CN102977023A - (-)-meptazinol phenylamino carbamate-L-(+)-tartrate type-III crystal - Google Patents

(-)-meptazinol phenylamino carbamate-L-(+)-tartrate type-III crystal Download PDF

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CN102977023A
CN102977023A CN2012104738294A CN201210473829A CN102977023A CN 102977023 A CN102977023 A CN 102977023A CN 2012104738294 A CN2012104738294 A CN 2012104738294A CN 201210473829 A CN201210473829 A CN 201210473829A CN 102977023 A CN102977023 A CN 102977023A
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tartrate
meptazinol
phenyl urethan
type wafern
meptazinol phenyl
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CN102977023B (en
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彭亮
刘海宁
于大林
张永霞
王东武
丛日刚
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DISHA PHARMACEUTICAL GROUP SHANDONG DISHA PHARMACEUTICAL Co Ltd
Weihai Weitai Medical Technology Development Co Ltd
Disha Pharmaceutical Group Co Ltd
Weihai Disu Pharmaceutical Co Ltd
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Abstract

The invention relates to a (-)-meptazinol phenylamino carbamate-L-(+)-tartrate type-III crystal and a preparation method thereof. The (-)-meptazinol phenylamino carbamate-L-(+)-tartrate type-III crystal provided by the invention is stable and is characterized in that the degrees of angles 2[theta] of characteristic peaks shown in an X-ray powder diffractogram are 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, and relative intensities corresponding to the peaks are respectively 31, 27, 11, 10, 13, 100, 26, 11, 11, 14, 42, 84, 28, 49, 15, 14, 10, 10, 10, 11 and 10. The melting point of the (-)-meptazinol phenylamino carbamate-L-(+)-tartrate type-III crystal provided by the invention is 86.3-88.9 DEG C.

Description

A kind of (-)-meptazinol phenyl urethan-L-(+)-tartrate III N-type waferN
Technical field the present invention relates to (-)-meptazinol phenyl urethan-L-(+)-tartrate III 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 III N-type waferN.
Technical scheme of the present invention is: a kind of (-)-meptazinol phenyl urethan-L-(+)-tartrate III 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: 9.3,10.2,12.1,13.4,14.2,15.5,16.4,16.9,18.2,18.8,19.6,20.7,22.2,22.6,23.4,24.3,24.8,25.6,27.1,27.5 and 28.6 ° of 2 θ, the relative intensity at corresponding peak be 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 III N-type waferN, the characteristic absorbance cm that its infrared spectra shows -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 III N-type waferN, its fusing point is: 86.3～88.9 ℃.
The present invention (-)-meptazinol phenyl urethan-L-(+)-tartrate III N-type waferN is characterized in that the absorption peak of dsc differential thermogram at about 84～98 ℃, and peak value is at about 92 ℃.
The present invention (-)-meptazinol phenyl urethan-L-(+)-tartrate III N-type waferN, its preparation method is: 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.
The present invention (-)-meptazinol phenyl urethan-L-(+)-preferred technical scheme of tartrate III N-type waferN preparation method is that the volume ratio of Virahol and dioxane is 1: (1～3), concentration are 2.5%～15% (mass volume ratio).
The present invention (-)-meptazinol phenyl urethan-L-(+)-preferred technical scheme of tartrate III N-type waferN preparation method is that 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: obtained a kind of stable the present invention (-)-meptazinol phenyl urethan-L-(+)-tartrate III N-type waferN.
Description of drawings:
Fig. 1: (-)-meptazinol phenyl urethan-L-(+)-tartrate III N-type waferN X-ray powder diffraction collection of illustrative plates.
Fig. 2: (-)-meptazinol phenyl urethan-L-(+)-tartrate III N-type waferN infared spectrum.
Fig. 3: (-)-meptazinol phenyl urethan-L-(+)-tartrate III N-type waferN 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 the 30ml dioxane, suitably heating makes its whole dissolvings, then the Virahol that adds while hot 10ml in the system places system under 10～15 ℃ of environment insulation to leave standstill 4 days, filters, and with a small amount of dioxane washing leaching cake, collect filter cake, place IR bake in 50 ℃ of dryings 3 hours, get white crystal.The position at the characteristic peak 2 θ angles 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, the relative intensity at corresponding peak be 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 that its infrared spectra shows -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 ℃; The absorption peak of its dsc differential thermogram is at about 84～98 ℃, and peak value is at about 92 ℃.
Embodiment 2 is in the single port bottle of 100ml, get 6.0g unbodied (-)-meptazinol phenyl urethan-L-(+)-tartrate and be dissolved in the 20ml dioxane, suitably heating makes its whole dissolvings, then the Virahol that adds while hot 20ml in the system places system under 10～15 ℃ of environment insulation to leave standstill 4 days, filters, and with a small amount of dioxane washing leaching cake, collect filter cake, place IR bake in 50 ℃ of dryings 3 hours, get white crystal; The position at the characteristic peak 2 θ angles 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, the relative intensity at corresponding peak be 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 that its infrared spectra shows -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 ℃; The absorption peak of its dsc differential thermogram is at about 84～98 ℃, and peak value is at about 92 ℃.
Test example 1:
Cholinesterase inhibition testing method measurement (-)-meptazinol phenyl urethan-L-(+)-tartrate III 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
Figure BSA00000807646000031
Experimental data shows that (-)-meptazinol phenyl urethan-L-(+)-tartrate III 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
Figure BSA00000807646000032
Figure BSA00000807646000041
Experimental data shows: what the stability of left-handed meptazinol phenyl urethan-L-(+)-tartrate III 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 III N-type waferN, 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 be respectively: 31,27,11,10,13,100,26,11,11,14,42,84,28,49,15,14,10,10,10,11,10.
2. according to claim 1 (-)-meptazinol phenyl urethan-L-(+)-tartrate III N-type waferN, the characteristic absorbance cm that its infrared spectra shows -1Be expressed as: 2854.7,2696.5,1400.3,1303.9,1253.7,1153.4,1118.7,1068.6,887.3,871.8.
3. according to claim 1 (-)-meptazinol phenyl urethan-L-(+)-tartrate III N-type waferN, its fusing point is: 86.3～88.9 ℃.
4. according to claim 1 (-)-meptazinol phenyl urethan-L-(+)-tartrate III N-type waferN is characterized in that the absorption peak of dsc differential thermogram at about 84～98 ℃, and peak value is at about 92 ℃.
5. according to claim 1 the preparation method of (-)-meptazinol phenyl urethan-L-(+)-tartrate III 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 III 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 2.5%～15%.
7. according to claim 5 the preparation method of (-)-meptazinol phenyl urethan-L-(+)-tartrate III 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%.
CN201210473829.4A 2012-11-09 2012-11-09 A kind of (-)-meptazinol phenyl urethan-L-(+)-tartrate type III crystal Expired - Fee Related CN102977023B (en)

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Citations (2)

* Cited by examiner, † Cited by third party
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

Patent Citations (2)

* Cited by examiner, † Cited by third party
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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