CN114075109B - Preparation method of flurbiprofen axetil and prepared crystal form - Google Patents
Preparation method of flurbiprofen axetil and prepared crystal form Download PDFInfo
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- CN114075109B CN114075109B CN202010846838.8A CN202010846838A CN114075109B CN 114075109 B CN114075109 B CN 114075109B CN 202010846838 A CN202010846838 A CN 202010846838A CN 114075109 B CN114075109 B CN 114075109B
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- ALIVXCSEERJYHU-UHFFFAOYSA-N Flurbiprofen axetil Chemical compound FC1=CC(C(C)C(=O)OC(OC(C)=O)C)=CC=C1C1=CC=CC=C1 ALIVXCSEERJYHU-UHFFFAOYSA-N 0.000 title claims abstract description 113
- 229950005941 flurbiprofen axetil Drugs 0.000 title claims abstract description 108
- 239000013078 crystal Substances 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 80
- 239000007787 solid Substances 0.000 claims abstract description 39
- 239000012065 filter cake Substances 0.000 claims abstract description 37
- 238000003756 stirring Methods 0.000 claims abstract description 30
- 239000003960 organic solvent Substances 0.000 claims abstract description 23
- 239000000047 product Substances 0.000 claims abstract description 17
- 238000005406 washing Methods 0.000 claims abstract description 11
- 238000001035 drying Methods 0.000 claims abstract description 7
- 238000001816 cooling Methods 0.000 claims abstract description 6
- 238000002425 crystallisation Methods 0.000 claims abstract description 4
- 230000008025 crystallization Effects 0.000 claims abstract description 4
- 238000010438 heat treatment Methods 0.000 claims abstract description 4
- 238000001914 filtration Methods 0.000 claims abstract description 3
- 238000004321 preservation Methods 0.000 claims abstract description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 73
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 24
- 239000012046 mixed solvent Substances 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 23
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 230000008569 process Effects 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- 239000012535 impurity Substances 0.000 claims description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 7
- 150000002170 ethers Chemical class 0.000 claims description 7
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims description 6
- 125000001033 ether group Chemical group 0.000 claims description 6
- ACKALUBLCWJVNB-UHFFFAOYSA-N ethylidene diacetate Chemical compound CC(=O)OC(C)OC(C)=O ACKALUBLCWJVNB-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 238000001556 precipitation Methods 0.000 claims description 6
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 5
- IIASCQBFNHWZBE-UHFFFAOYSA-N 1-bromoethyl acetate Chemical compound CC(Br)OC(C)=O IIASCQBFNHWZBE-UHFFFAOYSA-N 0.000 claims description 4
- UJEGHEMJVNQWOJ-UHFFFAOYSA-N 1-heptoxyheptane Chemical compound CCCCCCCOCCCCCCC UJEGHEMJVNQWOJ-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 4
- 238000002411 thermogravimetry Methods 0.000 claims description 4
- 238000001757 thermogravimetry curve Methods 0.000 claims description 4
- KTUQUZJOVNIKNZ-UHFFFAOYSA-N butan-1-ol;hydrate Chemical compound O.CCCCO KTUQUZJOVNIKNZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 238000000746 purification Methods 0.000 abstract description 19
- 239000003814 drug Substances 0.000 abstract description 12
- 238000004519 manufacturing process Methods 0.000 abstract description 11
- 230000008901 benefit Effects 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 6
- 238000000199 molecular distillation Methods 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 238000004587 chromatography analysis Methods 0.000 abstract 1
- 238000003860 storage Methods 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 22
- 229960002390 flurbiprofen Drugs 0.000 description 9
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- CGKKDGMMKSOGLM-UHFFFAOYSA-N 1-chloroethyl acetate Chemical compound CC(Cl)OC(C)=O CGKKDGMMKSOGLM-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000000202 analgesic effect Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000013557 residual solvent Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 2
- 208000004550 Postoperative Pain Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- -1 flurbiprofen ester Chemical class 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- GMWWZJJDGANKRY-UHFFFAOYSA-N 1-acetyloxyethyl propanoate Chemical compound CCC(=O)OC(C)OC(C)=O GMWWZJJDGANKRY-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- 206010058019 Cancer Pain Diseases 0.000 description 1
- 102000013392 Carboxylesterase Human genes 0.000 description 1
- 108010051152 Carboxylesterase Proteins 0.000 description 1
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102100035792 Kininogen-1 Human genes 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000000114 Pain Threshold Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 208000002847 Surgical Wound Diseases 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 238000004455 differential thermal analysis Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 108010017796 epoxidase Proteins 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000002682 general surgery Methods 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
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- 238000012544 monitoring process Methods 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 230000000399 orthopedic effect Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 230000037040 pain threshold Effects 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/52—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a purification method of flurbiprofen axetil and an obtained crystal form, wherein the method comprises the following steps: (1) Adding an organic solvent into the crude flurbiprofen axetil oily substance, and heating to dissolve under stirring; (2) cooling the flurbiprofen axetil solution system; (3) Separating out solid from the flurbiprofen axetil solution system, and carrying out heat preservation, stirring and crystallization; (4) And (3) carrying out temperature control filtration on the system, washing with an organic solvent, and drying a filter cake to obtain a flurbiprofen axetil white solid, namely a crystal form A of the flurbiprofen axetil. The method provided by the invention has the advantages of simple operation, low cost and high efficiency, can prepare and obtain a high-purity product without using special equipment such as short-range molecular distillation or preparation chromatography, and has the technical advantages of convenience and high efficiency in production, low cost, convenience in storage and use and the like.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a purification method of flurbiprofen axetil and an obtained crystal form.
