CN104844557B - A kind of preparation method of sofalcone known impurities - Google Patents
A kind of preparation method of sofalcone known impurities Download PDFInfo
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- CN104844557B CN104844557B CN201410054596.3A CN201410054596A CN104844557B CN 104844557 B CN104844557 B CN 104844557B CN 201410054596 A CN201410054596 A CN 201410054596A CN 104844557 B CN104844557 B CN 104844557B
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- C07—ORGANIC CHEMISTRY
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- C07D321/00—Heterocyclic compounds containing rings having two oxygen atoms as the only ring hetero atoms, not provided for by groups C07D317/00 - C07D319/00
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Abstract
The invention discloses a kind of preparation method for treating known impurities in Gastric Ulcer Treatment sofalcone bulk drug.The invention provides one kind is with sofalcone as raw material, the impurity sterling is obtained by photocatalysis [2+2] cycloaddition reaction, column chromatography, recrystallization method.The present invention has convieniently synthesized, and the characteristics of not high to the conversion requirements for reacting, products obtained therefrom purity is high, can provide qualified impurity reference substance for the quality control of sofalcone.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of preparation method of the known impurities of sofalcone.
Background technology
Sofalcone [2 '-carboxymethoxyl -4,4 '-two (3- methyl-2-butene epoxides) chalcone] is artificial synthesized one kind
Iso-amylene chalcone（Structure Formulas I）, which acts on and in subprostrate sophora (Sophora Subprostrata Chun et T.Chen) points
From the natural products rope legal (sophoradin) for obtaining quite, there is a very strong antiulcer action, and peso legal stable.Suo Fa
Ketone is researched and developed by Japanese Taisho Pharmaceutical Co., Ltd, and first in Japan's listing, which treats gastric ulcer and chronic gastritis effect within 1999
Mechanism be activity by suppressing prostaglandin metabolism enzyme, increase in stomach lining Prostaglandin.Additionally, the medicine also has
Promote the effect of stomach mucus CBF.Show through clinical research and the popularization and application in more than ten years, the medicine to peptic ulcer, especially
It is that there is to gastric ulcer preferable curative effect, can also be used for the treatment of the diseases such as chronic gastritis.
Have 2 impurity in Japanese Pharmacopoeia sofalcone quality standard, impurity therein 1. " ring type double O- [2,2- dimethyl-
4- (4- (3- methyl-2-butene epoxides)-phenyl) -3- ((4- oxygen -2- carboxymethoxyls)-benzoyl) cyclobutane -1- methyl -] } "
Commercially do not sell, the synthetic method of the impurity was also reported without open source information.
Sofalcone impurity synthetically prepared, contribute to carrying out in a deep going way for sofalcone bulk drug and quality of the pharmaceutical preparations research.According to
Sofalcone impurity prepared by the present invention can be used for the qualitative and quantitative analysis of impurity in sofalcone quality standard research, it can also be used to
The quality control of sofalcone production process, so that improve the product quality of sofalcone.
The Yuan Yan enterprises of Japan（Taisho Pharmaceutical Co., Ltd）The one of a sofalcone has been formulated in the standard of sofalcone
Known impurities are planted, its structure is as follows：
Compound shown in Formula II is the dimer of sofalcone, does not commercially sell, domestic and international at present also not any
Document report and patent refer to the synthesis of the impurity and purification process.
Content of the invention
It is an object of the invention to provide a kind of preparation method of above-mentioned sofalcone known impurities Formula II compound.
The purpose of the present invention can be realized by following measures：
A 2 '-carboxymethoxyl of () compound of formula I -4,4 '-two (3- methyl-2-butene epoxides) chalcone is in room temperature, illumination bar
Under part, reaction generates the mixture containing Formula II compound；
B illumination product that step (a) is obtained by () is separated through silicagel column or gel filtration chromatography, is obtained containing Formula II compound
Crude product；
C crude product refining that step (b) is obtained by (), obtains sterling Formula II compound.
I.e. with sofalcone as raw material, the impurity is prepared using photocatalysis [2+2] cycloaddition reaction.Specifically preparation technology is,
Sofalcone solid is paved into thin layer, in daylight, incandescent lamp etc. in illumination（From lamp and artificial light source）Under the conditions of place, Gu
There is dimerization reaction in body surface face, part generates the compound of Formula II, solid color burn.By illumination of the gained containing Formula II compound
Purify through silica gel column chromatography or gel filtration chromatography after product dissolving, high performance liquid chromatography detection elution profile merges Formula II chemical combination
Thing peak area normalization percentage is not less than 30% wash-out position, and solvent evaporated, with acetone water solution（Plus formic acid or acetic acid acid
Change）Crystallization is recrystallized, and Formula II pure compounds are obtained.
In described step (c), in acetone-water mixture, the ratio of acetone and water is 1:0.1～1.
