CN102977022A - (-)-meptazinol phenyl carbamate-L-(+)-tartrate IV type crystal - Google Patents
(-)-meptazinol phenyl carbamate-L-(+)-tartrate IV type crystal Download PDFInfo
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- CN102977022A CN102977022A CN2012104738275A CN201210473827A CN102977022A CN 102977022 A CN102977022 A CN 102977022A CN 2012104738275 A CN2012104738275 A CN 2012104738275A CN 201210473827 A CN201210473827 A CN 201210473827A CN 102977022 A CN102977022 A CN 102977022A
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- tartrate
- meptazinol phenyl
- phenyl urethan
- type wafern
- meptazinol
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- 239000013078 crystal Substances 0.000 title abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 6
- 238000001757 thermogravimetry curve Methods 0.000 claims description 5
- 238000002835 absorbance Methods 0.000 claims description 4
- 238000010521 absorption reaction Methods 0.000 claims description 4
- 238000002329 infrared spectrum Methods 0.000 claims description 4
- 229960000365 meptazinol Drugs 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 3
- 239000011549 crystallization solution Substances 0.000 claims 2
- 238000010438 heat treatment Methods 0.000 claims 1
- 238000002844 melting Methods 0.000 abstract 1
- 230000008018 melting Effects 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229940095064 tartrate Drugs 0.000 description 3
- 102100033639 Acetylcholinesterase Human genes 0.000 description 2
- 108010022752 Acetylcholinesterase Proteins 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000005764 inhibitory process Effects 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
- 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
- 238000005259 measurement Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
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Abstract
The invention relates to a (-)-meptazinol phenyl carbamate-L-(+)-tartrate IV type crystal and a preparation method. The invention provides a stable (-)-meptazinol phenyl carbamate-L-(+)-tartrate IV type crystal which is characterized in that the positions of the characteristic peak 2(theta) angle displayed by an X-ray powder diffraction pattern are 9.7, 10.7, 12.6, 15.1, 15.9, 16.9, 17.3, 18.6, 19.0, 19.9, 20.6, 21.3, 22.1, 23.0, 24.2, 25.4, 27.4. 28.3, 28.8, 31.1, 31.9, 33.5 and 35.8-degree 2(theta) respectively; and the relative intensities of corresponding peaks are 16, 47, 21, 16, 100, 10, 12, 11, 13, 35, 25, 72, 22, 83, 22, 11, 10, 10, 10, 11, 11, 10 and 10 respectively. The melting point of the crystal provided by the invention is 90.9-93.2 DEG C.
Description
Technical field the present invention relates to (-)-meptazinol phenyl urethan-L-(+)-tartrate IV N-type waferN and preparation method.
Background technology Chinese patent application 200710038209.7 discloses a kind of (-)-meptazinol carbaniloyl ester cpds and salt thereof that the treatment dementia effect is arranged.Animal experiment finds that (-)-meptazinol phenyl urethan-L-(+)-tartrate is active desirable, it is possible drug candidate, but test finds that unbodied (-)-meptazinol phenyl urethan-L-(+)-tartrate stability is undesirable, is not suitable for doing 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: a kind of stable (-)-meptazinol phenyl urethan-L-(+)-tartrate is provided.
Through a large amount of experimental studies, the inventor has found a kind of stable (-)-meptazinol phenyl urethan-L-(+)-tartrate IV N-type waferN.
Technical scheme of the present invention is: a kind of (-)-meptazinol phenyl urethan-L-(+)-tartrate IV N-type waferN, the position that it is characterized in that the characteristic peak 2 θ angles that X-ray powder diffraction figure shows is respectively: 9.7,10.7,12.6,15.1,15.9,16.9,17.3,18.6,19.0,19.9,20.6,21.3,22.1,23.0,24.2,25.4,27.4,28.3,28.8,31.1,31.9,33.5,35.8 ° 2 θ, the relative intensity at corresponding peak be respectively: 16,47,21,16,100,10,12,11,13,35,25,72,22,83,22,11,10,10,10,11,11,10,10.
The present invention (-)-meptazinol phenyl urethan-L-(+)-tartrate IV N-type waferN, the characteristic absorbance cm that its infrared spectra shows
-1Be expressed as: 3317.6,2966.5,1716.7,1600.9,1541.1,1444.7,1205.5,1124.5,1066.6,1016.5,995.3,904.6,804.3,760.0,696.3,507.3,484.1.