Background
The chemical name of flurbiprofen axetil is: chemical name: (±) -2- (2-fluoro-4-biphenylyl) propionic acid-1-acetoxyethyl ester, having molecular formula of C 19H19FO4, molecular weight of 330.36, and structural formula:
Flurbiprofen axetil is a novel non-steroidal anti-inflammatory analgesic, is a precursor drug of flurbiprofen, and is an NMPA approved first non-steroidal targeted analgesic. Flurbiprofen axetil has certain lipophilicity, the targeting effect and the fat-soluble characteristic of the flurbiprofen axetil enable the flurbiprofen axetil to easily cross cells, and the flurbiprofen axetil can be targeted and gathered at surgical incisions and inflammation sites after entering a human body, and is rapidly hydrolyzed to generate flurbiprofen under the action of carboxylesterase, and the epoxidase (COX) is inhibited at the spinal cord and the periphery to reduce prostaglandin synthesis, and meanwhile, the sensitivity of sensory nerve fibers to noxious stimuli is reduced, and the pain threshold is raised, so that the pre-analgesic effect is exerted. It has been found that advanced use of cyclooxygenase inhibitors eliminates the pre-onset latency period, making it an ideal drug for advanced analgesia, and flurbiprofen axetil reduces the elevated levels of bradykinin in the immunoreactive mediators in tissues. In recent years, the traditional Chinese medicine composition has been widely applied to postoperative pain relief and cancer patients of orthopedics, general surgery, neurosurgery, obstetrics and gynecology and chest surgery patients, and has long action time and low adverse reaction.
Flurbiprofen axetil injection is marketed in 2004 under the trade name "Kai-fen" by Beijing Tide pharmaceutical Co., ltd, and is used for the treatment of postoperative and cancer pain. Once the medicine is marketed, the medicine has the advantages of short acting time, strong medicine effect, long medicine effect duration and the like, relieves the pain of a plurality of operation wounds and cancer patients, creates huge social benefits, makes up the market deficiency of the market nonsteroidal anti-inflammatory medicine injection, and has great clinical application value.
The different synthetic routes of flurbiprofen axetil reported in the current literature, for example, the method of synthesizing flurbiprofen axetil by esterification of flurbiprofen and ethyl 1-bromoacetate is adopted in the invention patent CN201310079429. X.
Chinese patent CN201210574448.5 reports a method for synthesizing flurbiprofen ester as a target compound by esterification reaction of flurbiprofen and 1-chloroethyl acetate.
The invention patent CN201510023365.0 reports that (+/-) -2- (2-fluoro-4-biphenyl) -propionic acid is used as a starting material to be subjected to condensation, reduction, diazotization, halogenation and Suzuki coupling reaction with 1-chloroethyl acetate to prepare flurbiprofen axetil and the like.
The current mature route is mainly prepared by the one-step esterification reaction of flurbiprofen and 1-chloroethyl acetate or 1-bromoethyl acetate, and the synthetic route is as follows:
The route is a synthetic strategy with industrial production value.
However, during the course of the research, it was found that this route, in addition to producing a series of impurities similar to flurbiprofen axetil structure, inevitably produces some impurities of small molecular structure, such as 1, 1-ethylene glycol diacetate, the mechanism of formation of which is shown below:
One aspect is the production during the synthesis of intermediates:
Another aspect is the production during the synthesis of flurbiprofen axetil:
The impurity 1, 1-ethylene glycol diacetate has weak ultraviolet absorption, is not easy to detect by an ultraviolet detector, and can accurately measure the content of the impurity 1, 1-ethylene glycol diacetate by gas chromatography. This impurity has a very adverse effect on the quality of the drug and therefore requires the development of a rational purification process to be removed during the purification process.
Since flurbiprofen axetil is liquid in character, the purification methods reported at present are mainly silica gel column chromatography, reduced pressure distillation and molecular distillation. However, in actual operation, the temperature of reduced pressure distillation is too high, the heat transfer efficiency is low, and the sample is exposed to high temperature for a long time, so that the flurbiprofen axetil is decomposed. The molecular distillation equipment has high price and low energy production, severely restricts the yield of industrial production, ensures the high vacuum degree reached by the system pressure, has higher material sealing requirement, and has moderate distance between the evaporation surface and the condensation surface, large equipment processing difficulty and high manufacturing cost. The silica gel column chromatography has the defects of long purification period, large required solvent quantity and the like, so that the production cost of the product is high.
