CN114075109A - Preparation method of flurbiprofen axetil and prepared crystal form - Google Patents
Preparation method of flurbiprofen axetil and prepared crystal form Download PDFInfo
- Publication number
- CN114075109A CN114075109A CN202010846838.8A CN202010846838A CN114075109A CN 114075109 A CN114075109 A CN 114075109A CN 202010846838 A CN202010846838 A CN 202010846838A CN 114075109 A CN114075109 A CN 114075109A
- Authority
- CN
- China
- Prior art keywords
- flurbiprofen axetil
- water
- flurbiprofen
- temperature
- heptane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229950005941 flurbiprofen axetil Drugs 0.000 title claims abstract description 107
- 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 101
- 239000013078 crystal Substances 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title description 5
- 238000000034 method Methods 0.000 claims abstract description 68
- 239000007787 solid Substances 0.000 claims abstract description 38
- 238000003756 stirring Methods 0.000 claims abstract description 36
- 239000012065 filter cake Substances 0.000 claims abstract description 30
- 239000003960 organic solvent Substances 0.000 claims abstract description 19
- 238000005406 washing Methods 0.000 claims abstract description 17
- 239000000047 product Substances 0.000 claims abstract description 14
- 238000001816 cooling Methods 0.000 claims abstract description 13
- 238000001035 drying Methods 0.000 claims abstract description 10
- 238000001914 filtration Methods 0.000 claims abstract description 10
- 238000010438 heat treatment 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
- 238000004321 preservation Methods 0.000 claims abstract description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 75
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 27
- 239000012046 mixed solvent Substances 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- 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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 150000002170 ethers Chemical class 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- -1 (+ -) -1-acetoxyethyl Chemical group 0.000 claims description 9
- 239000012535 impurity Substances 0.000 claims description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- 238000002411 thermogravimetry Methods 0.000 claims description 8
- 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 150000001298 alcohols Chemical class 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-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
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 4
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- KTUQUZJOVNIKNZ-UHFFFAOYSA-N butan-1-ol;hydrate Chemical compound O.CCCCO KTUQUZJOVNIKNZ-UHFFFAOYSA-N 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 230000008569 process Effects 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
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- 230000008901 benefit Effects 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 4
- 230000009467 reduction Effects 0.000 abstract description 2
- 238000004237 preparative chromatography Methods 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 23
- 238000000746 purification Methods 0.000 description 17
- 238000001228 spectrum Methods 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 13
- 238000001514 detection method Methods 0.000 description 10
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 8
- 229960002390 flurbiprofen Drugs 0.000 description 8
- 238000007664 blowing Methods 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000000199 molecular distillation Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000243 solution Substances 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
- 230000009471 action Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 230000000694 effects 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
- 238000002386 leaching Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000013557 residual solvent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 229940122204 Cyclooxygenase inhibitor Drugs 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 208000004550 Postoperative Pain Diseases 0.000 description 2
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 2
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 208000002847 Surgical Wound Diseases 0.000 description 2
- 238000007605 air drying Methods 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 238000009833 condensation Methods 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
- 230000000857 drug effect Effects 0.000 description 2
- ACKALUBLCWJVNB-UHFFFAOYSA-N ethylidene diacetate Chemical compound CC(=O)OC(C)OC(C)=O ACKALUBLCWJVNB-UHFFFAOYSA-N 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000001757 thermogravimetry curve 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
- 238000005481 NMR spectroscopy Methods 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
- 238000006069 Suzuki reaction reaction Methods 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
- 230000003110 anti-inflammatory effect Effects 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
- 201000011510 cancer Diseases 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
- 238000007796 conventional method Methods 0.000 description 1
- 238000000354 decomposition reaction 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
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
- 230000028993 immune response Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 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
- 238000012545 processing Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000004044 response Effects 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
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Images
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a method for purifying flurbiprofen axetil and an obtained crystal form, wherein the method comprises the following steps: (1) adding an organic solvent into the oily substance of the crude flurbiprofen axetil, and heating to dissolve the oily substance 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) filtering the system at a controlled temperature, washing with an organic solvent, and drying a filter cake to obtain a white flurbiprofen axetil solid, namely the crystal form A of the flurbiprofen axetil. The method provided by the invention has the advantages that the operation is simple, the cost is low, and the efficiency is high, the method can be used for preparing a high-purity product without special equipment such as short-range molecular rectification or preparative chromatography, and the like, and meanwhile, the method has the technical advantages of convenience and high efficiency in production, cost reduction, 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 method for purifying flurbiprofen axetil and an obtained crystal form.
