CN107936045A - A kind of preparation method of high-purity Flurbiprofen known impurities - Google Patents
A kind of preparation method of high-purity Flurbiprofen known impurities Download PDFInfo
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- CN107936045A CN107936045A CN201711246970.XA CN201711246970A CN107936045A CN 107936045 A CN107936045 A CN 107936045A CN 201711246970 A CN201711246970 A CN 201711246970A CN 107936045 A CN107936045 A CN 107936045A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
- C07F3/02—Magnesium compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
Abstract
The invention discloses a kind of preparation method of Flurbiprofen known impurities B, including by the tetrahydrofuran solution of 4 bromine of starting material, 2 fluorine biphenyl, with magnesium through grignard reaction, with 2 bromine 2 of side chain, it is acidified after the coupling docking of 3 dimethyl succinic acid sodium, the crude product of the Flurbiprofen impurity is made, the Flurbiprofen impurity B of high-purity can be obtained by recrystallization, i.e. 2 (2 fluorine, 4 xenyl) 2,3 dimethyl succinic acids.The preparation method of the present invention is easy to operate, and the reaction time is short, and the purity of product is high, high income, suitable industrialized production.The impurity B of synthesis can be used for the Qualitative and quantitative analysis of impurity, so as to improve the drug safety of Flurbiprofen.
Description
Technical field
The invention belongs to medical science and Pharmaceutical Analysis field, is more specifically to known to a kind of high-purity Flurbiprofen
Impurity preparation method, and impurity 2- (the fluoro- 4- xenyls of 2-) -2,3- dimethyl succinic acids are as Flurbiprofen quality control
The purposes of standard items.
Background technology
Entitled (±) -2- (the fluoro- 4- xenyls of the 2-)-propionic acid of Flurbiprofen (flurbiprofen) chemistry, white or class are white
Color crystalline powder.It is readily soluble in methanol, ethanol, acetone or ether, dissolved in acetonitrile, it is almost insoluble in water.Molecular formula
For C15H13FO2.Flurbiprofen (CAS：5104-49-4, flurbiprofen) molecular formula is as follows：
Flurbiprofen is a kind of fluorine-containing non-steroidal anti-inflammatory drugs, is clinically primarily adapted for use in rheumatoid arthritis, Bones and joints
Inflammation, ankylosing spondylitis etc..Soft tissue disease's (as sprained and straining) and light moderate pain be can also be used for (after such as dysmenorrhoea and operation
Pain, toothache etc.) symptomatic treatment.
The eighties in last century, Japanese three large bamboo hat with a conical crown and broad brim companies develop the approval listing of Flurbiprofen Babu cream, and clinically make extensively
With.China is from three large bamboo hat with a conical crown and broad brim company import Flurbiprofen Babu creams (trade name " Zepu think of "), and big with drugloading rate, skin is anti-without allergy
Should and stimulation, without pain and noresidue is drawn during stripping, the advantages that easy to autonomous medication, show good market prospects.
In order to ensure the drug safety of Flurbiprofen and quality, it is necessary to rigorous scrupulous research be carried out to its related impurities, by impurity control
Make the limits in safe and reasonable.
Now only have the Flurbiprofen related impurities that European Pharmacopoeia standard is included, mainly have：Impurity A (formula A), impurity B (formula
B), impurity C (formula C), impurity D (formula D) and impurity E (formula E), and the related impurities such as Flurbiprofen synthesis technique intermediate.
2- (the fluoro- 4- xenyls of 2-) -2,3- dimethyl succinic acids (it is popular to be known as Flurbiprofen impurity B, hereafter by this letter
Claim), since the compound is rarely reported in open source literature, it also there are no the correlation for preparing the impurity (formula B) in the prior art
Report.
Therefore, its correlative study for Flurbiprofen impurity is significant, can be used for miscellaneous in Flurbiprofen production
Matter Qualitative and quantitative analysis, so as to improve the quality standard of Flurbiprofen, for Flurbiprofen safe medication provide it is important
Directive significance.
The content of the invention
Blank in terms of the purpose of the present invention is filling up Flurbiprofen impurity B synthesis, there is provided one kind prepares high-purity fluorine ratio
The method of ibuprofen impurity B.Flurbiprofen impurity B has very high technical difficulty in synthesis, and the bromo- 2- fluorine biphenyl of 4- is through anhydrous nothing
Oxygen condition grignard reaction, then with side chain (bromo- 2, the 3- dimethyl succinic acids sodium of 2-, in the art routine techniques obtain) coupling pair
Connect, synthetic route is as follows：
The technical scheme is that：A kind of high-purity Flurbiprofen impurity preparation method, it is characterized in that, with the bromo- 2- of 4-
Fluorine biphenyl (compound 1) is raw material, grignard reaction occurs with magnesium powder, then (bromo- 2, the 3- dimethyl succinic acids sodium of 2-, changes with side chain
Compound 4) coupling docking, acidifying, up to impurity B.
This method comprises the following steps：
(1) the bromo- 2- fluorine biphenyl of 4- and anhydrous tetrahydro furan are uniformly mixed, be added dropwise in magnesium powder under nitrogen protection；
(2) under the conditions of controlling 20~65 DEG C of temperature, stirring reaction 1~2h, TLC monitoring reaction process；
(3) after the completion of reacting, grignard reaction liquid is cooled to room temperature, spare.
(4) under nitrogen protection, it is slowly added to bromo- 2, the 3- dimethyl succinic acids sodium of 2-；20~65 DEG C of stirring reactions 1 of temperature control~
2h。
(5) after the completion of reacting, solvent is removed under reduced pressure, adds toluene and dilute hydrochloric acid, stirs rising temperature for dissolving, separates organic phase；
Water phase toluene extracts once, merges organic phase, and with purifying water washing to neutrality, cool down crystallization after the precipitation solid that is concentrated under reduced pressure, mistake
Filter obtains off-white powder, dry, up to the crude product of 2- (the fluoro- 4- xenyls of 2-) -2,3- dimethyl succinic acids.
(6) the recrystallizing and refining step by above-mentioned impurity crude product by appropriate solvent, obtains the impurity.
Further, the molar ratio of the bromo- 2- fluorine biphenyl of wherein 4- and magnesium powder is 1.0: 1.0~1.2；
Preferably, the molar ratio of the bromo- 2- fluorine biphenyl of 4- and magnesium powder is 1.0: 1.1.
Further, the volume of tetrahydrofuran is 2~6 times of the bromo- 2- fluorine biphenyl weight of 4-；
Further, grignard reaction liquid and bromo- 2, the 3- dimethyl succinic acids sodium molar ratios of 2- are 1.0: 1.0~1.5,
Preferably, grignard reaction liquid and bromo- 2, the 3- dimethyl succinic acids sodium molar ratios of 2- are 1.0: 1.1
Further, the preparation method of the impurity B (formula B) further includes following purification step：
(a) by the mixed solvent or isopropanol of the mixed solvent of the impurity crude product first alcohol and water, either second alcohol and water
With the mixed solvent of water, dissolve by heating, wherein, methanol/ethanol/isopropyl alcohol and water mixed volume ratio is methanol/ethanol/isopropanol
: water=1~5: 1 (v/v)；
(b) under heat-retaining condition, 0.5~1h of proper amount of active carbon decoloration；Activated carbon dosage 1%~10%；
(c) insulation filtering, filtrate are cooled to 0~10 DEG C, 1~2h of stirring and crystallizing, and filtering, filter cake is dried under reduced pressure, up to 2-
The highly finished product of (the fluoro- 4- xenyls of 2-) -2,3- dimethyl succinic acids
Preferably, the mixed volume ratio of first alcohol and water is methanol: water=1: 1；The mixture of ethanol/isopropyl alcohol and water
Product ratio is ethanol/isopropanol: water=2: 1.
Further, the dosage of activated carbon is the 2~5% of the impurity crude product in step (b).
The invention discloses a kind of known impurities of Flurbiprofen, i.e. 2- (the fluoro- 4- xenyls of 2-) -2,3- dimethyl butyrates two
The preparation method of acid, has no related report in existing literature.For the present invention using the bromo- 2- fluorine biphenyl of 4- as raw material, tetrahydrofuran is molten
Agent and magnesium powder generation Grignard Reagent, then with bromo- 2, the 3- dimethyl succinic acids sodium of 2- (routine techniques acquisition in the art) coupling pair
Connect, the crude product of the Flurbiprofen impurity is made, the known impurities (formula B) of the Flurbiprofen of high-purity can be obtained by recrystallization.
The beneficial effects of the invention are as follows：The preparation method of the present invention is easy to operate, and the reaction time is short, and the purity of product is high,
High income, suitable industrialized production.The impurity B of synthesis can be used for the Qualitative and quantitative analysis of impurity, so as to improve fluorine ratio
The drug safety of ibuprofen.
Embodiment
It should be understood that those skilled in the art give content disclosed herein, the present invention can be carried out it is various without departing from
Various modifications and improvements in spirit and scope of the invention.They should all fall the patent defined in claims hereof and protect
In the range of shield.Moreover, it should be understood that embodiment provided herein is merely to illustrate the purpose of invention, and should not be construed as to this
The limitation of invention.
The present invention is described in further detail with reference to specific embodiment.
Embodiment 1
Magnesium powder (2.55g, 0.105mol) is added into reaction bulb, under nitrogen protection stirring, the bromo- 2- fluorine biphenyl of 4- is added dropwise
Anhydrous tetrahydro furan (125ml) solution of (25.1g, 0.1mol), controls 20~35 DEG C of temperature, is added dropwise, temperature rising reflux
(65 DEG C) reaction 2h, TLC monitoring reactions finish；Nitrogen protection decline warms to room temperature, and is slowly added to bromo- 2, the 3- dimethyl butyrates of 2-
Diacid sodium (26.9g, 0.1mol), finishes, and heat up 65 DEG C of reaction 2h.；Reaction finishes, and removes solvent under reduced pressure, adds toluene
(125ml) and dilute hydrochloric acid (125ml), stands after stirring rising temperature for dissolving, separates organic phase, water is mutually with toluene (50ml) extraction one
It is secondary, merge organic phase, for purifying water washing to neutrality, organic phase has been concentrated under reduced pressure into solid precipitation, stops concentration, and cool down crystallization,
It is obtained by filtration off-white powder, depressurizes 50 DEG C of dryings, up to the crude product of 2- (the fluoro- 4- xenyls of 2-) -2,3- dimethyl succinic acids,
25.3g, molar yield 80.0%.
Embodiment 2
By crude product 10g, first alcohol and water (1: 1, v/v) 70ml of 2- (the fluoro- 4- xenyls of 2-) -2,3- dimethyl succinic acids,
Stirring is lower to be dissolved by heating, and adds activated carbon 0.2g, reflux decoloration 0.5h, heat filtering, lower 0~10 DEG C of the cooling of filtrate stirring, crystallization
1h, filtering, the 45 DEG C of dryings of filter cake reduced vacuum, obtain 2- (the fluoro- 4- xenyls of 2-) -2,3- dimethyl succinic acid highly finished product 7.72g,
HPLC purity 99.1%, yield 77.2%.
Embodiment 3
By crude product 10g, second alcohol and water (2: 1, v/v) 50ml of 2- (the fluoro- 4- xenyls of 2-) -2,3- dimethyl succinic acids,
Stirring is lower to be dissolved by heating, and adds activated carbon 0.5g, reflux decoloration 0.5h, heat filtering, lower 0~10 DEG C of the cooling of filtrate stirring, crystallization
1h, filtering, the 45 DEG C of dryings of filter cake reduced vacuum, obtain 2- (the fluoro- 4- xenyls of 2-) -2,3- dimethyl succinic acid highly finished product 7.55g,
HPLC purity 99.4%, yield 75.5%.
Embodiment 4
Magnesium powder (2.67g, 0.11mol) is added into reaction bulb, under nitrogen protection stirring, the bromo- 2- fluorine biphenyl of 4- is added dropwise
Anhydrous tetrahydro furan (125ml) solution of (25.1g, 0.1mol), controls 20~35 DEG C of temperature, is added dropwise, temperature rising reflux
(65 DEG C) reaction 2h, TLC monitoring reactions finish；Nitrogen protection decline warms to room temperature, and is slowly added to bromo- 2, the 3- dimethyl butyrates of 2-
Diacid sodium (29.6g, 0.11mol), finishes, and heat up 65 DEG C of reaction 2h.；Reaction finishes, and removes solvent under reduced pressure, adds toluene
(125ml) and dilute hydrochloric acid (125ml), stands after stirring rising temperature for dissolving, separates organic phase, water is mutually with toluene (50ml) extraction one
It is secondary, merge organic phase, for purifying water washing to neutrality, organic phase has been concentrated under reduced pressure into solid precipitation, stops concentration, and cool down crystallization,
It is obtained by filtration off-white powder, depressurizes 50 DEG C of dryings, up to the crude product of 2- (the fluoro- 4- xenyls of 2-) -2,3- dimethyl succinic acids,
25.8g, molar yield 81.6%.
Embodiment 5
By the crude product 10g of 2- (the fluoro- 4- xenyls of 2-) -2,3- dimethyl succinic acids, isopropyl alcohol and water (2: 1, v/v)
55ml, stirs lower heating for dissolving, adds activated carbon 0.5g, and flow back decoloration 0.5h, heat filtering, 0~10 DEG C of cooling under filtrate stirring,
Crystallization 1h, filtering, the 45 DEG C of dryings of filter cake reduced vacuum, obtain 2- (the fluoro- 4- xenyls of 2-) -2,3- dimethyl succinic acid highly finished product
7.48g, HPLC purity 99.3%, yield 74.8%.
Embodiment 6
By crude product 10g, first alcohol and water (1: 1, v/v) 70ml of 2- (the fluoro- 4- xenyls of 2-) -2,3- dimethyl succinic acids,
Stirring is lower to be dissolved by heating, and adds activated carbon 0.5g, reflux decoloration 0.5h, heat filtering, lower 0~10 DEG C of the cooling of filtrate stirring, crystallization
1h, filtering, the 45 DEG C of dryings of filter cake reduced vacuum, obtain 2- (the fluoro- 4- xenyls of 2-) -2,3- dimethyl succinic acid highly finished product 7.60g,
HPLC purity 99.2%, yield 76.0%.
The spectral data of impurity B：
1, mass spectrometric data MS (ESI-Neg)：[M-H]-=315.1, it is consistent with molecular weight analyte 316；
2, nucleus magnetic hydrogen spectrum data1H-NMR (deuterated methanol, Brooker 300MHz)：δ ppm 1.275-1.298 (d ,-CH-
CH3,3H, J=6.9Hz)；1.544,1.753 (s ,-C-CH3,3H)；(3.305-3.321 m ,-CH-CH3,1H)；7.7190-
7.531 (m ,-CH-CH (phenyl ring), 8H).
Claims (3)
1. a kind of already known processes impurity B of Flurbiprofen, i.e.,：The preparation of 2- (the fluoro- 4- xenyls of 2-) -2,3- dimethyl succinic acids
Method, it is characterised in that this method comprises the following steps：
(1) the bromo- 2- fluorine biphenyl of 4- and anhydrous tetrahydro furan are uniformly mixed, the volume of wherein tetrahydrofuran is under nitrogen protection
2~6 times of the bromo- 2- fluorine biphenyl weight of 4-；The molar ratio of the bromo- 2- fluorine biphenyl of 4- and magnesium powder is 1.0: 1.0~1.2；
(2) under the conditions of controlling 20~65 DEG C of temperature, stirring reaction 1~2h, TLC monitoring reaction process；
(3) after the completion of reacting, grignard reaction liquid is cooled to room temperature, spare.
(4) under nitrogen protection, bromo- 2, the 3- dimethyl succinic acids sodium of 2-, grignard reaction liquid and bromo- 2, the 3- dimethyl of 2- are slowly added to
Sodium succinate molar ratio is 1.0: 1.0~1.5,20~65 DEG C of 1~2h of stirring reaction of temperature control.
(5) after the completion of reacting, solvent is removed under reduced pressure, adds toluene and dilute hydrochloric acid, stirs rising temperature for dissolving, separates organic phase；Water phase
Toluene extracts once, merges organic phase, and with purifying water washing to neutrality, cool down crystallization after the precipitation solid that is concentrated under reduced pressure, and filters
It is dry to off-white powder, up to the crude product of 2- (the fluoro- 4- xenyls of 2-) -2,3- dimethyl succinic acids
(6) the recrystallizing and refining step by above-mentioned impurity crude product by appropriate solvent, obtains the impurity.
2. preparation method according to claim 1, it is characterised in that the purification step of step (6) includes the following steps：
(a) by the mixed solvent of the impurity crude product first alcohol and water, the either mixed solvent of second alcohol and water or isopropyl alcohol and water
Mixed solvent, dissolve by heating, wherein, methanol/ethanol/isopropyl alcohol and water mixed volume ratio is methanol/ethanol/isopropanol: water
=1~5: 1；
(b) under heat-retaining condition, 0.5~1h of proper amount of active carbon decoloration；Activated carbon dosage 1%~10%；
(c) insulation filtering, filtrate are cooled to 0~10 DEG C, 1~2h of stirring and crystallizing, and filtering, filter cake is dried under reduced pressure, up to 2- (2-
Fluoro- 4- xenyls) -2,3- dimethyl succinic acids highly finished product.
3. preparation method according to claim 2, it is characterised in that first alcohol and water mixed volume in the step (1)
Than for 1: 1, ethanol/isopropyl alcohol and water mixed volume ratio is 2: 1.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112457182A (en) * | 2020-12-16 | 2021-03-09 | 江苏慧聚药业有限公司 | Preparation method of flurbiprofen impurity |
| CN113956160A (en) * | 2021-12-23 | 2022-01-21 | 北京茗泽中和药物研究有限公司 | Preparation method of flurbiprofen impurity F |
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|---|---|---|---|---|
| GB2065656A (en) * | 1979-12-19 | 1981-07-01 | Upjohn Co | Preparing arylpropionic acids |
| US4518799A (en) * | 1979-12-19 | 1985-05-21 | The Upjohn Company | Processes for the preparation of hydratropic acids |
| CN104447310A (en) * | 2013-09-18 | 2015-03-25 | 南京卡文迪许生物工程技术有限公司 | Defluorinated flurbiprofen axetil compound, and preparation method, pharmaceutical composition and application thereof |
| CN105407718A (en) * | 2013-06-04 | 2016-03-16 | 维奥姆生物科学有限公司 | Coated particles and compositions comprising same |
| CN106905143A (en) * | 2017-01-05 | 2017-06-30 | 武汉先路医药科技股份有限公司 | Crystal formation of flurbiprofen sodium and preparation method thereof |
-
2017
- 2017-12-01 CN CN201711246970.XA patent/CN107936045B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2065656A (en) * | 1979-12-19 | 1981-07-01 | Upjohn Co | Preparing arylpropionic acids |
| US4518799A (en) * | 1979-12-19 | 1985-05-21 | The Upjohn Company | Processes for the preparation of hydratropic acids |
| CN105407718A (en) * | 2013-06-04 | 2016-03-16 | 维奥姆生物科学有限公司 | Coated particles and compositions comprising same |
| CN104447310A (en) * | 2013-09-18 | 2015-03-25 | 南京卡文迪许生物工程技术有限公司 | Defluorinated flurbiprofen axetil compound, and preparation method, pharmaceutical composition and application thereof |
| CN106905143A (en) * | 2017-01-05 | 2017-06-30 | 武汉先路医药科技股份有限公司 | Crystal formation of flurbiprofen sodium and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112457182A (en) * | 2020-12-16 | 2021-03-09 | 江苏慧聚药业有限公司 | Preparation method of flurbiprofen impurity |
| CN113956160A (en) * | 2021-12-23 | 2022-01-21 | 北京茗泽中和药物研究有限公司 | Preparation method of flurbiprofen impurity F |
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