CN102977023B - A kind of (-)-meptazinol phenyl urethan-L-(+)-tartrate type III crystal - Google Patents
A kind of (-)-meptazinol phenyl urethan-L-(+)-tartrate type III crystal Download PDFInfo
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- CN102977023B CN102977023B CN201210473829.4A CN201210473829A CN102977023B CN 102977023 B CN102977023 B CN 102977023B CN 201210473829 A CN201210473829 A CN 201210473829A CN 102977023 B CN102977023 B CN 102977023B
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- type iii
- tartrate
- phenyl urethan
- iii crystal
- meptazinol phenyl
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- 239000013078 crystal Substances 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000009413 insulation Methods 0.000 claims description 4
- 229940095064 tartrate Drugs 0.000 claims description 4
- 239000011549 crystallization solution Substances 0.000 claims 2
- 238000012360 testing method Methods 0.000 description 4
- 238000001757 thermogravimetry curve Methods 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 206010013786 Dry skin Diseases 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 229960000365 meptazinol Drugs 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- JLICHNCFTLFZJN-OAHLLOKOSA-N 3-[(3s)-3-ethyl-1-methylazepan-3-yl]phenol Chemical compound C=1C=CC(O)=CC=1[C@]1(CC)CCCCN(C)C1 JLICHNCFTLFZJN-OAHLLOKOSA-N 0.000 description 1
- 206010048650 Cholinesterase inhibition Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to (-)-meptazinol phenyl urethan-L-(+)-tartrate type III crystal and preparation method.The invention provides a kind of stable (-)-meptazinol phenyl urethan-L-(+)-tartrate type III crystal, it is characterized in that the position at the characteristic peak 2 θ angle that X-ray powder diffraction figure shows respectively: 9.3, 10.2, 12.1, 13.4, 14.2, 15.5, 16.4, 16.9, 18.2, 18.8, 19.6, 20.7, 22.2, 22.6, 23.4, 24.3, 24.8, 25.6, 27.1, 27.5 and 28.6 ° of 2 θ, the relative intensity at corresponding peak is respectively: 31, 27, 11, 10, 13, 100, 26, 11, 11, 14, 42, 84, 28, 49, 15, 14, 10, 10, 10, 11, 10.Its fusing point of crystal of the present invention is 86.3 ~ 88.9 DEG C.
Description
Technical field the present invention relates to (-)-meptazinol phenyl urethan-L-(+)-tartrate type III crystal and preparation method.
Background technology Chinese patent application 200710038209.7 discloses a kind of (-)-meptazinol carbaniloyl ester cpds and the salt thereof that have treatment dementia effect.Animal experiment finds that (-)-meptazinol phenyl urethan-L-(+)-tartrate is active desirable, it is possible drug candidate, but test finds unbodied (-)-meptazinol phenyl urethan-L-, and (+)-tartrate stability is undesirable, is not suitable for making pharmaceutical preparation.Prior art exigence a kind of stable (-)-meptazinol phenyl urethan-L-(+)-tartrate is for the preparation of pharmaceutical preparation.
Summary of the invention
Goal of the invention of the present invention is: provide a kind of stable (-)-meptazinol phenyl urethan-L-(+)-tartrate.
Through a large amount of experimental studies, the present inventor has found a kind of stable (-)-meptazinol phenyl urethan-L-(+)-tartrate type III crystal.
Technical scheme of the present invention is: a kind of (-)-meptazinol phenyl urethan-L-(+)-tartrate type III crystal, it is characterized in that the position at the characteristic peak 2 θ angle that X-ray powder diffraction figure shows respectively: 9.3, 10.2, 12.1, 13.4, 14.2, 15.5, 16.4, 16.9, 18.2, 18.8, 19.6, 20.7, 22.2, 22.6, 23.4, 24.3, 24.8, 25.6, 27.1, 27.5 and 28.6 ° of 2 θ, the relative intensity at corresponding peak is respectively: 31, 27, 11, 10, 13, 100, 26, 11, 11, 14, 42, 84, 28, 49, 15, 14, 10, 10, 10, 11, 10.