Background
The chemical name of flurbiprofen axetil is: chemical name: (+/-) -2- (2-fluoro-4-biphenyl) propionic acid-1-acetoxy ethyl ester with molecular formula of C19H19FO4Molecular weight of 330.36, structural formula:
the flurbiprofen axetil is a novel nonsteroidal anti-inflammatory analgesic, is a prodrug of flurbiprofen, and is a first nonsteroidal targeted analgesic approved by NMPA. The flurbiprofen axetil has certain lipophilicity, and the characteristics of targeting effect and lipid solubility of the flurbiprofen axetil enable the flurbiprofen to easily cross cells, can be targeted and gathered at surgical incisions and inflammation parts after entering a human body, can be rapidly hydrolyzed under the action of carboxylesterase to generate flurbiprofen, reduces prostaglandin synthesis by inhibiting Cyclooxygenase (COX) at spinal cords and periphery, and simultaneously reduces the sensitivity of sensory nerve fibers to noxious stimulation and raises the pain threshold so as to play a role in advanced analgesia. The research finds that the advanced use of the cyclooxygenase inhibitor can eliminate the latent period before the onset of action, so that the cyclooxygenase inhibitor becomes an ideal medicament for advanced analgesia, and the flurbiprofen axetil can also reduce the rising level of bradykinin which is an immune response medium in tissues. The traditional Chinese medicine composition is widely applied to postoperative pain relief and cancer patients of orthopedic patients, general surgery patients, neurosurgery patients, obstetrics and gynecology patients and thoracic surgery patients in recent years, and has long action time and low adverse reaction.
Flurbiprofen axetil injection is sold in 2004 by Beijing Taide pharmaceutical corporation under the trade name "Kaifen" at home for the treatment of postoperative and cancer pain. Once the Kaifen comes into the market, the Kaifen has the advantages of short response time, strong drug effect, long drug effect duration and the like, relieves the pain of a plurality of patients suffering from surgical wounds and cancers, creates great social benefit, makes up for the market shortage of the non-steroidal anti-inflammatory drug injection in the market, and has great clinical application value.
The different synthetic routes of flurbiprofen axetil reported in the literature at present, for example, patent of invention cn201310079429.x adopts a method for synthesizing flurbiprofen axetil by esterification reaction of flurbiprofen and 1-ethyl bromoacetate.
The chinese patent CN201210574448.5 discloses a method for synthesizing flurbiprofen and 1-chloroethyl acetate through esterification reaction to obtain the target compound flurbiprofen axetil.
The invention patent CN201510023365.0 reports that the flurbiprofen axetil and the like are prepared by taking (+/-) -2- (2-fluoro-4-biphenyl) -propionic acid as a starting material and 1-chloroethyl acetate through condensation, reduction, diazotization halogenation and Suzuki coupling reaction.
The current relatively mature route is mainly prepared by flurbiprofen and 1-chloroethyl acetate or 1-bromoethyl acetate through one-step esterification reaction, and the synthetic route is as follows:
the route is a synthetic strategy with industrial production value.
However, in the course of research, it was found that the route, besides producing a series of impurities similar to flurbiprofen axetil structure, inevitably produces some small molecular structure impurities, such as 1, 1-glycol diacetate, and the mechanism of formation of the impurities 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-glycol diacetate has weak ultraviolet absorption, is not easy to detect by an ultraviolet detector, and can accurately determine the content thereof by gas chromatography. This impurity has a very adverse effect on the quality of the drug, and therefore it is necessary to develop a rational purification method to remove it during the purification process.
Since the flurbiprofen axetil is liquid, the currently reported purification methods mainly include 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, which can cause the decomposition of flurbiprofen axetil. The molecular distillation equipment is expensive, the yield is low, the yield of industrial production is severely limited, the molecular distillation device must ensure high vacuum degree of system pressure, the requirement on material sealing is high, the distance between an evaporation surface and a condensation surface is moderate, the equipment processing difficulty is high, and the manufacturing cost is high. The silica gel column chromatography has the defects of long purification period, large solvent amount and the like, so that the production cost of the product is high.
Therefore, it is very important to develop a more efficient purification method which is easy to be industrialized.
Disclosure of Invention
Aiming at the defects 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 method for purifying flurbiprofen axetil, comprising the steps of:
(1) adding an organic solvent into the crude flurbiprofen axetil, and heating to dissolve the flurbiprofen axetil 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) filtering the system at a controlled temperature, washing with an organic solvent, and drying a filter cake to obtain the flurbiprofen axetil white solid crystal.
