.2,20.01 ° ± 0.2,21.93 ° ± 0.2,22.92 ° ± 0.2,23.57 ° ± 0.2,23.85 ° ± 0.2,25.41 ° ± 0.2,25.69 ° ± 0.2 and 29.25 ° ± 0.2 2 θ in its X-ray diffractogram.As shown in Figure 1, X-ray powder diffraction data are as shown in table 1 for the complete X-ray powder diffraction of aprepitant crystal formation provided by the present invention.
Table 1 aprepitant crystal form X-ray powder diffraction data
Aprepitant crystal formation provided by the present invention, adopts DSC Q10P V9.8 Build 296 model differential thermal analyzers, heats up with the speed of 10 DEG C/min, and it absorbs heat deflection at 254.98 DEG C.Its differential scanning calorimetric analysis (DSC) collection of illustrative plates as shown in Figure 2.
Adopt PE Spectrum RX I type infrared spectrometer, the aprepitant crystal formation providing is provided by KBr pressed disc method, as shown in Figure 3, it is at 3449.86cm for its infrared absorption pattern
-1, 2978.16cm
-1, 2944.08cm
-1, 1704.84cm
-1, 1510.15cm
-1, 1280.18cm
-1, 1132.54cm
-1, 1060.43cm
-1and 835.64cm
-1there is obvious characteristic peak.
The present invention also discloses the preparation method of above-mentioned aprepitant crystal formation, comprises the steps:
(1) aprepitant is dissolved in the mixing solutions of tetrahydrofuran (THF) and water, stirring heating, is cooled to room temperature;
(2) separate aprepitant crystal formation.
In above-mentioned preparation method's step (1), Heating temperature is 30-80 DEG C, and be 2 hours heat-up time.
Described in above-mentioned preparation method's step (1), the volume ratio of tetrahydrofuran (THF) and water is 1:1.5-1:8.
Described in above-mentioned preparation method's step (1), the cumulative volume of the mixing solutions of tetrahydrofuran (THF) and water and aprepitant ratio are 10mL:1g-60mL:1g.
In above-mentioned preparation method's step (2), separate aprepitant crystal formation and adopt filtration to drain, 45 DEG C of vacuum-dryings obtain aprepitant crystal formation for 8 hours.
In aforesaid method, aprepitant can prepare by the following method:
By starting raw material (2R, 3S)-2-[(1R)-1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group]-3-(4-fluorophenyl)-morpholine hydrochloride and 5-chloromethyl-2,4-dihydro [1,2,4] triazole-3-one or 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate is in organic solvent, under salt of wormwood exists, under room temperature, react 4-8 hour, reaction solution is added drop-wise in water, separating out solid is Aprepitant, the preferred acetonitrile of organic solvent or DMSO.
The present invention adopts water and tetrahydrofuran (THF) mixed solvent, and production cost is lower, simple to operate, and yield is high, can reach more than 90%.
Brief description of the drawings
Fig. 1 is aprepitant crystal formation x-ray diffractogram of powder spectrum of the present invention.
Fig. 2 is aprepitant crystal formation DSC collection of illustrative plates of the present invention.
Fig. 3 is aprepitant crystal formation infrared spectra collection of illustrative plates of the present invention.
Fig. 4 be aprepitant crystal formation of the present invention at 40 DEG C, under the humidity of RH70%, place the X ray diffracting data of 30 days.
Embodiment
The term that used in the present invention, except as otherwise noted, generally has the implication that those of ordinary skill in the art understand conventionally.
Below in conjunction with specific embodiment comparable data, the present invention is described in further detail.Should be understood that these embodiment just in order to demonstrate the invention, but not limit the scope of the invention by any way.
In following examples, various processes and the method do not described in detail are ordinary methods as known in the art.
Embodiment 1
Starting raw material (2R, 3S)-2-[(1R)-1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group]-3-(4-fluorophenyl)-morpholine hydrochloride (5g 10.56mmoL), acetonitrile 50mL adds, 5-chloromethyl-2,4-dihydro [1,2,4] triazole-3-one (2.8g 21.12mmoL), salt of wormwood (0.97g 6.33moL), under room temperature, react 8 hours, reaction solution is added drop-wise in water, and separating out solid is Aprepitant.
Aprepitant 1.65g obtained above is dissolved in the mixing solutions of tetrahydrofuran (THF) and water (tetrahydrofuran (THF)/water 6.6mL/9.9mL), stir, be warmed up to 60 DEG C, react 2 hours, be down to stirring at room temperature, after 30min, filter and drain, 45 DEG C of vacuum-drying 8 hours, obtain aprepitant crystal formation, yield: 90%.
