CN103193659A - Novel crystal form of (-)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl) phenol hydrochloride and preparation method thereof - Google Patents
Novel crystal form of (-)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl) phenol hydrochloride and preparation method thereof Download PDFInfo
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- CN103193659A CN103193659A CN 201310084349 CN201310084349A CN103193659A CN 103193659 A CN103193659 A CN 103193659A CN 201310084349 CN201310084349 CN 201310084349 CN 201310084349 A CN201310084349 A CN 201310084349A CN 103193659 A CN103193659 A CN 103193659A
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Abstract
The invention relates to a novel crystal form of (-)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl) crystal-type phenol hydrochloride and a preparation method thereof. The chemical name of tapentadol hydrochloride is called as (-)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl) phenol hydrochloride which is used for preparing medicines for relieving moderately and seriously acute pain.
Description
Technical field
The present invention relates to tapentadol hydrochloride new crystal and preparation method thereof
Background technology
Tapentadol hydrochloride, chemical name: (-)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2 methyl-propyl) phenolate hydrochlorate, chemical structural formula is as follows:
Tapentadol hydrochloride is a kind of oral pain alleviating medicine that acts on central nervous system of novelty, and it can activate opiate receptor, and especially μ 2 acceptors can be used to alleviate moderate and severe acute pain.Initial Public Offering in 2008 is used for alleviating moderate and severe acute pain.
Reported two kinds of crystal formations of tapentadol hydrochloride among the patent US 7994364B2, be respectively A crystal formation and B crystal formation, the inventor has found a kind of stable new crystal in the research crystallisation process.
Summary of the invention
The invention provides a kind of new crystal of tapentadol hydrochloride.The new crystal of tapentadol hydrochloride of the present invention, its X-ray powder diffraction pattern is about 10.1(8.7 at reflection angle 2 θ), 14.4(6.1), 18.2(4.8), 20.3(4.3), 25.4(3.4), 30.7(2.9) located charateristic avsorption band.
Among the present invention, the mensuration of 2 θ values is used Cu-K α light source, precision is ± 0.2 °, therefore, " pact " in above-mentioned " the X-ray powder diffraction pattern is about at reflection angle 2 θ " should be defined as 2 θ ± 0.2 °, represent above-mentioned 2 θ values of getting and allowed certain reasonably limit of error, its limit of error is ± 0.2 °.
Another object of the present invention is the preparation method who discloses the new crystal of tapentadol hydrochloride.
The preparation method of the new crystal of tapentadol hydrochloride of the present invention, its process comprise with hydrochloric acid that he sprays him and are dissolved in heating for dissolving in the acetonitrile, add methyl tertiary butyl ether, slowly stirring and crystallizing.It is characterized in that the consumption of acetonitrile is 10-500 times, the consumption of methyl tertiary butyl ether is 0.1-5 times of acetonitrile consumption.
Description of drawings
Fig. 1 is the X-ray powder diffraction pattern of tapentadol hydrochloride new crystal
Embodiment
Can further describe the present invention by following embodiment, yet invention of the present invention is not limited to following experimental example, the scope that these embodiment do not limit the present invention in any way.Some change that those skilled in the art has done in the scope of claim and adjustment also should belong to scope of the present invention.
Embodiment 1
In the 3L reaction flask, add the 15g tapentadol hydrochloride, add the 1.5L acetonitrile under the room temperature, the reflux dissolving adds methyl tertiary butyl ether 750mL, places and slowly stirs 30～60min under the ice bath, filter, with a small amount of 30% methyl tertiary butyl ether-acetonitrile washing, 35-45 ℃ of vacuum-drying is spent the night.Namely get the tapentadol hydrochloride new crystal.
The mensuration of the X-ray powder diffraction of embodiment 2 tapentadol hydrochloride new crystal
Place on the powder diffractometer by the tapentadol hydrochloride powder of X-ray powder diffraction method with new crystal, scanning speed with 4 degree/min scans between 3-50 degree 2 θ angles, use Cu-K α, 50Kv～30mA X-radiation, used step-length is 0.02 degree by 2 θ.With the X-ray powder diffraction of 2 θ angles and spacing (d value) expression at about 10.1(8.7), 14.4(6.1), 18.2(4.8), 20.3(4.3), 25.4(3.4), 30.7(2.9) located charateristic avsorption band, as shown in Figure 1.The concrete data of the X-ray powder diffraction pattern of described crystal formation are in table 1.