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 comprises: a mixed solvent of alcohols and water having a carbon number of 1 to 4; or
The mixed solvent of ethers and alkanes includes: C2-C7 ethers/C5-C10 alkanes.
In the method of the present invention, as one of embodiments, the alkane solvent in the step (1) includes: hexane, heptane, octane, or petroleum ether; or
The mixed solvent of the alcohol solvent and water comprises: methanol/water, ethanol/water, isopropanol/water, or tert-butanol/water; or
The mixed solvent of the ethers and the alkanes comprises: methyl tert-ether/n-heptane, isopropyl ether/n-heptane.
In the method of the present invention, as one embodiment, the mass/volume ratio of the crude flurbiprofen axetil to the organic solvent in step (1) is 1:1 to 30, preferably 1:1 to 10, and as an exemplary illustration, may be 1: 1. 1:2, 1: 3. 1: 4. 1: 5. 1: 6. 1: 7. 1: 8. 1: 9 or 1: 10.
when a mixed solvent is used in the method of the present invention, the ratio of the different solvents of the mixed solvent may be a ratio that is conventional in the art, and as an exemplary illustration,
when a mixed solvent of an alcohol solvent and water is adopted, the volume ratio of the alcohol to the water is preferably 2-3: 1, for example, may be 2: 1. or 3: 1;
when the mixed solvent of the ether and the alkane is adopted, the volume ratio of the ether to the alkane is 1: 2-4; for example, the ratio of 1: 2. 1: 3. or 1: 4.
in the method of the present invention, as one embodiment, the temperature for raising the temperature to the dissolution in the step (1) is 30 to 130 ℃, preferably 35 to 60 ℃, and more preferably 40 to 50 ℃; in the step (1), stirring and heating are carried out until the time for dissolving lasts for 0.5-5 hours, and as an illustrative description, the time can be 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5 or 1.0 hour; preferably 0.5 to 2 hours, more preferably 0.5 to 1 hour; optionally, the time includes stirring for 0-0.5 hours after dissolution.
In one embodiment of the method of the present invention, the flurbiprofen axetil solution system in the step (2) is cooled to-30 ℃ to 30 ℃, preferably to-10 ℃ to 10 ℃, and more preferably to-10 ℃ to 0 ℃.
In one embodiment of the method of the present invention, the cooling time in the step (2) lasts for 0.5 to 6 hours, and more preferably 1 to 2 hours.
In one embodiment of the method of the present invention, the stirring crystallization time after the solid is precipitated in the step (3) is 0.5 to 20 hours, and more preferably 2 to 4 hours.
In the method of the present invention, as one embodiment, the organic solvent 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
The mixed solvent of the alcohol solvent and water comprises: a mixed solvent of alcohols and water having a carbon number of 1 to 4; or
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 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
The mixed solvent of alcohols and water includes: methanol/water, ethanol/water, isopropanol/water, n-butanol/water; or
The mixed solvent of ethers and alkanes includes: methyl tert-ether/n-heptane, isopropyl ether/n-heptane, heptyl ether/n-heptane.
In one embodiment of the method of the present invention, the temperature of the organic solvent for leaching the filter cake in the step (4) is-30 ℃ to 30 ℃, preferably-10 ℃ to 10 ℃, and 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 leaching 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 temperature of the air-blast drying of the filter cake in the step (4) is 10 ℃ to 30 ℃, preferably 20 ℃ to 30 ℃, and more preferably 25 ℃ to 28 ℃.
In the method, as one of the embodiments, the purity of the flurbiprofen axetil prepared by the method is more than or equal to 99.5%, and the purity of the flurbiprofen axetil prepared by the two times of purification by the method is more than or equal to 99.9%;
in the method of the present invention, as one embodiment, the content of 1, 1-ethylene glycol diacetate as an impurity in the flurbiprofen axetil prepared by the method is less than 0.1%.
In one embodiment of the method of the present invention, the yield of flurbiprofen axetil is 80% or more.
In the method of the present invention, the crude flurbiprofen axetil may be obtained by a conventional method in the art, and as one embodiment, the method further includes, but is not limited to, obtaining the crude flurbiprofen axetil by the following preparation: adding (+/-) -2- (2-fluoro-4-biphenyl) -propionic acid, inorganic base and 1-bromoethyl acetate into a solvent, controlling the temperature to react, washing a reaction product, and concentrating under reduced pressure to obtain the compound.
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 invention, as one embodiment, the form a has an X-ray powder diffraction (XRPD) pattern corresponding to that shown in figure 7.