Therefore, it is very important to develop a purification method which is more efficient and easy to industrialize.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention aims to provide a purification method which is simple to operate, low in cost and high in efficiency, so that the production cost is reduced, and the production efficiency is improved.
In order to achieve the above object, the present invention provides a purification method of flurbiprofen axetil, which is characterized by comprising the following steps:
(1) Adding an organic solvent into the crude flurbiprofen axetil product, and heating to dissolve under stirring;
(2) Cooling the flurbiprofen axetil solution system;
(3) Separating out solid from the flurbiprofen axetil solution system, and carrying out heat preservation, stirring and crystallization;
(4) And (3) carrying out temperature control filtration on the system, washing with an organic solvent, and drying a filter cake to obtain flurbiprofen axetil white solid crystals.
In the method of the present invention, as one embodiment, the organic solvent in the step (1) is selected from one, two or more mixed solvents of the following solvents:
The alkane solvents include: C5-C10 alkanes and mixtures thereof;
The mixed solvent of the alcohol solvent and water includes: a mixed solvent of C1-C4 alcohols/water; or alternatively
The mixed solvent of ethers and alkanes includes: C2-C7 ethers/C5-C10 alkanes.
In the method of the present invention, as one embodiment, the alkane solvent in the step (1) includes: hexane, heptane, octane, or petroleum ether; or alternatively
The mixed solvent of the alcohol solvent and water comprises: methanol/water, ethanol/water, isopropanol/water, or t-butanol/water; or alternatively
The mixed solvent of the ether and the alkane comprises: methyl tertiary ether/n-heptane, isopropyl ether/n-heptane.
In the process of the present invention, as one embodiment, the mass/volume ratio of the crude flurbiprofen axetil product to the organic solvent in the step (1) is 1:1 to 30, preferably 1:1 to 10, and as an exemplary illustration, it may be 1:1. 1:2, 1: 3. 1: 4. 1: 5. 1: 6. 1: 7. 1: 8. 1:9 or 1:10.
In the method of the present invention, when a mixed solvent is used, the ratio between different solvents of the mixed solvent may be a ratio conventional in the art, and as an exemplary illustration,
When a mixed solvent of an alcohol solvent and water is used, the volume ratio of the alcohol to water may preferably be 2 to 3:1, for example, may be 2: 1. or 3:1, a step of;
When a mixed solvent of ether and alkane is adopted, the volume ratio of ether to alkane is 1:2 to 4; for example, it may be 1: 2. 1: 3. or 1:4.
In the method of the present invention, as one embodiment, the temperature in the step (1) is raised to a dissolution temperature of 30 to 130 ℃, preferably 35 to 60 ℃, more preferably 40 to 50 ℃; the stirring and heating to dissolve in the step (1) lasts for 0.5-5 hours, and can be 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5 or 1.0 hours as exemplified; preferably 0.5 to 2 hours, more preferably 0.5 to 1 hour; optionally, the time includes stirring for 0 to 0.5 hours after dissolution.
In the method of the present invention, as one embodiment, the flurbiprofen axetil solution system in the step (2) is cooled to-30 ℃ to 30 ℃, preferably-10 ℃ to 10 ℃, more preferably-10 ℃ to 0 ℃.
In the method of the present invention, as one embodiment, the cooling time in the step (2) is continued for 0.5 to 6 hours, more preferably 1 to 2 hours.
In the method of the present invention, as one embodiment, the stirring crystallization time after the solid is precipitated in the step (3) is preferably 0.5 to 20 hours, more preferably 2 to 4 hours.
In the method of the present invention, as one embodiment, the organic solvent used for washing the filter cake in the step (4) is selected from one or more than one of the following solvents:
The alkane solvents include: C5-C10 alkanes and mixtures thereof; or alternatively
The mixed solvent of the alcohol solvent and water includes: a mixed solvent of C1-C4 alcohols/water; or alternatively
The mixed solvent of ethers and alkanes includes: C2-C7 ethers/C5-C10 alkanes;
The same organic solvent as in step (1) is preferred.
In the method of the present invention, as one embodiment, the organic solvent used for washing the filter cake in the step (4) is selected from one or more than one of the following solvents:
The alkane solvents include: hexane, heptane, octane, petroleum ether, n-decane; or alternatively
The mixed solvent of alcohols and water includes: methanol/water, ethanol/water, isopropanol/water, n-butanol/water; or alternatively
The mixed solvent of ethers and alkanes includes: methyl tertiary ether/n-heptane, isopropyl ether/n-heptane, heptyl ether/n-heptane.
In the method of the present invention, as one embodiment, the temperature of the organic solvent used for washing the cake in the step (4) is-30 to 30 ℃, preferably-10 to 10 ℃, more preferably-10 to 0 ℃.
In the method of the present invention, as one embodiment, the mass/volume ratio of the filter cake to the organic solvent for washing the filter cake in the step (4) is 1:1 to 10, preferably 1:1 to 3, and more preferably 1:1.
In the method of the present invention, as one embodiment, the filter cake blast drying temperature in the step (4) is 10 to 30 ℃, preferably 20 to 30 ℃, more preferably 25 to 28 ℃.
