CN104059056B - A kind of fumaric acid Lu handkerchief replaces fragrant crystal formation B and preparation method thereof - Google Patents
A kind of fumaric acid Lu handkerchief replaces fragrant crystal formation B and preparation method thereof Download PDFInfo
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- CN104059056B CN104059056B CN201410289491.6A CN201410289491A CN104059056B CN 104059056 B CN104059056 B CN 104059056B CN 201410289491 A CN201410289491 A CN 201410289491A CN 104059056 B CN104059056 B CN 104059056B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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Abstract
Fragrant crystal formation B is replaced the present invention relates to a kind of fumaric acid Lu handkerchief, the characteristic peak of the X-ray powder diffraction figure of the crystal formation B represents to be located at 5.9 °, 6.7 °, 8.0 °, 11.7 °, 12.0 °, 12.9 °, 14.5 °, 16.7 °, 17.2 °, 18.9 °, 19.7 °, 20.2 °, 22.3 °, 24.4 °, 25.9 °, 27.0 °, 28.8 °, 30.7 ° with 2 θ ± 0.2 °；The described θ of the angle of diffraction 2 is the distinctive characteristic peaks of crystal formation B at 5.9 ° of (a), 12.9 ° of (b), 22.3 ° of (c), 27.0 ° of (d)；The described θ of the angle of diffraction 2 is located at 8.0 °, 12.0 °, 14.5 °, 16.7 °, 17.2 °, 18.9 °, 19.7 °, 20.2 °, 24.4 °, 25.9 °, and display is with the X x ray diffraction spectral lines that relative line intensity is more than 30；The fusing point of the crystal formation B is 186 ± 2 DEG C.
Description
Technical field
The present invention relates to figure (1) shown in 4- [1- (5- methvl-pyridinium -3- ylmethyls)-piperidines -4- subunits] -4,9- dihydros -
The crystal formation B of 1- thias-benzo [f] Azulene -10- ketone fumarates, and preparation method thereof.
Background technology
30 national anaphylactia epidemiology survey results that world's allergy tissue is announced are shown:In these states
In 1,200,000,000 total populations of family, 22% (25 000 ten thousand people) suffers from the anaphylactia that IgE is mediated, such as allergic rhinitis, asthma, knot
The quality of life of film inflammation, eczema, food hypersenstivity, drug allergy and severe allergic reaction etc., influence children and adult, severe total
Allergic reaction even threat to life.Estimate according to WHO, the whole world there are about 1.5 hundred million asthmatic patients, wherein more than 50% adult and at least
80% child patient induces by intolerance factors, and dies from asthma person every year more than 180,000 people.
During by 2010, the people for having 40% to 50% is suffered from allergy by the whole world, wherein global allergic rhinitis curative
The sales volume of thing has reached 6,000,000,000 dollars.WHO anaphylactia be classified as 21 century need primary study and preventing and treating three big diseases
One of disease.The incidence of disease of China's anaphylactia is up to 37.3% according to statistics, and the southeastern coastal areas incidence of disease is higher than inland, big city
The regional incidence of disease of city's particularly industry prosperity is higher than rural area, and this is mainly the allergic rhinitis caused by air pollution, very
To being asthma.The use of the underproof finishing material of other, paint, and underproof cosmetics outflow market, make trouble
The people of allergic dermatitis, which transfers toward, to increase.
Fumaric acid Lu handkerchief is invented by Mindong Lijiexun Pharmaceutical Co., Ltd., Fujian Prov. doctor Lin Tongjun for fragrant, and is declared
PCT Patent, application number PCT/CN2012/077591, patent publication No. is WO2013000406, into China, the U.S., Europe
Continent, Japanese national application stage, experiment show that fumaric acid Lu handkerchief is that a kind of multi-path suppresses allergic drug comprehensively for sweet smell, its advantage
It is that (1) eliminates the methyl (causing sedation) on Ketotifen nitrogen-atoms, remains the antihistaminicum and stably of its parent nucleus
Mast cell is acted on.(2) introducing 3- picolyls functional group (contributes to antiplatelet activity factor to act on and suppress acidophil
Effect).Advantage is with multiple anti-allergic effects.That is (1) antihistamine effect, (2) mast cell stabilization, (3) anti-blood
Platelet activation factor is acted on, (4) anti-eosinophil effect.And (5) it reduces the maincenter side effect of Ketotifen.
Not yet retrieve to study for the crystal formation of sweet smell about fumaric acid Lu handkerchief at present and report, the present invention is first there is provided rich horse
Sour Lu's handkerchief is for fragrant crystal formation research and preparation method.