In the method of the present invention, as one embodiment, the form A has a DSC thermogram having an endothermic peak at 32 to 34 ℃ and an endothermic onset at 30 to 32 ℃.
In the method of the present invention, as one embodiment, the form a has a DSC thermogram as shown in figure 8.
In the methods of the present invention, as one embodiment, the crystalline form a has a thermogravimetric analysis substantially similar to the thermogravimetric analysis (TGA) thermogram shown in figure 9.
The technical effects are as follows: the invention refines the flurbiprofen axetil into a solid state by a proper method, and can avoid the purification by special equipment such as molecular distillation and column chromatography, thereby greatly reducing the production cost, simplifying the operation and improving the production capacity. The solid flurbiprofen axetil bulk drug has numerous advantages in the aspects of convenient finished product packaging, transferring operation, weighing, preparation production feeding and the like, and is more suitable for industrial production.
Drawings
Fig. 1 is an HPLC spectrum of the crude flurbiprofen axetil prepared in example 1.
Fig. 2 is a high-resolution mass spectrum of the crude flurbiprofen axetil prepared in example 1.
Fig. 3 is an HNMR spectrum of the crude flurbiprofen axetil prepared in example 1.
Fig. 4 is a CNMR spectrum of the crude flurbiprofen axetil prepared in example 1.
Fig. 5 is an HPLC spectrum of a white solid of flurbiprofen axetil purified in example 2.
Fig. 6 is an HPLC spectrum 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 spectrum of crystalline form a of flurbiprofen axetil purified in example 3.
Figure 9 is a TGA profile of crystalline form a of flurbiprofen axetil purified in example 3.
Fig. 10 is an HPLC spectrum of a white solid of flurbiprofen axetil purified in example 4.
FIG. 11 is a diffraction (X-Ray) spectrum of a white solid powder of flurbiprofen axetil purified in example 4.
Fig. 12 is an HPLC spectrum of a white solid of flurbiprofen axetil purified in example 5.
FIG. 13 is a diffraction (X-Ray) spectrum of a white solid powder of flurbiprofen axetil purified in example 5.
Fig. 14 is an HPLC spectrum of a white solid of flurbiprofen axetil purified in example 6.
Fig. 15 is an HPLC spectrum of a white solid of flurbiprofen axetil purified in example 7.
Fig. 16 is an HPLC spectrum of a white solid of flurbiprofen axetil purified in example 8.
Fig. 17 is an HPLC spectrum of a white solid of flurbiprofen axetil purified in example 9.
FIG. 18 is a diffraction (X-Ray) spectrum of a white solid powder of flurbiprofen axetil purified in example 9.
Fig. 19 is an HPLC spectrum of purified flurbiprofen axetil of comparative example 1.
Detailed Description
The following examples and test examples are intended to further illustrate the present invention, but are not intended to limit the effective scope of the present invention in any way.
Experimental materials:
1. reagents:
| numbering | Name (R) | Manufacturer of the product | Specification of |
| 1 | Flurbiprofen | Self-made | 99.918％ |
| 2 | 1-Bromoethyl acetate | Ark Pharm | / |
| 3 | K2CO3 | Tianjin Fu Chen | AR |
| 4 | Acetonitrile | MREDA | AR |
| 5 | N-heptane | Tianjin Damao | AR |
| 6 | NaHCO3 | Tianjin Fu Chen | AR |
| 7 | Na2SO4 | Tianjin Fu Chen | AR |
2. Instrumentation and equipment
| Numbering | Instrumentation and equipment | Manufacturer of the |
|
| 1 | Liquid chromatography | Waters | |
| 2 | Waters high performance | Waters | |
| 3 | Bruker nuclear magnetic resonance apparatus (400M) | WUHAN ZHONGKE MR TECHNOLOGY Co.,Ltd. | |
| 4 | Gas chromatograph | Agilent |
The method adopts the following synthetic route:
example 1: and (3) synthesizing the compound flurbiprofen axetil.
Adding 200ml of tetrahydrofuran, 200.00g of flurbiprofen, 177.75g of ethyl 1-bromoacetate and 124.48g of anhydrous potassium carbonate, stirring and heating, keeping the temperature of a reaction system at 50 ℃ for reaction for 12 hours (monitoring the reaction by TLC) until the reaction is complete, cooling the reaction system to room temperature, carrying out suction filtration, leaching a filter cake with 200ml of tetrahydrofuran, combining filtrates, carrying out reduced pressure rotary evaporation at 60 ℃ to obtain 256.60g of crude flurbiprofen axetil as a colorless liquid, wherein the yield is 94.9%. Detection by HPLC: purity 99.449% (fig. 1); high resolution mass spectrometry: 353.1163[ M + Na ]]+(FIG. 2), the theoretical calculation value of the molecular ion peak of flurbiprofen axetil is as follows: 353.1160[ M + H]+In accordance with the error range of high-resolution mass spectrumThe measured values correspond to the theoretical values.