The present invention (-)-meptazinol phenyl urethan-L-(+)-tartrate type III crystal, the characteristic absorbance cm of its infrared spectra display
-1be expressed as: 2854.7,2696.5,1400.3,1303.9,1253.7,1153.4,1118.7,1068.6,887.3,871.8.
The present invention (-)-meptazinol phenyl urethan-L-(+)-tartrate type III crystal, its fusing point is: 86.3 ~ 88.9 DEG C.
The present invention (-)-meptazinol phenyl urethan-L-(+)-tartrate type III crystal, it is characterized in that the absorption peak of dsc differential thermogram is at about 84 ~ 98 DEG C, peak value is at about 92 DEG C.
The present invention (-)-meptazinol phenyl urethan-L-(+)-tartrate type III crystal, its preparation method is: get unbodied (-)-meptazinol phenyl urethan-L-(+)-tartrate and be dissolved in dioxane, suitable heating makes it all dissolve, Virahol is added while hot in system, then under system being placed in 10 ~ 15 DEG C of environment, insulation leaves standstill, and filters.
The present invention (-)-meptazinol phenyl urethan-L-(+)-preferred technical scheme of tartrate type III crystal preparation method is the volume ratio of Virahol and dioxane is 1: (1 ~ 3), concentration is 2.5% ~ 15% (mass volume ratio).
The present invention (-)-meptazinol phenyl urethan-L-(+)-preferred technical scheme of tartrate type III crystal preparation method is the volume ratio of Virahol and dioxane is 1: 3, and preferred concentration is 2.5% (mass volume ratio).
The invention has the beneficial effects as follows: obtain a kind of stable the present invention (-)-meptazinol phenyl urethan-L-(+)-tartrate type III crystal.
Accompanying drawing illustrates:
Fig. 1: (-)-meptazinol phenyl urethan-L-(+)-tartrate type III X-ray powder diffraction spectrum.
Fig. 2: (-)-meptazinol phenyl urethan-L-(+)-tartrate type III crystal infared spectrum.
Fig. 3: (-)-meptazinol phenyl urethan-L-(+)-tartrate type III crystal dsc differential thermogram.
Embodiment 1 is in the single port bottle of 100ml, get 1.0g unbodied (-)-meptazinol phenyl urethan-L-(+)-tartrate and be dissolved in 30ml dioxane, suitable heating makes it all dissolve, in system, add the Virahol of 10ml while hot, under then system being placed in 10 ~ 15 DEG C of environment, insulation leaves standstill 4 days, filters, and with a small amount of dioxane washing leaching cake, collect filter cake, be placed in IR bake in 50 DEG C of dryings 3 hours, obtain white crystal.The position at the characteristic peak 2 θ angle that its X-ray powder diffraction figure shows is respectively: 9.3,10.2,12.1,13.4,14.2,15.5,16.4,16.9,18.2,18.8,19.6,20.7,22.2,22.6,23.4,24.3,24.8,25.6,27.1,27.5 and 28.6 ° of 2 θ, and the relative intensity at corresponding peak is respectively: 31,27,11,10,13,100,26,11,11,14,42,84,28,49,15,14,10,10,10,11,10; The characteristic absorbance cm of its infrared spectra display
-1be expressed as: 2854.7,2696.5,1400.3,1303.9,1253.7,1153.4,1118.7,1068.6,887.3,871.8; Its fusing point is: 86.3 ~ 88.9 DEG C; The absorption peak of its dsc differential thermogram is at about 84 ~ 98 DEG C, and peak value is at about 92 DEG C.
Embodiment 2 is in the single port bottle of 100ml, get 6.0g unbodied (-)-meptazinol phenyl urethan-L-(+)-tartrate and be dissolved in 20ml dioxane, suitable heating makes it all dissolve, in system, add the Virahol of 20ml while hot, under then system being placed in 10 ~ 15 DEG C of environment, insulation leaves standstill 4 days, filters, and with a small amount of dioxane washing leaching cake, collect filter cake, be placed in IR bake in 50 DEG C of dryings 3 hours, obtain white crystal; The position at the characteristic peak 2 θ angle that its X-ray powder diffraction figure shows is respectively: 9.3,10.2,12.1,13.4,14.2,15.5,16.4,16.9,18.2,18.8,19.6,20.7,22.2,22.6,23.4,24.3,24.8,25.6,27.1,27.5 and 28.6 ° of 2 θ, and the relative intensity at corresponding peak is respectively: 31,27,11,10,13,100,26,11,11,14,42,84,28,49,15,14,10,10,10,11,10; The characteristic absorbance cm of its infrared spectra display
-1be expressed as: 2854.7,2696.5,1400.3,1303.9,1253.7,1153.4,1118.7,1068.6,887.3,871.8; Its fusing point is: 86.8 ~ 88.9 DEG C; The absorption peak of its dsc differential thermogram is at about 84 ~ 98 DEG C, and peak value is at about 92 DEG C.