Table 1:
Peak position, d value and relative intensity table
| The peak tagmeme | 2θ | The d value | I/II |
| 1 | 9.094 | 9.7163 | 5.2 |
| 2 | 10.132 | 8.7231 | 14.8 |
| 3 | 14.490 | 6.1079 | 16.9 |
| 4 | 15.093 | 5.8652 | 6.0 |
| 5 | 15.954 | 5.5505 | 8.6 |
| 6 | 16.980 | 5.2174 | 11.6 |
| 7 | 18.252 | 4.8566 | 100 |
| 8 | 18.841 | 4.7060 | 7.1 |
| 9 | 20.359 | 4.3584 | 42.0 |
| 10 | 21.682 | 4.0954 | 23.5 |
| 11 | 22.533 | 3.9426 | 8.5 |
| 12 | 24.249 | 3.6674 | 7.4 |
| 13 | 25.457 | 3.4960 | 20.2 |
| 14 | 26.604 | 3.3478 | 4.7 |
| 15 | 27.599 | 3.2293 | 7.6 |
[0019]?
| 16 | 30.729 | 2.9072 | 23.9 |
| 17 | 34.387 | 2.6058 | 5.3 |
Embodiment 3
He sprays his many analgesic activities to mouse
Get 30 of KM kind mouse, male and female half and half, body weight 18-22g is divided into 3 groups at random, 10 every group.Be respectively model contrast, he sprays, and he is many (the listing sample: trade(brand)name NUCYNTA) group, he sprays his many new crystal (embodiment 1 described new crystal) and organizes.Each organizes equal gastric infusion, two treatment groups all give same dose he spray his many activeconstituentss, about 20.55mg/kg mouse body weight, model control group are irritated the physiological saline that stomach gives equal volume.Behind the administration 45min, each mouse abdominal injection 0.6% acetum 0.1mL/10g.The mouse writhing reaction times that occurs in the observation 15min is calculated the analgesia inhibiting rate, compares between organizing.The result shows, with respect to model control group, each treatment group all has significant analgesia role, significant difference (P＜0.01), two administration groups relatively, he of new crystal of the present invention is sprayed his multipotency and is brought into play him greatly and spray his many analgesic activities, under same dose, its analgesia intensity obviously be better than going on the market he spray that he is many.See Table 1
Table 1 medicine to the restraining effect of mouse acetic acid writhing response (
N=10)
Claims (7)
1. one kind (-)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2 methyl-propyl) phenolate hydrochlorate crystal formation, it is characterized in that Cu-K α
1Radiation, with the X-ray powder diffraction of 2 θ angles and spacing (d value) expression at about 10.1(8.7), 14.4(6.1), 18.2(4.8), 20.3(4.3), 25.4(3.4), 30.7(2.9) located charateristic avsorption band.
2. (-) of claim 1-(1R 2R)-preparation method of 3-(3-dimethylamino-1-ethyl-2 methyl-propyl) phenolate hydrochlorate crystal formation, by he sprays him and is dissolved in heating for dissolving in the acetonitrile with hydrochloric acid, adds methyl tertiary butyl ether, slowly stirring and crystallizing.
3. preparation method according to claim 2 is characterized in that, the consumption of preferred acetonitrile is 10-500 times, and the consumption of methyl tertiary butyl ether is 0.1-10 times of acetonitrile consumption.
4. preparation method according to claim 3 is characterized in that, the consumption of preferred acetonitrile is 50-200 times, and the consumption of methyl tertiary butyl ether is 0.2-5 times of acetonitrile consumption.
5. preparation method according to claim 4 is characterized in that, the consumption of preferred acetonitrile is 80-120 times, and the consumption of methyl tertiary butyl ether is 0.4-0.6 times of acetonitrile consumption.
6. preparation method according to claim 5 is characterized in that, the consumption of preferred acetonitrile is 100 times, and the consumption of methyl tertiary butyl ether is 0.5 times of acetonitrile consumption.
7. according to the described arbitrary crystal formation of claim 1～6, it is characterized in that: for the preparation of the purposes of alleviating in moderate and the severe acute pain medicine.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 201310084349 CN103193659A (en) | 2013-03-15 | 2013-03-15 | Novel crystal form of (-)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl) phenol hydrochloride and preparation method thereof |
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| CN 201310084349 CN103193659A (en) | 2013-03-15 | 2013-03-15 | Novel crystal form of (-)-(1R, 2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl) phenol hydrochloride and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103553940A (en) * | 2013-11-07 | 2014-02-05 | 南京艾德凯腾生物医药有限责任公司 | Preparation method of new crystal form tapentadol hydrochloride |
| WO2015117576A1 (en) | 2014-02-04 | 2015-08-13 | Zentiva, K.S. | A solid form of tapentadol maleate and a method of its preparation |
-
2013
- 2013-03-15 CN CN 201310084349 patent/CN103193659A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103553940A (en) * | 2013-11-07 | 2014-02-05 | 南京艾德凯腾生物医药有限责任公司 | Preparation method of new crystal form tapentadol hydrochloride |
| WO2015117576A1 (en) | 2014-02-04 | 2015-08-13 | Zentiva, K.S. | A solid form of tapentadol maleate and a method of its preparation |
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Application publication date: 20130710 |