HNMR (400M, DMSO-d 6): 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-d 6): 18.1855, respectively; 19.0630, respectively; 20.4066, respectively; 43.6811, respectively; 88.4700, respectively; 115.2435, respectively; 123.9570, respectively; 127.7284, respectively; 128.5027, respectively; 128.6362, respectively; 130.6661, respectively; 134.7209, respectively; 141.7928, respectively; 157.6352, respectively; 160.0844, respectively; 168.5392, respectively; 171.5338 (fig. 4).
Example 2: purification of flurbiprofen axetil compound
To the crude flurbiprofen axetil (30.00g) obtained in example 1 was added n-heptane (300ml),stirring deviceStirring for 0.5h, raising the temperature to 45 ℃, completely dissolving the system, keeping the temperature of the system, continuously stirring for 0.5h, cooling the reaction system for 1h to-10 ℃, separating out solids, keeping the temperature, stirring for 2h, filtering the system, washing a filter cake with-10 ℃ n-heptane with a mass/volume ratio of 1:1, and then carrying out forced air drying on the filter cake at 25 ℃ to obtain 26.10g of flurbiprofen axetil white solid, wherein the yield is 87.0%, and the HPLC detection shows that: purity 99.731% (fig. 5).
Example 3: purification of flurbiprofen axetil compound
To flurbiprofen axetil (sample of example 2) (10.00g) was added n-heptane (100ml),stirring the mixtureWhen the temperature is raised to 45 ℃ in the next 1h, the system is completely dissolved and clear, the temperature of the system is kept and stirring is continued for 0.5h, the temperature of the reaction system is reduced to-10 ℃ in 2h, the temperature is kept and stirring is continued for 2h after solid is separated out, the system is filtered, a filter cake is washed by n-heptane at-10 ℃ in a mass/volume ratio of 1:1, then the filter cake is dried by air blowing at 25 ℃ to obtain 8.50g of flurbiprofen axetil white solid, the yield is 85.0%, and the HPLC detection shows that: purity 99.905% (fig. 6), the product was examined by X-Ray powder diffraction (X-Ray) (fig. 7), differential thermal analysis (DSC) (fig. 8), and thermogravimetric analysis (TGA) (fig. 9), and the crystalline form of the solid powder was named form a.
Example 4: purification of flurbiprofen axetil compound
Adding isopropanol (6ml) into flurbiprofen axetil (3.00g) obtained in example 1, stirring for 0.5h until the temperature rises to 45 ℃, completely dissolving the system, keeping the system temperature, continuously stirring for 0.5h, adding purified water (3ml) into the system, cooling the reaction system for 1h to 0 ℃, separating out solids, keeping the temperature, stirring for 2h, filtering the system, washing a filter cake with isopropanol/water 2:1(V/V) at the temperature of 0 ℃ in a mass/volume ratio of 1:1, and then carrying out forced air drying at the temperature of 25 ℃ to obtain 2.82g of flurbiprofen axetil white solid with the yield of 94.00%, wherein the yield is detected by HPLC: purity 99.937% (fig. 10), X-Ray powder diffraction (X-Ray) was performed on the product (fig. 11), the product being form a.
Example 5: purification of flurbiprofen axetil compound
Adding isopropyl ether (6ml) into flurbiprofen axetil (3.00g) obtained in example 1, stirring for 0.5h until the temperature rises to 45 ℃, completely dissolving the system, keeping the system temperature, continuously stirring for 0.5h, adding n-heptane (18ml) into the system, cooling the reaction system for 1h to-5 ℃, keeping the temperature and stirring for 2h after solid is precipitated, filtering the system, washing a filter cake with isopropyl ether/n-heptane 1:3(V/V) at-5 ℃ in a mass/volume ratio of 1:1, and then drying the filter cake by air blast at 25 ℃ to obtain 2.5g of flurbiprofen axetil white solid, wherein the yield is 83.6%, and the content is detected by HPLC: purity 99.984% (fig. 12), X-Ray powder diffraction (X-Ray) was performed on the product (fig. 13), and the product was form a.