In the method, as one of the implementation modes, the purity of the flurbiprofen axetil prepared by the method is more than or equal to 99.5 percent, and the purity of the flurbiprofen axetil prepared by the method for two times is more than or equal to 99.9 percent;
in the method of the present invention, as one embodiment, the impurity 1, 1-ethylene glycol diacetate content in the flurbiprofen axetil prepared by the method is less than 0.1%.
In the method of the present invention, as one embodiment, the yield of flurbiprofen axetil in the method is 80% or more.
In the process of the present invention, the crude flurbiprofen axetil can be obtained as a liquid crude flurbiprofen axetil in a manner conventional in the art, and as one embodiment, the process further includes, but is not limited to, the preparation of the crude flurbiprofen axetil as follows: adding (+/-) -2- (2-fluoro-4-biphenyl) -propionic acid, inorganic base and 1-bromoethyl acetate into a solvent, controlling the temperature for reaction, washing the reaction product, and concentrating under reduced pressure to obtain the product.
The invention provides a crystal form A of (+ -) -2- (2-fluoro-4-biphenyl) propionic acid-1-acetoxyethyl ester (flurbiprofen axetil), which is characterized in that an X-ray powder diffraction (XRPD) pattern of the crystal form A has characteristic peaks at 9.6+/-0.2 degrees, 13.8+/-0.2 degrees, 16.3+/-0.2 degrees, 17.2+/-0.2 degrees, 17.7+/-0.2 degrees, 21.4+/-0.2 degrees, 21.9+/-0.2 degrees, 23.6+/-0.2 degrees, 26.0+/-0.2 degrees and 30.4+/-0.2 degrees.
In the method of the present invention, as one embodiment, the form a has an X-ray powder diffraction (XRPD) pattern similar to that shown in figure 7.
In the method of the present invention, as one embodiment, the crystal form a starts to absorb heat at 30 to 32 ℃ and has a DSC thermogram with an endothermic peak at 32 to 34 ℃.
In the method of the present invention, as one embodiment, the form a has a DSC thermogram as shown in figure 8.
In the method of the present invention, as one embodiment, the crystalline form a has a thermogram substantially similar to the thermogram of figure 9 (TGA).
The technical effects are as follows: the flurbiprofen axetil is refined into a solid state by a proper method, so that the purification by means of special equipment such as molecular distillation and column chromatography can be avoided, the production cost is greatly reduced, the operation is simplified, and the production capacity is improved. The solid flurbiprofen axetil bulk drug has numerous advantages in the aspects of convenient finished product packaging, transfer operation, weighing, preparation production and feeding and the like, and is more suitable for industrial production.
Drawings
FIG. 1 is an HPLC chart of crude flurbiprofen axetil prepared in example 1.
FIG. 2 is a high resolution mass spectrum of crude flurbiprofen axetil prepared in example 1.
FIG. 3 is a HNMR spectrum of crude flurbiprofen axetil prepared in example 1.
FIG. 4 is a CNMR spectrum of crude flurbiprofen axetil prepared in example 1.
Fig. 5 is an HPLC profile of the purified flurbiprofen axetil white solid of example 2.
FIG. 6 is an HPLC profile of a white solid of flurbiprofen axetil purified in example 3.
FIG. 7 is a powder diffraction (X-Ray) spectrum of crystalline form A of flurbiprofen axetil purified in example 3.
FIG. 8 is a DSC plot of crystalline form A of flurbiprofen axetil purified in example 3.
Fig. 9 is a TGA profile of crystalline form a of flurbiprofen axetil purified in example 3.
Fig. 10 is an HPLC profile of the purified flurbiprofen axetil white solid of example 4.
FIG. 11 is a graph of the white solid powder diffraction (X-Ray) spectrum of the purified flurbiprofen axetil of example 4.
Fig. 12 is an HPLC profile of the purified flurbiprofen axetil white solid of example 5.
FIG. 13 is a graph of the white solid powder diffraction (X-Ray) spectrum of the purified flurbiprofen axetil of example 5.
Fig. 14 is an HPLC profile of the purified flurbiprofen axetil white solid of example 6.
Fig. 15 is an HPLC profile of the purified flurbiprofen axetil white solid of example 7.
Fig. 16 is an HPLC profile of the purified flurbiprofen axetil white solid of example 8.
Fig. 17 is an HPLC profile of the purified flurbiprofen axetil white solid of example 9.
FIG. 18 is a graph of the white solid powder diffraction (X-Ray) spectrum of flurbiprofen axetil purified in example 9.
FIG. 19 is an HPLC chromatogram of purified flurbiprofen axetil of comparative example 1.
Detailed Description
The following examples and test examples serve to further illustrate the invention but do not limit the effective scope of the invention in any way.