The content of the invention
The present invention relates to figure (1) shown in 4- [1- (5- methvl-pyridinium -3- ylmethyls)-piperidines -4- subunits] -4,9- dihydros -
The crystal formation B of 1- thias-benzo [f] Azulene -10- ketone fumarates, and preparation method thereof.
A kind of fumaric acid Lu handkerchief replaces fragrant crystal formation B, and the characteristic peak of the X-ray powder diffraction figure of the crystal formation B is with 2 θ ± 0.2 °
Represent positioned at 5.9 °, 6.7 °, 8.0 °, 11.7 °, 12.0 °, 12.9 °, 14.5 °, 16.7 °, 17.2 °, 18.9 °, 19.7 °, 20.2 °,
At 22.3 °, 24.4 °, 25.9 °, 27.0 °, 28.8 °, 30.7 °；The described θ of the angle of diffraction 2 is in 5.9 ° of (a), 12.9 ° of (b), (c)
22.3 °, at 27.0 ° of (d) be the distinctive characteristic peaks of crystal formation B；The described θ of the angle of diffraction 2 be located at 8.0 °, 12.0 °, 14.5 °, 16.7 °,
At 17.2 °, 18.9 °, 19.7 °, 20.2 °, 24.4 °, 25.9 °, display is spread out with relative line intensity for more than 30 X-ray
Penetrate spectral line；The fusing point of the crystal formation B is 186 ± 2 DEG C.
Wherein, fragrant crude product is replaced to be dissolved in appropriate amount solvent orange 2 A with fumaric acid Lu handkerchief, heating stirring backflow prepares saturated solution, so
After naturally cool to room temperature, then at 2-8 DEG C of standing crystallization, separate out bar-shaped crystallization, filter, washed with 2-8 DEG C of appropriate amount solvent orange 2 A,
45 DEG C are dried under reduced pressure, and produce；Described solvent orange 2 A is the ethanol solution of dichloromethane 95%, dichloromethane ethanol solution, acetic acid
Ethyl ester ethanol solution, the ethanol solution of ethyl acetate 95%, acetone ethanol solution, the ethanol solution of acetone 95% and acetone
Methanol solution.
Wherein, described dichloromethane and 95% ethanol, dichloromethane and ethanol, ethyl acetate and absolute ethyl alcohol, acetic acid
The volume ratio of ethyl ester and 95% ethanol is 4：1 to 1：4；Described acetone and absolute ethyl alcohol, acetone and 95% ethanol, acetone and first
The volume ratio of alcohol is 1：1 to 8：1.
Above-mentioned Crystal type B in 100 times of micro- visors in it is bar-shaped it is brilliant practise, its fusing point is 186 ± 2 DEG C, influence because
Investigated 10 days under the conditions of element, its stability is consistent with crystal formation A, there is that stability is good.
Beneficial effects of the present invention are：Sweet smell crystal formation B and preparation method are replaced there is provided a kind of fumaric acid Lu handkerchief.
Brief description of the drawings
The present invention is further described with embodiment for explanation below in conjunction with the accompanying drawings：
Fig. 1 is 4- [1- (5- methvl-pyridinium -3- ylmethyls)-piperidines -4- subunits] -4,9- dihydros -1- thias-benzo [f]
The structural formula of Azulene -10- ketone fumarates；
Fig. 2 fumaric acid Lu handkerchief replaces fragrant crystal formation A characteristic peak；
Fig. 3：Fumaric acid Lu handkerchief replaces fragrant crystal formation B powder diffraction spectrums；
Fig. 4：Embodiment fumaric acid Lu handkerchief contrasts for sweet smell crystal formation B powder diffraction spectrums；
Fig. 5：Embodiment fumaric acid Lu handkerchief replaces fragrant crystal formation B DSC collection of illustrative plates；
Fig. 6：Embodiment fumaric acid Lu handkerchief replaces fragrant crystal formation 100 times of visor pictures of B.
Embodiment
Embodiment 1
Fragrant free alkali is replaced to be dissolved in the ethanol solution (1 of appropriate amount 20ml dichloromethane 95% with 1.0g fumaric acid with Lu's 1.0g handkerchief：
1, w/w), stirring reaction 1hr at room temperature, is concentrated under reduced pressure into 25-30% volumes, solution naturally cools to room temperature, then at 2-8 DEG C
Crystallization is stood, bar-shaped crystallization, filtering, with the 2-8 DEG C of ethanol solution solution (1 of dichloromethane 95% is separated out：1, w/w) wash, 45 DEG C
It is dried under reduced pressure, produces.