Example 6: purification of flurbiprofen axetil compound
Adding n-decane (150ml) into the flurbiprofen axetil (10.00g) obtained in example 1, stirring for 1h until the temperature rises to 40 ℃, completely dissolving the system, keeping the system temperature, continuously stirring for 0.5h, cooling the reaction system for 2h to-10 ℃, separating out solids, keeping the temperature, stirring for 2h, filtering the system, washing a filter cake with-10 ℃ n-heptane with a mass/volume ratio of 1:1, and then drying the filter cake by air blowing at 28 ℃ to obtain 8.20g of flurbiprofen axetil white solids with a yield of 82.0%, wherein the yield is detected by HPLC: purity 99.813% (fig. 14).
Example 7: purification of flurbiprofen axetil compound
Adding n-butanol (9ml) into flurbiprofen axetil (3.00g) obtained in example 1, stirring for 0.5h until the temperature is raised to 40 ℃, completely dissolving the system, keeping the system temperature, continuously stirring for 0.5h, adding purified water (3ml) into the system, cooling the reaction system to 0 ℃ for 1h, separating out solids, keeping the temperature, stirring for 2h, filtering the system, washing a filter cake with n-butanol/water (3: 1(V/V) at 0 ℃ in a mass/volume ratio of 1:1, and then drying the filter cake by air blowing at 25 ℃ to obtain 2.70g of flurbiprofen axetil white solid, wherein the yield is 90.00%, and the content is detected by HPLC: purity 99.927% (fig. 15).
Example 8: purification of flurbiprofen axetil compound
Adding heptyl ether (8ml) into flurbiprofen axetil (3.00g) obtained in example 1, stirring for 1h, when the temperature is raised to 50 ℃, completely dissolving the system, adding n-heptane (16ml) into the system, cooling the reaction system for 2h to-10 ℃, keeping the temperature and stirring for 2h after solid is precipitated, filtering the system, washing a filter cake with-10 ℃ heptyl ether/n-heptane 1:2(V/V) in a mass/volume ratio of 1:1, and then drying the filter cake by air blowing at 28 ℃ to obtain 2.51g of flurbiprofen axetil white solid with the yield of 83.7%, wherein the HPLC detection: purity 99.982% (fig. 16).
Example 9: purification of flurbiprofen axetil compound
Adding methyl tert-ether (30ml) into the crude flurbiprofen axetil (30.00g) obtained in example 1, stirring for 0.5h until the temperature is raised to 50 ℃, completely dissolving the system, keeping the system temperature, continuously stirring for 0.5h, adding n-heptane (120ml) into the system, cooling the reaction system for 1h to 0 ℃, separating out a solid, keeping the temperature, stirring for 2h, filtering the system, washing a filter cake with the methyl tert-ether/n-heptane 1:4(V/V) at the temperature of 0 ℃ in a mass/volume ratio of 1:1, and then drying the filter cake by air blowing at 28 ℃ to obtain 26.10g of white flurbiprofen axetil solid with the yield of 87.0%, which is detected by HPLC: purity 99.84% (fig. 17), X-Ray powder diffraction (X-Ray) was performed on 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); weighing crude flurbiprofen axetil (10.00g), loading, separating, collecting main peak component, and rotary steaming at 60 deg.C under reduced pressure to obtain flurbiprofen axetil colorless oily substance 4.85g, yield 48.5%, and purity 99.760% by HPLC (FIG. 19).
Experimental example 1: stability study of flurbiprofen axetil form a
And (3) carrying out stability inspection on the flurbiprofen axetil crystal form A, standing for 3 months at room temperature, and detecting appearance, HPLC (high performance liquid chromatography) and X-ray powder diffraction at 0 day and 90 days respectively. And (3) detection results: the X-ray powder diffraction detection result shows that after the sample is placed for 3 months, the crystal form of the sample is unchanged and still is the crystal form A, and the detection result and the appearance of HPLC are shown in the following table:
experimental example 2: impurity and residual solvent detection of flurbiprofen axetil crystal form A
The samples of example 9 and comparative example 1 were measured for impurity 1B (1, 1-ethylene glycol diacetate) and residual solvent by gas chromatography, and the conditions and results are shown in the following table:
gas chromatography conditions:
a chromatographic column: 60X 0.32nm, 1.8 μm;
flow rate: 2.5 ml/min;
equilibrium temperature: 85 ℃;
temperature rising procedure: 45-200 ℃;
sample preparation: precisely weighing 1.00g of flurbiprofen axetil, adding DMF10ml to a constant volume, and obtaining the solution as a test solution.