Embodiment 2
Starting raw material (2R, 3S)-2-[(1R)-1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group]-3-(4-fluorophenyl)-morpholine hydrochloride (6g 12.67mmoL), DMSO 50mL adds, salt of wormwood (3.49g 25.32moL), 5-chloromethyl-2, under 4-dihydro [1,2,4] triazole-3-one (2.19g 16.47mmoL) room temperature, react 4 hours, reaction solution is added drop-wise in water, and separating out solid is Aprepitant.
Aprepitant 1g obtained above is dissolved in the mixing solutions of tetrahydrofuran (THF) and water (tetrahydrofuran (THF)/water 6.6mL/13.4mL), stir, be warmed up to 60 DEG C, react 2 hours, be down to stirring at room temperature, after 30min, filter and drain, 45 DEG C of vacuum-drying 8 hours, obtain aprepitant crystal formation, yield: 90%.
Embodiment 3
Starting raw material (2R, 3S)-2-[(1R)-1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group]-3-(4-fluorophenyl)-morpholine hydrochloride (5g 10.56mmoL), acetonitrile 50mL adds, 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate (2.8g 21.12mmoL), salt of wormwood (0.97g 6.33moL), under room temperature, react 6 hours, be heated to 70 DEG C of reactions, be down to stirring at room temperature, reaction solution is added drop-wise in water, and separating out solid is Aprepitant.
Aprepitant 3.3g obtained above is dissolved in the mixing solutions of tetrahydrofuran (THF) and water (tetrahydrofuran (THF)/water 26.6mL/106.4mL), stir, be warmed up to 80 DEG C, react 2 hours, be down to stirring at room temperature, after 30min, filter and drain, 45 DEG C of vacuum-drying 8 hours, obtain aprepitant crystal formation, yield: 91%.
Embodiment 4:
Starting raw material (2R, 3S)-2-[(1R)-1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group]-3-(4-fluorophenyl)-morpholine hydrochloride (6g 12.67mmoL), DMSO 50mL adds, salt of wormwood (3.49g 25.32moL), under 2-(the chloro-1-ethylidene of 2-) hydrazides methyl-formiate (2.19g 16.47mmoL) room temperature, react 7 hours, be heated to 105 DEG C of reactions, be down to stirring at room temperature, reaction solution is added drop-wise in water, and separating out solid is Aprepitant.
Aprepitant 4g obtained above is dissolved in the mixing solutions of tetrahydrofuran (THF) and water (tetrahydrofuran (THF)/water 26.6mL/213.4mL), stir, be warmed up to 40 DEG C, react 2 hours, be down to stirring at room temperature, after 30min, filter and drain, 45 DEG C of vacuum-drying 8 hours, obtain aprepitant crystal formation, yield: 90.5%.
Embodiment 5
The aprepitant crystal formation that the inventive method is prepared, at 40 DEG C, places under the humidity of RH70% 30 days, analyzes with x-ray powder diffraction instrument, and result shows that X-ray powder diffraction data did not change (accompanying drawing 4) compared with 0 day.The aprepitant stable crystal form that adopts technical solution of the present invention to make is described.
Claims (5)
1. a preparation method for aprepitant crystal formation, is characterized in that comprising the steps:
(1) aprepitant is dissolved in the mixing solutions of tetrahydrofuran (THF) and water, stirring heating, is cooled to room temperature;
(2) separate aprepitant crystal formation, in described aprepitant crystal formation x-ray diffractogram of powder 8.17 ° ± 0.2, 12.08 ° ± 0.2, 13.40 ° ± 0.2, 15.31 ° ± 0.2, 16.61 ° ± 0.2, 16.99 ° ± 0.2, 17.17 ° ± 0.2, 17.61 ° ± 0.2, 18.43 ° ± 0.2, 18.71 ° ± 0.2, 19.44 ° ± 0.2, 20.01 ° ± 0.2, 20.63 ° ± 0.2, 21.94 ° ± 0.2, 23.57 ° ± 0.2, 23.87 ° ± 0.2, 24.77 ° ± 0.2, 25.41 ° ± 0.2, 25.68 ° ± 0.2, 29.25 ° ± 0.2 2 θ have distinctive X diffraction ray peak.
2. the preparation method of aprepitant crystal formation as claimed in claim 1, is characterized in that described step (1) Heating temperature is 30-80 DEG C, and be 2 hours heat-up time.
3. the preparation method of aprepitant crystal formation as claimed in claim 1, is characterized in that described step (2) separates aprepitant crystal formation and adopts filtration to drain, and 45 DEG C of vacuum-dryings obtain aprepitant crystal formation for 8 hours.
4. the preparation method of the aprepitant crystal formation as described in claim 1-2, the volume ratio that it is characterized in that the described tetrahydrofuran (THF) of described step (1) and water is 1:1.5-1:8.
5. the preparation method of the aprepitant crystal formation as described in claim 1-2, is characterized in that cumulative volume and the aprepitant ratio of the mixing solutions of the described tetrahydrofuran (THF) of described step (1) and water is 10mL:1g-60mL:1g.
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| CN103788082A (en) * | 2012-10-30 | 2014-05-14 | 天津卡普希科技有限公司 | Preparation method of aprepitant III crystal form substance |
| CN111943904B (en) * | 2019-05-15 | 2023-05-05 | 南京正大天晴制药有限公司 | Refining method of key intermediate of neurokinin 1 receptor antagonist |
| CN110776502B (en) * | 2019-12-06 | 2021-04-20 | 广州白云山汉方现代药业有限公司 | Refining method of aprepitant |
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|---|---|---|---|---|
| CN1106390C (en) * | 1997-07-02 | 2003-04-23 | 麦克公司 | Polymorphic form of tachykinin receptor antagonist 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl) phenyl) ethoxy)-3-(S)-(4-fluoro) phenyl-4-(3-5(oxo-1H,4H-1,2,4-triazolo methylmorpholine |
| WO2007044829A2 (en) * | 2005-10-06 | 2007-04-19 | Dr. Reddy's Laboratories Ltd. | Preparation of aprepitant |
| WO2007088483A1 (en) * | 2006-02-03 | 2007-08-09 | Glenmark Pahrmaceuticals Limited | Amorphous and crystalline forms of aprepitant and processes for the preparation thereof |
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| WO2008044102A1 (en) * | 2006-10-13 | 2008-04-17 | Glenmark Pharmaceuticals Limited | Polymorph form of aprepitant and process for the preparation thereof |
| WO2008104512A2 (en) * | 2007-02-27 | 2008-09-04 | Sandoz Ag | Novel polymorphs of aprepitant and processes for preparation |
| WO2010140132A1 (en) * | 2009-06-02 | 2010-12-09 | Ranbaxy Laboratories Limited | Process for the preparation of crystalline aprepitant having form i content |
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| WO2007044829A2 (en) * | 2005-10-06 | 2007-04-19 | Dr. Reddy's Laboratories Ltd. | Preparation of aprepitant |
| WO2007088483A1 (en) * | 2006-02-03 | 2007-08-09 | Glenmark Pahrmaceuticals Limited | Amorphous and crystalline forms of aprepitant and processes for the preparation thereof |
| WO2007112457A2 (en) * | 2006-03-29 | 2007-10-04 | Dr. Reddy's Labortories, Ltd. | Aprepitant polymorph mixtures |
| WO2008044102A1 (en) * | 2006-10-13 | 2008-04-17 | Glenmark Pharmaceuticals Limited | Polymorph form of aprepitant and process for the preparation thereof |
| WO2008104512A2 (en) * | 2007-02-27 | 2008-09-04 | Sandoz Ag | Novel polymorphs of aprepitant and processes for preparation |
| WO2010140132A1 (en) * | 2009-06-02 | 2010-12-09 | Ranbaxy Laboratories Limited | Process for the preparation of crystalline aprepitant having form i content |
| CN102525879A (en) * | 2010-12-31 | 2012-07-04 | 江苏正大天晴药业股份有限公司 | Method for preparing aprepitant solid dispersing composition |
Non-Patent Citations (3)
| Title |
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| Doris E. Braun，等.Packing polymorphism of a conformationally flexible molecule (aprepitant).《New Journal of Chemistry》.2008,第32卷(第10期),第1677-1685页. * |
| Karel M. J. Brands,等.Efficient Synthesis of NK1 Receptor Antagonist Aprepitant Using a Crystallization-Induced Diastereoselective Transformation.《J. Am. Chem. Soc.》.2003,第125卷(第8期),第2129-2135页. * |
| Roy Helmy，等.Characterization and Quantitation of Aprepitant Drug Substance Polymorphs by Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy.《Anal. Chem.》.2002,第75卷(第3期),第605-611页. * |
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