Embodiment 2
Fragrant crude product is replaced to be dissolved in the ethanol solution (1 of appropriate amount 20ml dichloromethane 95% with 1g fumaric acid Lu handkerchief：1, w/w), plus
Thermal agitation flows back and above-mentioned solution to sample is suitably added dropwise and is completely dissolved, and is prepared into saturated solution, saturated solution is naturally cooled to
Room temperature, then at 2-8 DEG C of standing crystallization, separates out bar-shaped crystallization, filtering, with the 2-8 DEG C of ethanol solution (1 of dichloromethane 95%：1, w/w)
Washing, 45 DEG C are dried under reduced pressure, and produce.
Embodiment 3
Fragrant free alkali is replaced to be dissolved in appropriate amount 20ml dichloromethane ethanol solution (1 with 1.0g fumaric acid with Lu's 1.0g handkerchief：1, w/
W), stirring reaction 1hr at room temperature, is concentrated under reduced pressure into 25-30% volumes, solution naturally cools to room temperature, then at 2-8 DEG C of standing
Crystallization, separates out bar-shaped crystallization, filtering, with 2-8 DEG C of dichloromethane ethanol solution (1：1, w/w) wash, 45 DEG C are dried under reduced pressure, i.e.,
.
Embodiment 4
Fragrant free alkali is replaced to be dissolved in appropriate amount 20ml ethyl acetate ethanol solution (1 with 1.0g fumaric acid with Lu's 1.0g handkerchief：
1, w/w), stirring reaction 1hr at room temperature, is concentrated under reduced pressure into 25-30% volumes, solution naturally cools to room temperature, then at 2-8 DEG C
Crystallization is stood, bar-shaped crystallization, filtering, with 2-8 DEG C of ethyl acetate ethanol solution (1 is separated out：1, w/w) wash, 45 DEG C of decompressions
Dry, produce.
Embodiment 5
Fragrant free alkali is replaced to be dissolved in appropriate amount 20ml acetone ethanol solution solution with 1.0g fumaric acid with Lu's 1.0g handkerchief
(3.5：1, w/w), stirring reaction 1hr at room temperature, is concentrated under reduced pressure into 25-30% volumes, solution naturally cools to room temperature, then at
2-8 DEG C of standing crystallization, separates out bar-shaped crystallization, filtering, with the 2-8 DEG C of ethanol solution (3.5 of ethyl acetate 95%：1, w/w) wash, 45
DEG C it is dried under reduced pressure, produces.
Embodiment 6
Fragrant crude product is replaced to be dissolved in appropriate amount 20ml acetone ethanol solution (3.5 with 1g fumaric acid Lu handkerchief：1, w/w), heat
It is stirred at reflux and above-mentioned solution to sample is suitably added dropwise and be completely dissolved, is prepared into saturated solution, saturated solution naturally cools to room
Temperature, then at 2-8 DEG C of standing crystallization, separates out bar-shaped crystallization, filtering, with 2-8 DEG C of acetone ethanol solution (3.5：1, w/w) wash
Wash, 45 DEG C are dried under reduced pressure, and produce.
Embodiment 7
Fragrant free alkali is replaced to be dissolved in appropriate amount 20ml acetone methanol solutions solution (3.5 with 1.0g fumaric acid with Lu's 1.0g handkerchief：1,
W/w), stirring reaction 1hr at room temperature, is concentrated under reduced pressure into 25-30% volumes, solution naturally cools to room temperature, quiet then at 2-8 DEG C
Crystallization is put, bar-shaped crystallization, filtering, with 2-8 DEG C of acetone methanol solution (3.5 is separated out：1, w/w) wash, 45 DEG C are dried under reduced pressure, i.e.,
.
Embodiment 8
Gained fumaric acid Lu of Example 1 to 7 handkerchief replaces fragrant crystal formation B, and grinding, sampling carries out X-ray powder diffraction, radiation
Source is Cu-Ka, and collection of illustrative plates is shown in Fig. 3-4.
Embodiment 9
Fumaric acid Lu handkerchief of embodiment 1 or 2 is detected for sweet smell crystal formation B with differential scanning calorimetric (DSC) method, its fusing point
Decomposed at 186 ± 2 DEG C or so, see that collection of illustrative plates is shown in 5.
Embodiment 10
The gained fumaric acid Lu handkerchief of embodiment 1 or 2 is observed for sweet smell crystal formation B under 100 times of micro- visors, and it is shaped as bar-shaped knot
Crystalline substance, is shown in collection of illustrative plates 6.