And (3) detection process: and (5 ml) injecting the test solution into a headspace bottle, running detection, and recording a chromatogram.
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 significant technical advantages.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (22)
1. A method for purifying flurbiprofen axetil, comprising the steps of:
(1) adding an organic solvent into the crude flurbiprofen axetil, and heating to dissolve the flurbiprofen axetil 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) filtering the system at a controlled temperature, washing with an organic solvent, and drying a filter cake to obtain the flurbiprofen axetil white solid crystal.
2. The method according to claim 1, wherein the organic solvent in step (1) is selected from one, two or more of the following solvents:
the alkane solvents include: C5-C10 alkane or mixture thereof;
the mixed solvent of the alcohol solvent and water comprises: a mixed solvent of alcohols and water having a carbon number of 1 to 4; or
The mixed solvent of ethers and alkanes includes: C2-C7 ethers/C5-C10 alkanes.
3. The method according to claim 2, wherein, in step (1),
the alkane solvents comprise: hexane, heptane, octane or petroleum ether;
the mixed solvent of the alcohol solvent and water comprises: methanol/water, ethanol/water, isopropanol/water or tert-butanol/water;
the mixed solvent of the ethers and the alkanes comprises: methyl tert-ether/n-heptane, or isopropyl ether/n-heptane.
4. The method according to claim 1, wherein the mass/volume ratio of the crude flurbiprofen axetil to the organic solvent in the step (1) is 1: 1-30, preferably 1: 1-10.
5. The method according to claim 1, wherein the temperature of raising the temperature to dissolution in step (1) is 30 ℃ to 130 ℃, preferably 35 ℃ to 60 ℃, more preferably 40 ℃ to 50 ℃; the stirring and heating in the step (1) is carried out until the time for dissolving lasts for 0.5-5 hours, preferably 0.5-2 hours, and more preferably 0.5-1 hour.
6. The method according to claim 1, wherein the temperature of the flurbiprofen axetil solution system in the step (2) is reduced to-30 ℃ to 30 ℃, preferably to-10 ℃ to 10 ℃, and more preferably to-10 ℃ to 0 ℃.
7. The method according to claim 6, wherein the cooling time in the step (2) lasts for 0.5 to 6 hours, more preferably 1 to 2 hours.
8. The method according to claim 1, wherein the stirring time after the solid is precipitated in the step (3) is 0.5 to 20 hours, more preferably 2 to 4 hours.
9. The method according to claim 1, wherein the organic solvent for washing the filter cake in the step (4) is selected from one, two or more mixed solvents of the following solvents:
the alkane solvents include: C5-C10 alkane or mixture thereof; or
The mixed solvent of the alcohol solvent and water comprises: a mixed solvent of alcohols and water having a carbon number of 1 to 4; or
The mixed solvent of ethers and alkanes includes: C2-C7 ethers/C5-C10 alkanes;
the same organic solvent as in step (1) is preferred.
10. The method of claim 9, wherein in step (4), step (4) is performed
The alkane solvents comprise: hexane, heptane, octane, petroleum ether or n-decane;
the mixed solvent of the alcohol and the water comprises: methanol/water, ethanol/water, isopropanol/water, or n-butanol/water; preferably, the volume ratio of the alcohol to the water is 2-3: 1
The mixed solvent of the ethers and the alkanes comprises: methyl tert-ether/n-heptane, isopropyl ether/n-heptane, or heptyl ether/n-heptane; preferably, the volume ratio of ether to alkane is 1:2 to 4.
11. The method according to claim 1, wherein the temperature of the organic solvent for washing the filter cake in the step (4) is-30 ℃ to 30 ℃, preferably-10 ℃ to 10 ℃, and more preferably-10 ℃ to 0 ℃.
12. The method according to claim 1, wherein the mass/volume ratio of the filter cake to the organic solvent for washing the filter cake in the step (4) is 1: 1-10, preferably 1: 1-3, and more preferably 1: 1.
13. The process according to claim 1, wherein the temperature of the air blast drying of the filter cake in step (4) is 10 ℃ to 30 ℃, preferably 20 ℃ to 30 ℃, more preferably 25 ℃ to 28 ℃.
14. The method according to claim 1, wherein the purity of the flurbiprofen axetil prepared by the method is more than or equal to 99.5%.
15. The method according to claim 1, wherein the content of 1, 1-glycol diacetate as an impurity in the flurbiprofen axetil prepared by the method is less than 0.1%.