Experimental materials:
1. Reagents are as follows:
| Numbering device | Name of the name | Manufacturer' s | Specification of specification |
| 1 | Flurbiprofen | Homemade | 99.918％ |
| 2 | 1-Bromoethyl acetate | Ark Pharm | / |
| 3 | K2CO3 | Tianjin Fuchen | AR |
| 4 | Acetonitrile | MREDA | AR |
| 5 | N-heptane | Tianjin metallocene | AR |
| 6 | NaHCO3 | Tianjin Fuchen | AR |
| 7 | Na2SO4 | Tianjin Fuchen | AR |
2. Instrument and equipment
| Numbering device | Instrument and equipment | Manufacturer' s |
| 1 | Liquid chromatography-mass spectrometry instrument | Waters |
| 2 | Waters high performance liquid chromatograph | Waters |
| 3 | Bruker NMR apparatus (400M) | Wu Hanzhong family Spectroscopy Co.Ltd |
| 4 | Gas chromatograph | Agilent |
The method adopts the following synthetic route:
example 1: synthesis of flurbiprofen axetil.
Flurbiprofen (200.00 g), ethyl 1-bromoacetate (177.75 g) and anhydrous potassium carbonate (124.48 g) are added into tetrahydrofuran (800 ml), stirred and heated, the temperature of the reaction system is kept at 50 ℃ for reaction for 12 hours (TLC monitoring reaction) until the reaction is complete, the reaction system is cooled to room temperature, suction filtration is carried out, 200ml of tetrahydrofuran is used for leaching filter cakes, the filtrates are combined, and decompression and rotary evaporation are carried out at 60 ℃ to obtain a crude flurbiprofen ester product which is 256.60g as colorless liquid, and the yield is 94.9%. Detection by HPLC: purity 99.449% (figure 1); high resolution mass spectrometry: 353.1163[ M+Na ] + (FIG. 2), the theoretical calculation of the molecular ion peak of flurbiprofen axetil is: 353.1160[ M+H ] +, which is in line with the high resolution mass spectrum error range, and the measured value is in line with the theoretical value.
HNMR(400M,DMSO-d6)：1.37(m,6H);1.92(s,1.5H);2.05(s,1.5H);3.93(m,1H);6.79(m,1H);7.22(m,2H);7.24(m,1H);7.49(m,3H);7.54(m,2H)( Fig. 3).
CNMR(400M,DMSO-d6)：18.1855;19.0630;20.4066;43.6811;88.4700;115.2435;123.9570;127.7284;128.5027;128.6362;130.6661;134.7209;141.7928;157.6352;160.0844;168.5392;171.5338( Fig. 4).
Example 2: purification of flurbiprofen axetil
N-heptane (300 ml) was added to the crude flurbiprofen axetil product (30.00 g) obtained in example 1, the system was completely dissolved when the temperature was raised to 45 ℃ for 0.5h under stirring, the system temperature was kept for 0.5h, the reaction system was cooled to-10 ℃ and kept for 2h after solid precipitation, the system was filtered, the filter cake was washed with n-heptane at-10 ℃ in a mass/volume ratio of 1:1, and then the filter cake was air-dried at 25 ℃ to obtain flurbiprofen axetil white solid 26.10g, yield 87.0%, which was detected by HPLC: purity 99.731% (fig. 5).
Example 3: purification of flurbiprofen axetil
To flurbiprofen axetil (sample of example 2) (10.00 g) was added n-heptane (100 ml), the system was completely dissolved when the temperature was raised to 45 ℃ for 1h under stirring, the system temperature was kept for 0.5 hour, the reaction system was cooled to-10 ℃ for 2h, after solid was precipitated, the temperature was kept for 2 hours under stirring, the system was filtered, the filter cake was washed with n-heptane at-10 ℃ in a mass/volume ratio of 1:1, and then the filter cake was air-dried at 25 ℃ to obtain flurbiprofen axetil as a white solid 8.50g in 85.0% yield, as determined by HPLC: purity 99.905% (fig. 6), the product was checked by X-Ray powder diffraction (X-Ray) (fig. 7), differential thermal analysis (DSC) (fig. 8), thermogravimetric analysis (TGA) (fig. 9), and the crystalline form of the solid powder was named form a.
Example 4: purification of flurbiprofen axetil
Isopropyl alcohol (6 ml) was added to flurbiprofen axetil (3.00 g) obtained in example 1, the system was completely dissolved when the temperature was raised to 45 ℃ for 0.5h under stirring, the system temperature was kept stirring for 0.5h, purified water (3 ml) was added to the system, the reaction system was cooled to 0 ℃ for 1h, after solid precipitation, the temperature was kept stirring for 2h, the system was filtered, the filter cake was washed with isopropyl alcohol/water at 0 ℃ 2:1 (V/V) in a mass/volume ratio of 1:1, and then the filter cake was air-dried at 25 ℃ to obtain flurbiprofen axetil white solid 2.82g, yield 94.00%, as measured by HPLC: purity 99.937% (fig. 10), X-Ray powder diffraction (X-Ray) was performed on the product (fig. 11), which was form a.