The present invention (-)-meptazinol phenyl urethan-L-(+)-tartrate IV N-type waferN, its fusing point is: 90.9～93.2 ℃.
The present invention (-)-meptazinol phenyl urethan-L-(+)-tartrate IV N-type waferN is characterized in that the absorption peak of dsc differential thermogram at about 86～95 ℃, and peak value is at about 92 ℃.
The present invention (-)-meptazinol phenyl urethan-L-(+)-tartrate IV N-type waferN, its preparation method is: get (-)-meptazinol phenyl urethan-L-(+)-the tartrate amorphous substance puts in the single port flask, add the tetrahydrofuran (THF) dissolving, left standstill crystallization under 30 ℃ 5 days, and filtered and obtain white crystal.
The present invention (-)-meptazinol phenyl urethan-L-(+)-preferred technical scheme of tartrate IV N-type waferN preparation method, concentration is 5%～25% (mass volume ratio).
The present invention (-)-meptazinol phenyl urethan-L-(+)-preferred technical scheme of tartrate IV N-type waferN preparation method, concentration is 20% (mass volume ratio).
The invention has the beneficial effects as follows: obtained a kind of stable the present invention (-)-meptazinol phenyl urethan-L-(+)-tartrate IV N-type waferN.
Description of drawings:
Fig. 1: (-)-meptazinol phenyl urethan-L-(+)-tartrate IV N-type waferN X-ray powder diffraction collection of illustrative plates.
Fig. 2: (-)-meptazinol phenyl urethan-L-(+)-tartrate IV N-type waferN infared spectrum.
Fig. 3: (-)-meptazinol phenyl urethan-L-(+)-tartrate IV N-type waferN dsc differential thermogram.
Embodiment 1 is in the single port bottle of 100ml, add 12.5 gram (-)-meptazinol phenyl urethan-L-(+)-tartrate amorphous substances, the dissolving of 50ml tetrahydrofuran (THF) was left standstill crystallization 5 days under 30 ℃, the crystal that filtration is separated out, 60 ℃ of bakings got the IV N-type waferN in 3 hours in the baking oven.The position that it is characterized in that the characteristic peak 2 θ angles that X-ray powder diffraction figure shows is respectively: 9.7,10.7,12.6,15.1,15.9,16.9,17.3,18.6,19.0,19.9,20.6,21.3,22.1,23.0,24.2,25.4,27.4,28.3,28.8,31.1,31.9,33.5,35.8 ° of 2 θ, the relative intensity at corresponding peak be respectively: 16,47,21,16,100,10,12,11,13,35,25,72,22,83,22,11,10,10,10,11,11,10,10; The characteristic absorbance cm that its infrared spectra shows
-1Be expressed as: 3317.6,2966.5,1716.7,1600.9,1541.1,1444.7,1205.5,1124.5,1066.6,1016.5,995.3,904.6,804.3,760.0,696.3,507.3,484.1; Its fusing point is: the absorption peak of 90.9～93.2 ℃ of its dsc differential thermograms is at about 86～95 ℃, and peak value is at about 92 ℃.
Embodiment 2 is in the single port bottle of 100ml, add 3 gram (-)-meptazinol phenyl urethan-L-(+)-tartrate amorphous substances, the dissolving of 60ml tetrahydrofuran (THF), left standstill crystallization under 30 ℃ 5 days, the crystal that filtration is separated out, 50 ℃ of bakings got the IV N-type waferN in 3 hours in the baking oven, the position that it is characterized in that the characteristic peak 2 θ angles that X-ray powder diffraction figure shows is respectively: 9.7,10.7,12.6,15.1,15.9,16.9,17.3,18.6,19.0,19.9,20.6,21.3,22.1,23.0,24.2,25.4,27.4,28.3,28.8,31.1,31.9,33.5,35.8 ° 2 θ, the relative intensity at corresponding peak be respectively: 16,47,21,16,100,10,12,11,13,35,25,72,22,83,22,11,10,10,10,11,11,10,10; The characteristic absorbance cm that its infrared spectra shows
-1Be expressed as: 3317.6,2966.5,1716.7,1600.9,1541.1,1444.7,1205.5,1124.5,1066.6,1016.5,995.3,904.6,804.3,760.0,696.3,507.3,484.1; Its fusing point is: 90.9～93.2 ℃; The absorption peak of its dsc differential thermogram is at about 86～95 ℃, and peak value is at about 92 ℃.