It is 0.01～0.5 with the volume ratio of acetone-water total amount to add the amount of acidizing reagent in described step (c):1.
In described step (c), acetone consumption is 10 with the volume/weight ratio of impurity:1～100:1, unit is g/mL.
Specific embodiment
The present invention is further described in detail with reference to specific embodiment, the embodiment for being given is only for explaining
The bright present invention, rather than in order to limit the scope of the present invention.
In following examples, impurity purity test adopts the high performance liquid chromatography, testing conditions to be：
Mobile phase：Methanol-acetonitrile-water-glacial acetic acid（50:35:15:1）；Detection wavelength：238nm；Flow velocity：1mL/min；
The purity that sofalcone impurity is calculated using HPLC areas of peak normalization method.
The Structural Identification of impurity adopts 1H-NMR methods, 13C-NMR methods and LC-MS-ESI (+) method：
The detecting instrument of 1H-NMR, 13C-NMR：Bruker AV400NMR；Solvent is deuterated acetone（CD3COCD3）.
The detecting instrument of high resolution mass spectrum：Thermo Finnigan LCQ Advantage Max；
Embodiment 1
10g sofalcone solids are taken, is placed in colourless measuring cup, is paved into thin layer, be placed under periods of direct sunlight and place, add up irradiation
30h, in bottle, solid color burn is into brown；By solid in bottle with a small amount of acetone solution, proper silica gel mixes sample, lives to chromatograph through silica gel
Isolate and purify, with petroleum ether-acetone gradient elution（Eluent adds about 0.1% formic acid）, collect petroleum ether-acetone 5:1～4:1
Wash-out position；Eluting solvent is evaporated, solid about 0.5g is obtained, is redissolved with 50mL acetone, instilled formic acid 0.6mL, add 5mL
Water, heating clarify solution, and room temperature is placed and separates out crystallization；Crystallization is leached, is repeated above-mentioned crystallisation step, is obtained colorless needle crystals
0.2g, high performance liquid chromatography detection purity are 98%.
Carbon-13 nmr spectra data：
202.7,170.5,163.5,158.5,158.4,137.4,132.7,131.7,129.9,123.1,121.3,
114.9,106.4,101.3,67.9,65.4,65.3,51.7,50.5,50.3,39.9,29.6,25.7,18.4,18.1
Hydrogen nuclear magnetic resonance modal data：
7.25（2H,dd）,7.08（1H,d,J=8.8）,6.88（2H,dd）,6.48（1H,dd,J=2,8.8）,6.25（1H,
d,J=2）,5.44（1H,m）,4.86（1H,d）,4.84（2H,d）,4.53（Ha,d）,4.51（2H,t）,4.1（Hb,dd）,3.54
（1H,m）,2.35（1H,m）,1.76（3H,s）,1.75（3H,s）,1.29（3H,s）,0.83（3H,s）
High resolution mass spectrum data：
M/z is 901.4162, and molecular formula is C54H60O12
Embodiment 2
5g sofalcone solids are taken, are placed in colourless measuring cup, are paved into thin layer, placed under fluorescent lamp, add up irradiation 60h,
In bottle, solid color burn is into brown；By solid in bottle with a small amount of acetone solution, proper silica gel mixes sample, lives chromatography through silica gel
Purifying, with petroleum ether-acetone gradient elution（Eluent adds about 0.1% formic acid）, collect petroleum ether-acetone 5:1～4:1 washes
De- position；Solid about 0.3g is obtained, eluting solvent is evaporated, is redissolved with 30mL acetone, instilled formic acid 6mL, add 30mL water, heated
Clarify solution, room temperature is placed and separates out crystallization；Crystallization is leached, repeats above-mentioned crystallisation step, obtain colorless needle crystals 0.04g,
High performance liquid chromatography detection purity is 95%.
Carbon-13 nmr spectra data：
202.6,170.4,163.5,158.6,158.4,136.2,133.1,132.0,130.1,123.2,121.3,
115.1,106.5,101.6,68.1,65.4,65.4,51.8,50.5,50.3,40.2,29.6,25.8,18.5,18.2
Hydrogen nuclear magnetic resonance modal data：
7.25（2H,dd）,7.09（1H,d,J=8.8）,6.86（2H,dd）,6.47（1H,dd,J=2,8.8）,6.25（1H,
d,J=2）,5.44（1H,m）,4.87（1H,d）,4.85（2H,d）,4.54（Ha,d）,4.52（2H,t）,4.11（Hb,dd）,
3.54（1H,m）,2.36（1H,m）,1.77（3H,s）,1.76（3H,s）,1.30（3H,s）,0.84（3H,s）
High resolution mass spectrum data：
M/z is 901.4257, and molecular formula is C54H60O12
Embodiment 3
10g sofalcone solids are taken, is placed in colourless transparent plastic bag, is paved into thin layer, placed under high-pressure sodium lamp, add up to shine
40h is penetrated, solid color from pale yellow color deepens into brown in bag；By solid in bottle with a small amount of acetone solution, separate through gel chromatography
Purifying, is eluted with acetone, collects the brown colour band for eluting at first；Eluting solvent is evaporated, about 1g solids are obtained, with 10mL acetone
Redissolve, instill formic acid 6mL, add 2mL water, heating clarifies solution, and room temperature is placed and separates out crystallization；Crystallization is leached, is repeated
Above-mentioned crystallisation step, obtains colorless needle crystals about 0.3g, and high performance liquid chromatography detection purity is 93%.