Test example 1:
(-)-meptazinol phenyl urethan-L-(+)-tartrate type III crystal is measured to the inhibit activities record of AChE and rat blood serum BChE in rat brain homogenate in Table 1 according to the cholinesterase inhibition testing method that Chinese patent application 200710038209.7 provides.
Table 1
Experimental data shows, (-)-meptazinol phenyl urethan-L-(+)-tartrate type III crystal has certain inhibit activities to AChE in rat brain homogenate and rat blood serum BChE.
Test example 2: study on the stability
By the amorphous powder of embodiment 1 ~ embodiment 2 sample and (-)-meptazinol phenyl urethan-L-(+)-tartrate that are placed in open container, be placed in climatic chamber, be 40 DEG C in temperature, under relative humidity 65% condition, investigate stability.Respectively at 0 day, 5 days, 10 days sampling detection level, detected data logging in table 2.
Table 2
Experimental data shows: what the stability of left-handed meptazinol phenyl urethan-L-(+)-tartrate type III crystal will be good than the stability of the amorphous powder of left-handed meptazinol phenyl urethan-L-(+)-tartrate is many, has positive meaning to the preparation of preparation.
Claims (4)
1.
a kind of (-)-meptazinol phenyl urethan-L-(+)-tartrate type III crystal, it is characterized in that, the characteristic peak positions that X-ray powder diffraction figure shows is: 9.3, 10.2, 12.1, 13.4, 14.2, 15.5, 16.4, 16.9, 18.2, 18.8, 19.6, 20.7, 22.2, 22.6, 23.4, 24.3, 24.8, 25.6, 27.1, 27.5 and 28.6 ° of 2 θ, the relative intensity at corresponding peak is respectively: 31, 27, 11, 10, 13, 100, 26, 11, 11, 14, 42, 84, 28, 49, 15, 14, 10, 10, 10, 11, 10.
2.
the preparation method of (-)-meptazinol phenyl urethan-L-(+)-tartrate type III crystal described in a kind of claim 1, it is characterized in that, unbodied (-)-meptazinol phenyl urethan-L-(+)-tartrate is dissolved in dioxane, suitable heating makes it all dissolve, Virahol is added while hot in system, then under system being placed in 10 ~ 15 DEG C of environment, insulation leaves standstill, and filters.
3.
the preparation method of (-)-meptazinol phenyl urethan-L-(+) according to claim 2-tartrate type III crystal, it is characterized in that, the volume ratio of Virahol and dioxane is 1: (1 ~ 3), and the mass body volume concentrations of crystallization solution is 2.5% ~ 15%.
4.
the preparation method of (-)-meptazinol phenyl urethan-L-(+) according to claim 2-tartrate type III crystal, it is characterized in that, the volume ratio of Virahol and dioxane is 1: 3, and the mass body volume concentrations of crystallization solution is 2.5%.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1850804A (en) * | 2006-03-31 | 2006-10-25 | 复旦大学 | Optical-purity meptazinol orits salts, and preparing method |
| CN101020661A (en) * | 2007-03-19 | 2007-08-22 | 复旦大学 | (-)-meptazinol carbamate derivative and/or its salt and their prepn and use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1850804A (en) * | 2006-03-31 | 2006-10-25 | 复旦大学 | Optical-purity meptazinol orits salts, and preparing method |
| CN101020661A (en) * | 2007-03-19 | 2007-08-22 | 复旦大学 | (-)-meptazinol carbamate derivative and/or its salt and their prepn and use |
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