Test example 1:
Cholinesterase inhibition testing method measurement (-)-meptazinol phenyl urethan-L-(+)-tartrate IV N-type waferN that provides according to Chinese patent application 200710038209.7 is recorded in the table 1 the inhibition activity of AChE in the rat brain homogenate and rat blood serum BChE.
Table 1
Experimental data shows that (-)-meptazinol phenyl urethan-L-(+)-tartrate IV N-type waferN has certain inhibition active to AChE in the rat brain homogenate and rat blood serum BChE.
Test example 2: study on the stability
Embodiment 1～embodiment 2 samples of open container and the amorphous powder of (-)-meptazinol phenyl urethan-L-(+)-tartrate will be placed, place climatic chamber, be 40 ℃ 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 IV N-type waferN will be good than the stability of the amorphous powder of left-handed meptazinol phenyl urethan-L-(+)-tartrate is many, and the preparation of preparation is had positive meaning.
Claims (7)
1. one kind (-)-meptazinol phenyl urethan-L-(+)-tartrate IV N-type waferN, it is characterized in that the characteristic peak positions that X-ray powder diffraction figure shows is: 9.7,10.7,12.6,15.1,15.9,16.9,17.3,18.6,19.0,19.9,20.6,21.3,22.1,23.0,24.2,25.4,27.4,28.3,28.8,31.1,31.9,33.5,35.8 ° 2 θ, the relative intensity at corresponding peak be respectively: 16,47,21,16,100,10,12,11,13,35,25,72,22,83,22,11,10,10,10,11,11,10,10.
2. according to claim 1 (-)-meptazinol phenyl urethan-L-(+)-tartrate IV N-type waferN, the characteristic absorbance cm that its infrared spectra shows
-1Be expressed as: 3317.6,2966.5,1716.7,1600.9,1541.1,1444.7,1205.5,1124.5,1066.6,1016.5,995.3,904.6,804.3,760.0,696.3,507.3,484.1.
3. according to claim 1 (-)-meptazinol phenyl urethan-L-(+)-tartrate IV N-type waferN, its fusing point is: 90.9-93.2 ℃.
4. according to claim 1 (-)-meptazinol phenyl urethan-L-(+)-tartrate IV N-type waferN is characterized in that the absorption peak of dsc differential thermogram at about 86-95 ℃, and peak value is at about 92 ℃.
5. according to claim 1 the preparation method of (-)～meptazinol phenyl urethan-L-(+)-tartrate IV N-type waferN, it is characterized in that to get unbodied (-)-meptazinol phenyl urethan-L-(+)-tartrate and be dissolved in dioxane, suitably heating makes its whole dissolvings, in system, add Virahol while hot, then system is placed to be incubated under 10～15 ℃ of environment and leave standstill, filter.
6. according to claim 5 the preparation method of (-)-meptazinol phenyl urethan-L-(+)-tartrate IV N-type waferN, the volume ratio that it is characterized in that Virahol and dioxane is 1: (1～3), the mass body volume concentrations of crystallization solution is 5%～25%.
7. according to claim 5 the preparation method of (-)-meptazinol phenyl urethan-L-(+)-tartrate IV N-type waferN, the volume ratio that it is characterized in that Virahol and dioxane is 1: 3, the mass body volume concentrations of crystallization solution is 2.5%.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201210473827.5A CN102977022B (en) | 2012-11-09 | 2012-11-09 | (-)-meptazinol phenyl urethan-L-(+)-tartrate IV type crystal |
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| CN201210473827.5A CN102977022B (en) | 2012-11-09 | 2012-11-09 | (-)-meptazinol phenyl urethan-L-(+)-tartrate IV type crystal |
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| CN102977022A true CN102977022A (en) | 2013-03-20 |
| CN102977022B CN102977022B (en) | 2016-09-14 |
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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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Patent 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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Effective date of registration: 20160822 Address after: 264205 No. 1 South Qingdao Road, Weihai economic and technological development, Shandong Applicant after: Disha Pharmaceutical Industry Group Corp., Ltd. Applicant after: Weihai Disu Pharmaceutical Co., Ltd. Address before: 264205 No. 1 South Qingdao Road, Weihai economic and technological development, Shandong Applicant before: Disha Pharmaceutical Industry Group Corp., Ltd. Applicant before: Disha Pharmaceutical Group Shandong Disha Pharmaceutical Co., Ltd. Applicant before: Weihai Disu Pharmaceutical Co., Ltd. Applicant before: Weihai Weitai Medical Technology Development Co., Ltd. |
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