Carbon-13 nmr spectra data：
202.7,170.6,164.2,158.8,158.6,137.0,133.4,132.2,130.2,123.3,121.5,
115.5,106.6,101.8,68.2,65.4,65.4,51.9,50.5,50.3,40.2,29.8,25.9,18.6,18.4
Hydrogen nuclear magnetic resonance modal data：
7.24（2H,dd）,7.08（1H,d,J=8.8）,6.88（2H,dd）,6.48（1H,dd,J=2,8.8）,6.24（1H,
d,J=2）,5.42（1H,m）,4.86（1H,d）,4.85（2H,d）,4.53（Ha,d）,4.50（2H,t）,4.08（Hb,dd）,
3.53（1H,m）,2.35（1H,m）,1.76（3H,s）,1.75（3H,s）,1.28（3H,s）,0.83（3H,s）
High resolution mass spectrum data：
M/z is 901.4198, and molecular formula is C54H60O12.
Claims (7)
1. a kind of preparation method of Formula II compound, comprises the following steps：
A () compound of formula I 2'- carboxymethoxyl -4,4'- two (3- methyl-2-butene epoxides) chalcone is under room temperature, illumination condition
Reaction generates the mixture containing Formula II compound；
B illumination product that step (a) is obtained by () is separated through silicagel column or gel filtration chromatography, is obtained containing the thick of Formula II compound
Product；
C crude product refining that step (b) is obtained by (), obtains sterling Formula II compound.
2. preparation method as claimed in claim 1, it is characterised in that the compound of formula I described in step (a) is in solid form
It is placed under room temperature, illumination condition and is reacted.
3. preparation method as claimed in claim 1, it is characterised in that the illumination condition described in step (a) is selected from natural light
Source, the artificial light sources with the output of visible and/or near ultraviolet.
4. preparation method as claimed in claim 1, it is characterised in that the process for purification described in step (c) is recrystallization.
5. preparation method as claimed in claim 4, it is characterised in that used by the method for recrystallizing and refining described in step (c)
Solvent be acidified acetone-water mixture；Described acidizing reagent is formic acid or acetic acid.
6. preparation method as claimed in claim 5, it is characterised in that acetone in the acetone-water mixture described in step (c)
Ratio with water is 1:0.1～1.
7. preparation method as claimed in claim 5, it is characterised in that the amount of the addition acidizing reagent described in step (c) with
The volume ratio of acetone-water total amount is 0.01～0.5:1.
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| CN111253473B (en) * | 2020-03-09 | 2020-12-01 | 长沙晨辰医药科技有限公司 | Preparation method of bacitracin impurity L based on photocatalysis |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3928421A (en) * | 1973-10-30 | 1975-12-23 | Taisho Pharmaceutical Co Ltd | Anti-gastric ulcer chalcone ethers |
| JPH0558885A (en) * | 1991-02-12 | 1993-03-09 | Taisho Pharmaceut Co Ltd | Antiulcer agent |
| JP2011057667A (en) * | 2009-08-12 | 2011-03-24 | Taisho Pharmaceutical Co Ltd | Prophylactic or therapeutic agent for keratoconjunctive disease |
| CN102037346A (en) * | 2008-04-16 | 2011-04-27 | 明智全像公司 | Photopolymerizable compositions |
-
2014
- 2014-02-18 CN CN201410054596.3A patent/CN104844557B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3928421A (en) * | 1973-10-30 | 1975-12-23 | Taisho Pharmaceutical Co Ltd | Anti-gastric ulcer chalcone ethers |
| JPH0558885A (en) * | 1991-02-12 | 1993-03-09 | Taisho Pharmaceut Co Ltd | Antiulcer agent |
| CN102037346A (en) * | 2008-04-16 | 2011-04-27 | 明智全像公司 | Photopolymerizable compositions |
| JP2011057667A (en) * | 2009-08-12 | 2011-03-24 | Taisho Pharmaceutical Co Ltd | Prophylactic or therapeutic agent for keratoconjunctive disease |
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Address after: 300193 Tianjin City, Nankai District Anshan West Road No. 308 Applicant after: TIANJIN INSTITUTE OF PHARMACEUTICAL RESEARCH CO., LTD. Address before: 300193 Tianjin City, Nankai District Anshan West Road No. 308 Applicant before: Tianjin Drug Inst. |
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