Claims (3)
1. a kind of fumaric acid Lu handkerchief replaces fragrant crystal formation B, it is characterised in that：The characteristic peak of the X-ray powder diffraction figure of the crystal formation B with
2 θ ± 0.2 ° represent positioned at 5.9 °, 6.7 °, 8.0 °, 11.7 °, 12.0 °, 12.9 °, 14.5 °, 16.7 °, 17.2 °, 18.9 °,
At 19.7 °, 20.2 °, 22.3 °, 24.4 °, 25.9 °, 27.0 °, 28.8 °, 30.7 °；The described θ of the angle of diffraction 2 is in 5.9 ° of (a), (b)
12.9 °, 22.3 ° of (c), at 27.0 ° of (d) be the distinctive characteristic peaks of crystal formation B；The described θ of the angle of diffraction 2 be located at 8.0 °, 12.0 °,
At 14.5 °, 16.7 °, 17.2 °, 18.9 °, 19.7 °, 20.2 °, 24.4 °, 25.9 °, display have relative line intensity be 30 with
On X-ray diffraction spectral line；The fusing point of the crystal formation B is 186 ± 2 DEG C.
2. a kind of fumaric acid Lu handkerchief as claimed in claim 1 replaces fragrant crystal formation B preparation method, it is characterised in that：Use fumaric acid
Lu Pa replaces fragrant crude product to be dissolved in appropriate amount solvent orange 2 A, and heating stirring backflow prepares saturated solution, then naturally cools to room temperature, then at
2-8 DEG C of standing crystallization, separates out bar-shaped crystallization, and filtering is washed, 45 DEG C are dried under reduced pressure, and produce with 2-8 DEG C of appropriate amount solvent orange 2 A；It is described
Solvent orange 2 A be the ethanol solution of dichloromethane 95%, dichloromethane ethanol solution, ethyl acetate ethanol solution, acetic acid
The ethanol solution of ethyl ester 95%, acetone ethanol solution, the ethanol solution of acetone 95% or acetone methanol solution.
3. a kind of fumaric acid Lu handkerchief as claimed in claim 2 replaces fragrant crystal formation B preparation method, it is characterised in that：Described two
The volume ratio of chloromethanes and 95% ethanol, dichloromethane and ethanol, ethyl acetate and absolute ethyl alcohol, ethyl acetate and 95% ethanol
For 4：1 to 1：4；The volume ratio of described acetone and absolute ethyl alcohol, acetone and 95% ethanol, acetone and methanol is 1：1 to 8：1.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410289491.6A CN104059056B (en) | 2014-06-26 | 2014-06-26 | A kind of fumaric acid Lu handkerchief replaces fragrant crystal formation B and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410289491.6A CN104059056B (en) | 2014-06-26 | 2014-06-26 | A kind of fumaric acid Lu handkerchief replaces fragrant crystal formation B and preparation method thereof |
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| CN104059056B true CN104059056B (en) | 2017-08-25 |
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| CN117263923A (en) * | 2022-06-14 | 2023-12-22 | 福建省闽东力捷迅药业股份有限公司 | Lu Pati-fumaric acid crystal form C and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1391475A (en) * | 1999-09-13 | 2003-01-15 | 布里奇药品有限公司 | Optical isomers of ketotifen and therapeutically active metabolites thereof |
| CN1548044A (en) * | 2003-05-11 | 2004-11-24 | 山东绿因药业有限公司 | Fumaric acid-ketotifen dispersion tablet and its prepn process |
| WO2013000406A1 (en) * | 2011-06-28 | 2013-01-03 | Lin Tongjun | Benzocycloheptanethiophene derivatives for anti-allergic reactions |
-
2014
- 2014-06-26 CN CN201410289491.6A patent/CN104059056B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1391475A (en) * | 1999-09-13 | 2003-01-15 | 布里奇药品有限公司 | Optical isomers of ketotifen and therapeutically active metabolites thereof |
| CN1548044A (en) * | 2003-05-11 | 2004-11-24 | 山东绿因药业有限公司 | Fumaric acid-ketotifen dispersion tablet and its prepn process |
| WO2013000406A1 (en) * | 2011-06-28 | 2013-01-03 | Lin Tongjun | Benzocycloheptanethiophene derivatives for anti-allergic reactions |
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Address after: 355300 No.1 pharmaceutical industry road, Zherong County, Ningde City, Fujian Province Patentee after: Fujian Mindong lijiexin Pharmaceutical Co.,Ltd. Address before: 355300 pharmaceutical industry zone of Zherong County, Fujian, Ningde Patentee before: Fujian Mindong Rejuvenation Pharmaceutical Co.,Ltd. |