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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- 239000013078 crystal Substances 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000002464 receptor antagonist Substances 0.000 title abstract description 5
- 229940044551 receptor antagonist Drugs 0.000 title abstract description 5
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 claims abstract description 54
- 229960001372 aprepitant Drugs 0.000 claims abstract description 54
- 239000000843 powder Substances 0.000 claims abstract description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 60
- 230000015572 biosynthetic process Effects 0.000 claims description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 8
- 238000001291 vacuum drying Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 4
- 230000001186 cumulative effect Effects 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000002441 X-ray diffraction Methods 0.000 abstract description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- -1 (trifluoromethyl) phenyl Chemical group 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 238000000634 powder X-ray diffraction Methods 0.000 description 6
- 235000015320 potassium carbonate Nutrition 0.000 description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000000113 differential scanning calorimetry Methods 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 3
- ZLRBJVJEQXBAAI-UHFFFAOYSA-N 5-(chloromethyl)-1,2-dihydro-1,2,4-triazol-3-one Chemical compound ClCC1=NC(=O)NN1 ZLRBJVJEQXBAAI-UHFFFAOYSA-N 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- MDTUWBLTRPRXBX-UHFFFAOYSA-N 1,2,4-triazol-3-one Chemical compound O=C1N=CN=N1 MDTUWBLTRPRXBX-UHFFFAOYSA-N 0.000 description 1
- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 description 1
- 102000003676 Glucocorticoid Receptors Human genes 0.000 description 1
- 108090000079 Glucocorticoid Receptors Proteins 0.000 description 1
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 description 1
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229940108890 emend Drugs 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 102220014894 rs76757102 Human genes 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
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 |
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