16. The method according to claim 1, characterized in that the yield of flurbiprofen axetil is greater than or equal to 80%, preferably between 80% and 90%.
17. The method of claim 1, further comprising preparing a crude flurbiprofen axetil product by: adding (+/-) -2- (2-fluoro-4-biphenyl) -propionic acid, inorganic base and 1-bromoethyl acetate into a solvent, controlling the temperature to react, washing a reaction product, and concentrating under reduced pressure to obtain the compound.
18. A crystalline form a of (+ -) -1-acetoxyethyl 2- (2-fluoro-4-biphenylyl) propionate obtained by the method of any one of claims 1 to 17, characterized in that said crystalline form a has 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 ° by X-ray powder diffraction.
19. Form a of flurbiprofen axetil according to claim 18, characterized in that it is characteristic of X-ray powder diffraction as shown in figure 7.
20. Form a of flurbiprofen axetil according to claim 18, characterized in that it has a DSC thermogram with an endotherm beginning at 30-32 ℃ and an endotherm peak at 32-34 ℃.
21. Form a of flurbiprofen axetil according to claim 18, characterized in that it has the DSC thermogram characteristic shown in figure 8.
22. Crystalline form a of flurbiprofen axetil according to claim 18, characterized in that it has thermogravimetric analysis (TGA) thermogravimetric analysis characteristics similar to that shown in figure 9.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010846838.8A CN114075109B (en) | 2020-08-21 | 2020-08-21 | Preparation method of flurbiprofen axetil and prepared crystal form |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010846838.8A CN114075109B (en) | 2020-08-21 | 2020-08-21 | Preparation method of flurbiprofen axetil and prepared crystal form |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114075109A true CN114075109A (en) | 2022-02-22 |
| CN114075109B CN114075109B (en) | 2024-05-03 |
Family
ID=80282119
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010846838.8A Active CN114075109B (en) | 2020-08-21 | 2020-08-21 | Preparation method of flurbiprofen axetil and prepared crystal form |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114075109B (en) |
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 |
|---|
| "氟比洛芬酯报价", pages 46 - 47, Retrieved from the Internet <URL:https://china.guidechem.com/cas/429439.html?pageNo=3&> * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114075109B (en) | 2024-05-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA3023851C (en) | Crystal forms of crisaborole in free form and preparation method and use thereof | |
| CN104447600B (en) | A kind of Preparation Method And Their Intermediate impurity of Parecoxib sodium compound, preparation method and application | |
| MX2011000172A (en) | Process for preparation of esomeprazole sodium of high chemical purity and new forms of esomeprazole sodium. | |
| JP2016183193A (en) | Solid state forms of fidaxomicin and processes for preparation thereof | |
| CA3211594A1 (en) | Crystal form of pyridine nitrogen oxide compound and use thereof | |
| CN114249711A (en) | Method for preparing nicotine by resolution | |
| CN114075109A (en) | Preparation method of flurbiprofen axetil and prepared crystal form | |
| CN109897009B (en) | Apabetalone hydrate crystal form and preparation method thereof | |
| CN109438370B (en) | Methylpyrazine derivative anhydrous crystal form | |
| KR20130086534A (en) | Solid state forms of ixabepilone | |
| CN112707829B (en) | Toxolol crystal form and preparation method thereof | |
| JP3981520B2 (en) | Method for separating organic compounds | |
| CN111995614B (en) | Preparation method of thiohydroxy acetic anhydride | |
| KR102709537B1 (en) | An efficient crystallization process for preparing ultrapure treprostinil and crystal prepared therefrom | |
| TWI707851B (en) | Novel crystals of piperazine compounds | |
| EP3992173B1 (en) | Treprostinil monohydrate crystals and methods for preparation thereof | |
| EP4442689A1 (en) | Crystal form of fused ring derivative, and preparation method therefor and use thereof | |
| CN104844681A (en) | L-crystal form eplerenone refining method | |
| CN110724095B (en) | Preparation method of indacaterol acetate | |
| CN111484489B (en) | Amorphous B-RAF kinase dimer inhibitors | |
| CN105753820A (en) | Method for purifying dehydroandrographolide succinate | |
| CN117222643A (en) | Tergolian prazan crystal form B and preparation method thereof | |
| CN115925603A (en) | Preparation method of Sopyraum bromide | |
| CN111116655A (en) | Preparation method of high-optical-purity tenofovir benzyl ester phosphonamide prodrug | |
| CN105061273B (en) | Valnemulin tartrate polycrystalline forms and preparation methods thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |