CN107936045B - 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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- CN107936045B CN107936045B CN201711246970.XA CN201711246970A CN107936045B CN 107936045 B CN107936045 B CN 107936045B CN 201711246970 A CN201711246970 A CN 201711246970A CN 107936045 B CN107936045 B CN 107936045B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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
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Abstract
The invention discloses the preparation methods of Flurbiprofen known impurities B a kind of, including by the tetrahydrofuran solution of the bromo- 2- fluorine biphenyl of starting material 4-, with magnesium through grignard reaction, with side chain 2- bromo- 2, 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 recrystallizing, that is 2- (the fluoro- 4- xenyl of 2-) -2,3- dimethyl succinic acid.Preparation method of the invention is easy to operate, and the reaction time is short, the purity is high of product, high income, is suitable for industrialized production.The impurity B of synthesis can be used for the Qualitative and quantitative analysis of impurity, to improve the drug safety of Flurbiprofen.
Description
Technical field
The invention belongs to medical science and Pharmaceutical Analysis field, known to more specifically to a kind of high-purity Flurbiprofen
Impurity preparation method and impurity 2- (the fluoro- 4- xenyl of 2-) -2,3- dimethyl succinic acid are controlled as Flurbiprofen quality
The purposes of standard items.
Background technique
Entitled (±) -2- (the fluoro- 4- xenyl of the 2-)-propionic acid of Flurbiprofen (flurbiprofen) chemistry, white or class are white
Color crystalline powder.It is readily soluble in methanol, ethyl alcohol, acetone or ether, it is 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 dysmenorrhea 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 has drugloading rate big, skin is anti-without allergy from three large bamboo hat with a conical crown and broad brim company import Flurbiprofen Babu creams (trade name " Zepu think of ")
Should and stimulation, the advantages that when removing without drawing pain and noresidue, being convenient for autonomous medication, show good market prospects.
In order to guarantee the drug safety and quality of Flurbiprofen, need to carry out its related impurities rigorous scrupulous research, by impurity control
Make the limits in safe and reasonable.
Now only have the Flurbiprofen related impurities that European Pharmacopoeia standard is included, mainly has: impurity A (formula A), impurity B (formula
B), the related impurities such as impurity C (formula C), impurity D (formula D) and impurity E (formula E) and Flurbiprofen synthesis technology intermediate.
2- (the fluoro- 4- xenyl of 2-) -2,3- dimethyl succinic acid (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, significant for the correlative study of Flurbiprofen impurity, it 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.
Summary of the invention
The purpose of the present invention is filling up the blank of Flurbiprofen impurity B synthesis aspect, provides and a kind of prepare 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 acid sodium of 2-, in the art routine techniques obtain) coupling pair
It connects, synthetic route is as follows:
The technical scheme is that a kind of high-purity Flurbiprofen impurity preparation method, 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 acid sodium of 2- is changed with side chain
Close object 4) coupling docking, it is acidified to get impurity B.
This method comprises the following steps:
(1) the bromo- 2- fluorine biphenyl of 4- and anhydrous tetrahydro furan are uniformly mixed, are added dropwise in magnesium powder under nitrogen protection；
(2) under the conditions of controlling 20~65 DEG C of temperature, it is stirred to react 1~2h, TLC monitors reaction process；
(3) after the reaction was completed, grignard reaction liquid is cooled to room temperature, spare.
(4) under nitrogen protection, it is slowly added to bromo- 2, the 3- dimethyl succinic acid sodium of 2-；20~65 DEG C of temperature control be stirred to react 1~
2h。
(5) after the reaction was completed, solvent is removed under reduced pressure, toluene and dilute hydrochloric acid is added, stirs rising temperature for dissolving, separates organic phase；
The extraction of water phase toluene is primary, merges organic phase, and with purifying water washing to neutrality, the crystallization that cools down, mistake is concentrated under reduced pressure after solid is precipitated
Filter obtains off-white powder, the dry crude product to get 2- (the fluoro- 4- xenyl of 2-) -2,3- dimethyl succinic acid.
(6) the recrystallizing and refining step that above-mentioned impurity crude product is passed through to appropriate solvent, obtains the impurity.
Further, wherein the molar ratio of the bromo- 2- fluorine biphenyl of 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 acid sodium molar ratio of 2- are 1.0: 1.0~1.5,
Preferably, grignard reaction liquid and bromo- 2, the 3- dimethyl succinic acid sodium molar ratio 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 impurity crude product first alcohol and water perhaps second alcohol and water
It with the mixed solvent of water, dissolves 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) heat preservation filtering, filtrate are cooled to 0~10 DEG C, 1~2h of stirring and crystallizing, and filtering, filter cake is dried under reduced pressure to get 2-
The highly finished product of (the fluoro- 4- xenyl of 2-) -2,3- dimethyl succinic acid
Preferably, the mixed volume ratio of first alcohol and water is methanol: water=1: 1；Ethyl alcohol/isopropyl alcohol and water mixture
Product is than being ethyl alcohol/isopropanol: water=2: 1.
Further, the dosage of active 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- xenyl of 2-) -2,3- dimethyl butyrate 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 generate Grignard Reagent, then with bromo- 2, the 3- dimethyl succinic acid sodium of 2- (routine techniques acquisition in the art) coupling pair
It connects, the crude product of the Flurbiprofen impurity is made, the known impurities (formula B) of the Flurbiprofen of high-purity can be obtained by recrystallizing.
The beneficial effects of the present invention are: preparation method of the invention is easy to operate, the reaction time is short, the purity is high of product,
High income is suitable for industrialized production.The impurity B of synthesis can be used for the Qualitative and quantitative analysis of impurity, to improve fluorine ratio
The drug safety of ibuprofen.
Specific 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 in the patent that claims hereof defines and protect
It protects in range.Moreover, it should be understood that embodiment provided herein is merely to illustrate the purpose of invention, but should not be understood as to this
The limitation of invention.
The present invention is described in further detail combined with specific embodiments below.
Embodiment 1
Magnesium powder (2.55g, 0.105mol) is added into reaction flask, 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) reactions 2h, TLC monitor end of reaction；Nitrogen protection decline warms to room temperature, and is slowly added to bromo- 2, the 3- dimethyl butyrate of 2-
Diacid sodium (26.9g, 0.1mol), finishes, and heats up 65 DEG C and reacts 2h.；Toluene is added in end of reaction, evaporating solvent under reduced pressure
(125ml) and dilute hydrochloric acid (125ml) is stood after stirring rising temperature for dissolving, separates organic phase, and water phase extracts one with toluene (50ml)
It is secondary, merge organic phase, purifies water washing to neutrality, organic phase has been concentrated under reduced pressure into solid precipitation, stops concentration, and cool down crystallization,
Off-white powder is obtained by filtration, depressurizes 50 DEG C of dryings to get the crude product of 2- (the fluoro- 4- xenyl of 2-) -2,3- dimethyl succinic acid,
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- xenyl of 2-) -2,3- dimethyl succinic acid,
Stirring is lower to be dissolved by heating, and active carbon 0.2g, reflux decoloration 0.5h, heat filtering, lower 0~10 DEG C of the cooling of filtrate stirring, crystallization is added
1h, filtering, the 45 DEG C of dryings of filter cake reduced vacuum obtain 2- (the fluoro- 4- xenyl 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- xenyl of 2-) -2,3- dimethyl succinic acid,
Stirring is lower to be dissolved by heating, and active carbon 0.5g, reflux decoloration 0.5h, heat filtering, lower 0~10 DEG C of the cooling of filtrate stirring, crystallization is added
1h, filtering, the 45 DEG C of dryings of filter cake reduced vacuum obtain 2- (the fluoro- 4- xenyl 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 flask, 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) reactions 2h, TLC monitor end of reaction；Nitrogen protection decline warms to room temperature, and is slowly added to bromo- 2, the 3- dimethyl butyrate of 2-
Diacid sodium (29.6g, 0.11mol), finishes, and heats up 65 DEG C and reacts 2h.；Toluene is added in end of reaction, evaporating solvent under reduced pressure
(125ml) and dilute hydrochloric acid (125ml) is stood after stirring rising temperature for dissolving, separates organic phase, and water phase extracts one with toluene (50ml)
It is secondary, merge organic phase, purifies water washing to neutrality, organic phase has been concentrated under reduced pressure into solid precipitation, stops concentration, and cool down crystallization,
Off-white powder is obtained by filtration, depressurizes 50 DEG C of dryings to get the crude product of 2- (the fluoro- 4- xenyl of 2-) -2,3- dimethyl succinic acid,
25.8g, molar yield 81.6%.
Embodiment 5
By the crude product 10g of 2- (the fluoro- 4- xenyl of 2-) -2,3- dimethyl succinic acid, isopropyl alcohol and water (2: 1, v/v)
55ml stirs lower heating for dissolving, active carbon 0.5g is added, 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- xenyl 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- xenyl of 2-) -2,3- dimethyl succinic acid,
Stirring is lower to be dissolved by heating, and active carbon 0.5g, reflux decoloration 0.5h, heat filtering, lower 0~10 DEG C of the cooling of filtrate stirring, crystallization is added
1h, filtering, the 45 DEG C of dryings of filter cake reduced vacuum obtain 2- (the fluoro- 4- xenyl 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 preparation side of already known processes impurity B 2- (the fluoro- 4- xenyl of 2-) -2,3- dimethyl succinic acid of Flurbiprofen
Method, which is characterized in that this method comprises the following steps:
(1) the bromo- 2- fluorine biphenyl of 4- and anhydrous tetrahydro furan are uniformly mixed, wherein the volume of 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, it is stirred to react 1 ~ 2h, TLC monitors reaction process；
(3) after the reaction was completed, grignard reaction liquid is cooled to room temperature, spare；
(4) under nitrogen protection, bromo- 2, the 3- dimethyl succinic acid 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, and 20 ~ 65 DEG C of temperature control are stirred to react 1 ~ 2h
(5) after the reaction was completed, solvent is removed under reduced pressure, toluene and dilute hydrochloric acid is added, stirs rising temperature for dissolving, separates organic phase；Water phase
Toluene extraction is primary, merges organic phase, with purifying water washing to neutrality, the crystallization that cools down is concentrated under reduced pressure after solid is precipitated, filters
To off-white powder, the dry crude product to get 2- (the fluoro- 4- xenyl of 2-) -2,3- dimethyl succinic acid；
(6) the recrystallizing and refining step that above-mentioned impurity crude product is passed through to appropriate solvent, obtains the impurity.
2. preparation method according to claim 1, which is characterized in that the purification step of step (6) includes the following steps:
(a) by the mixed solvent of impurity crude product first alcohol and water perhaps 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 be 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) heat preservation filtering, filtrate are cooled to 0 ~ 10 DEG C, 1 ~ 2h of stirring and crystallizing, filtering, and filter cake is dried under reduced pressure that (2- is fluoro- to get 2-
4- xenyl) -2,3- dimethyl succinic acid highly finished product.
3. preparation method according to claim 2, which is characterized in that first alcohol and water mixed volume in the step (1)
Than for 1:1, ethyl alcohol/isopropyl alcohol and water mixed volume ratio is 2:1.
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| 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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| 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 |
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| NL8006488A (en) * | 1979-12-19 | 1981-07-16 | Upjohn Co | PROCESS FOR PREPARING ARYL-PROPIONIC ACIDS. |
| US4518799A (en) * | 1979-12-19 | 1985-05-21 | The Upjohn Company | Processes for the preparation of hydratropic acids |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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