Example 5: purification of flurbiprofen axetil
Isopropyl ether (6 ml) was added to flurbiprofen axetil (3.00 g) obtained in example 1, the system was completely dissolved when the temperature was raised to 45 ℃ for 0.5h under stirring, the system temperature was kept stirring for 0.5h, n-heptane (18 ml) was added to the system, the reaction system was cooled to-5 ℃ for 1h, after solid precipitation, the system was stirred for 2 h at the kept temperature, the system was filtered, the filter cake was washed with isopropyl ether/n-heptane 1:3 (V/V) at-5 ℃ in a mass/volume ratio of 1:1, and then the filter cake was air-dried at 25 ℃ to obtain flurbiprofen axetil as a white solid 2.5g, yield 83.6%, as measured by HPLC: purity 99.984% (fig. 12), X-Ray powder diffraction (X-Ray) of the product (fig. 13), form a.
Example 6: purification of flurbiprofen axetil
To flurbiprofen axetil (10.00 g) obtained in example 1 was added n-decane (150 ml), the system was completely dissolved when the temperature was raised to 40 ℃ for 1h under stirring, the system temperature was kept for 0.5 hour, the reaction system was cooled to-10 ℃ for 2h, after solid was precipitated, the temperature was kept for 2 hours under stirring, the system was filtered, the filter cake was washed with n-heptane at-10 ℃ in a mass/volume ratio of 1:1, and then the filter cake was air-dried at 28 ℃ to obtain 8.20g of flurbiprofen axetil as a white solid with a yield of 82.0%, as detected by HPLC: purity 99.813% (fig. 14).
Example 7: purification of flurbiprofen axetil
N-butanol (9 ml) was added to the flurbiprofen axetil (3.00 g) obtained in example 1, the system was completely dissolved when the temperature was raised to 40 ℃ for 0.5h under stirring, the system temperature was kept for 0.5h under stirring, purified water (3 ml) was added to the system, the reaction system was cooled to 0 ℃ for 1h, after solid was precipitated, the temperature was kept under stirring for 2h, the system was filtered, the filter cake was washed with 1:1 mass/volume ratio of 0 ℃ n-butanol/water 3:1 (V/V), and then the filter cake was air-dried at 25 ℃ to obtain flurbiprofen axetil white solid 2.70g, yield 90.00%, as measured by HPLC: purity 99.927% (fig. 15).
Example 8: purification of flurbiprofen axetil
To flurbiprofen axetil (3.00 g) obtained in example 1, heptyl ether (8 ml) was added, the system was completely dissolved when the temperature was raised to 50 ℃ with stirring, n-heptane (16 ml) was added to the system, the reaction system was cooled to-10 ℃ for 2 hours, after solid was precipitated, the temperature was kept stirring for 2 hours, the system was filtered, the filter cake was washed with-10 ℃ heptyl ether/n-heptane 1:2 (V/V) in a mass/volume ratio of 1:1, and then the filter cake was air-dried at 28 ℃ to obtain flurbiprofen axetil white solid 2.51g, yield 83.7%, as measured by HPLC: purity 99.982% (fig. 16).
Example 9: purification of flurbiprofen axetil
Methyl tertiary ether (30 ml) is added into the crude flurbiprofen axetil product (30.00 g) obtained in the example 1, the system is completely dissolved when the temperature is raised to 50 ℃ for 0.5h under stirring, the system temperature is kept to be continuously stirred for 0.5h, n-heptane (120 ml) is added into the system, the reaction system is cooled to 0 ℃ for 1h, after solid precipitation and the temperature is kept to be stirred for 2h, the system is filtered, a filter cake is washed by methyl tertiary ether/n-heptane at 0 ℃ 1:4 (V/V) in a mass/volume ratio of 1:1, then the filter cake is dried by blowing at 28 ℃ to obtain flurbiprofen axetil white solid 26.10g, the yield is 87.0 percent, and the reaction system is detected by HPLC: purity 99.84% (FIG. 17), and X-Ray powder diffraction (X-Ray) of the product (FIG. 18).
Comparative example 1
The flurbiprofen axetil obtained in example 1 was purified by column chromatography: eluent: ethyl acetate/n-heptane=1/15 (V/V); the crude flurbiprofen axetil (10.00 g) was weighed and loaded, the main peak component was collected and distilled under reduced pressure at 60℃to give 4.85g of a colorless oil of flurbiprofen axetil in a yield of 48.5% and a purity of 99.760% by HPLC (FIG. 19).
Experimental example 1: stability investigation of flurbiprofen axetil form A
Stability studies were performed on flurbiprofen axetil form a, which was left at room temperature for 3 months, and appearance, HPLC and X-ray powder diffraction were measured at day 0 and day 90, respectively. Detection result: the X-ray powder diffraction test showed that after 3 months of standing, the crystalline form of the sample was unchanged, and was still form a, and the HPLC test results and appearance are shown in the following table:
Experimental example 2: impurity and residual solvent detection of flurbiprofen axetil crystal form A
The impurity 1B (1, 1-ethylene glycol diacetate) and residual solvent were detected by gas chromatography for the samples of example 9 and comparative example 1, under the conditions and with the results set forth in the following table:
Gas chromatography conditions:
Chromatographic column: 60X 0.32nm,1.8 μm;
Flow rate: 2.5ml/min;
Equilibrium temperature: 85 ℃;
Heating program: 45-200 ℃;
Sample preparation: 1.00g of flurbiprofen axetil is precisely weighed, 10ml of DMF is added for constant volume, and the obtained solution is a sample solution.
The detection process comprises the following steps: 5ml of the sample solution is injected into a headspace bottle, detection is performed, and a chromatogram is recorded.
From the above data, the product obtained by the purification method of the present invention is superior to the product obtained by the column chromatography method in terms of related substances, residual solvents, content, etc., and the present invention has obvious technical advantages.
While the methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and combinations of the methods and applications described herein can be made and applied within the spirit and scope of the invention. Those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the present invention.
Claims (37)
1. A process for purifying flurbiprofen axetil, comprising the steps of:
(1) Adding an organic solvent into the crude flurbiprofen axetil product, and heating to dissolve under stirring;
(2) Cooling the flurbiprofen axetil solution system;
(3) Separating out solid from the flurbiprofen axetil solution system, and carrying out heat preservation, stirring and crystallization;
(4) Filtering the system at a controlled temperature, washing with an organic solvent, and drying a filter cake to obtain flurbiprofen axetil white solid crystals;
The organic solvent in the step (1) is selected from one, two or more than two of the following solvents:
alkane solvent: C5-C10 alkane or mixture thereof;
mixed solvent of alcohol solvent and water: a mixed solvent of C1-C4 alcohols/water; or alternatively
Mixed solvents of ethers and alkanes: C2-C7 ethers/C5-C10 alkanes.
2. The method according to claim 1, wherein in step (1),
The alkane solvent is as follows: hexane, heptane or octane;
the mixed solvent of the alcohol solvent and water is as follows: methanol/water, ethanol/water, isopropanol/water or t-butanol/water;
The mixed solvent of the ether and the alkane is as follows: methyl tertiary ether/n-heptane or isopropyl ether/n-heptane.
3. The process according to claim 1, wherein the mass/volume ratio of crude flurbiprofen axetil to organic solvent in step (1) is 1:1 to 30.
4. A process according to claim 3, wherein the mass/volume ratio of crude flurbiprofen axetil to organic solvent in step (1) is from 1:1 to 10.
5. The method according to claim 1, wherein the temperature in step (1) is raised to a dissolution temperature of 30 ℃ to 130 ℃; the stirring temperature in the step (1) is raised until the dissolution lasts for 0.5 to 5 hours.
6. The method according to claim 5, wherein the temperature in step (1) is raised to a temperature of 35 ℃ to 60 ℃.
7. The method according to claim 6, wherein the temperature in step (1) is raised to a dissolution temperature of 40 ℃ to 50 ℃.
8. The method according to claim 5, wherein the stirring in step (1) is heated to dissolve for 0.5 to 2 hours.
9. The method according to claim 8, wherein the stirring in step (1) is heated to dissolve for 0.5 to 1 hour.
10. The method according to claim 1, wherein the flurbiprofen axetil solution system in step (2) is cooled to-10 ℃ to 10 ℃.
11. The method according to claim 10, wherein the flurbiprofen axetil solution system in step (2) is cooled to-10 ℃ to 0 ℃.
12. The method of claim 6, wherein the cooling time in step (2) lasts 0.5 to 6 hours.
13. The method of claim 12, wherein the cooling time in step (2) lasts 1-2 hours.
14. The method according to claim 1, wherein the stirring time after precipitation of the solid in the step (3) is 0.5 to 20 hours.
15. The method according to claim 14, wherein the stirring time after precipitation of the solid in step (3) is 2 to 4 hours.
16. The method according to claim 1, wherein the organic solvent used for washing the filter cake in step (4) is the same organic solvent as in step (1).
17. The method of claim 16, wherein in step (4),
The alkane solvent is as follows: hexane, heptane, octane or n-decane;
The mixed solvent of the alcohol solvent and water is as follows: methanol/water, ethanol/water, isopropanol/water, or n-butanol/water;
The mixed solvent of the ether and the alkane comprises: methyl tertiary ether/n-heptane, isopropyl ether/n-heptane or heptyl ether/n-heptane.
18. The method according to claim 16, wherein the volume ratio of the alcohol solvent to the water in the mixed solvent of the alcohol and the water in the step (4) is 2 to 3:1.
19. The method according to claim 16, wherein the volume ratio of ether to alkane in the mixed solvent of ether and alkane in the step (4) is 1:2 to 4.
20. The method of claim 1, wherein the temperature of the organic solvent used to rinse the filter cake in step (4) is-10 ℃ to 10 ℃.
21. The method of claim 20, wherein the temperature of the organic solvent used to rinse the filter cake in step (4) is-10 ℃ to 0 ℃.
22. The method according to claim 1, wherein the mass/volume ratio of the filter cake to the organic solvent used for washing the filter cake in the step (4) is 1:1-10.
23. The method of claim 22, wherein the mass/volume ratio of filter cake to organic solvent used to rinse filter cake in step (4) is 1:1-3.
24. The method of claim 23, wherein the mass/volume ratio of filter cake to organic solvent used to rinse filter cake in step (4) is 1:1.
25. The method of claim 1, wherein the filter cake blast drying temperature in step (4) is from 10 ℃ to 30 ℃.
26. The method of claim 25, wherein the filter cake blast drying temperature in step (4) is 20 ℃ to 30 ℃.
27. The method of claim 1, wherein the filter cake blast drying temperature in step (4) is 25 ℃ to 28 ℃.
28. The process of claim 1, wherein the flurbiprofen axetil prepared by the process has a purity of 99.5% or more.
29. The process of claim 1, wherein the impurity 1, 1-ethylene glycol diacetate content of flurbiprofen axetil produced by the process is less than 0.1%.
30. The process of claim 1, wherein the process yields flurbiprofen axetil greater than or equal to 80%.
31. The process according to claim 1, characterized in that the yield of flurbiprofen axetil is 80% to 90%.
32. The process according to claim 1, characterized in that it further comprises the preparation of crude flurbiprofen axetil obtained by: adding (+/-) -2- (2-fluoro-4-biphenyl) -propionic acid, inorganic base and 1-bromoethyl acetate into a solvent, controlling the temperature for reaction, washing the reaction product, and concentrating under reduced pressure to obtain the product.
33. Form a of (±) -2- (2-fluoro-4-biphenylyl) propionic acid-1-acetoxyethyl ester obtainable by the process according to any of claims 1-32, characterized in that said form a has an X-ray powder diffraction with characteristic peaks at 9.6±0.2°,13.8±0.2°,16.3±0.2°,17.2±0.2°,17.7±0.2°,21.4±0.2°,21.9±0.2°,23.6±0.2°,26.0±0.2°,30.4±0.2°.
34. Form a of flurbiprofen axetil according to claim 33, characterized in that it is characterized by X-ray powder diffraction as shown in fig. 7.
35. Form a of flurbiprofen axetil according to claim 33, characterized in that the DSC thermogram of form a starts to absorb heat at 30-32 ℃ and has an endothermic peak at 32-34 ℃.
36. Form a of flurbiprofen axetil according to claim 33, characterized in that it has the DSC thermogram characteristics shown in figure 8.
37. Form a of flurbiprofen axetil according to claim 33, characterized in that it has thermogravimetric analysis characteristics similar to the thermogram of figure 9.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102381970A (en) * | 2011-12-08 | 2012-03-21 | 南京优科生物医药有限公司 | Method for preparing flurbiprofen axetil compound |
| CN103012144A (en) * | 2012-12-26 | 2013-04-03 | 哈药集团技术中心 | Preparation method of flurbiprofen axetil |
| CN103254075A (en) * | 2013-03-13 | 2013-08-21 | 武汉大安制药有限公司 | Preparation method of flurbiprofen axetil |
| CN103664606A (en) * | 2013-12-04 | 2014-03-26 | 广东嘉博制药有限公司 | Preparation methods of flurbiprofen axetil compound |
| CN104649906A (en) * | 2015-01-10 | 2015-05-27 | 山东威高药业股份有限公司 | Preparation method of flurbiprofen axetil |
| CN105777544A (en) * | 2016-04-13 | 2016-07-20 | 成都倍特药业有限公司 | Method for preparing S-(+)-flurbiprofen axetil high in optical purity |
| CN108558651A (en) * | 2018-06-13 | 2018-09-21 | 上海峰林生物科技有限公司 | A kind of preparation method of Flurbiprofen and the preparation method of flurbiprofen axetil |
-
2020
- 2020-08-21 CN CN202010846838.8A patent/CN114075109B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102381970A (en) * | 2011-12-08 | 2012-03-21 | 南京优科生物医药有限公司 | Method for preparing flurbiprofen axetil compound |
| CN103012144A (en) * | 2012-12-26 | 2013-04-03 | 哈药集团技术中心 | Preparation method of flurbiprofen axetil |
| CN103254075A (en) * | 2013-03-13 | 2013-08-21 | 武汉大安制药有限公司 | Preparation method of flurbiprofen axetil |
| CN103664606A (en) * | 2013-12-04 | 2014-03-26 | 广东嘉博制药有限公司 | Preparation methods of flurbiprofen axetil compound |
| CN104649906A (en) * | 2015-01-10 | 2015-05-27 | 山东威高药业股份有限公司 | Preparation method of flurbiprofen axetil |
| CN105777544A (en) * | 2016-04-13 | 2016-07-20 | 成都倍特药业有限公司 | Method for preparing S-(+)-flurbiprofen axetil high in optical purity |
| CN108558651A (en) * | 2018-06-13 | 2018-09-21 | 上海峰林生物科技有限公司 | A kind of preparation method of Flurbiprofen and the preparation method of flurbiprofen axetil |
Non-Patent Citations (1)
| Title |
|---|
| 刘桂艳等.《无机及分析化学实验》.华中师范大学出版社,2018,46-47. * |
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