CN101503355B - Synthesis and refining of triflusal - Google Patents
Synthesis and refining of triflusal Download PDFInfo
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- CN101503355B CN101503355B CN2009100009096A CN200910000909A CN101503355B CN 101503355 B CN101503355 B CN 101503355B CN 2009100009096 A CN2009100009096 A CN 2009100009096A CN 200910000909 A CN200910000909 A CN 200910000909A CN 101503355 B CN101503355 B CN 101503355B
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- RMWVZGDJPAKBDE-UHFFFAOYSA-N 2-acetyloxy-4-(trifluoromethyl)benzoic acid Chemical compound CC(=O)OC1=CC(C(F)(F)F)=CC=C1C(O)=O RMWVZGDJPAKBDE-UHFFFAOYSA-N 0.000 title claims abstract description 71
- 238000007670 refining Methods 0.000 title claims abstract description 19
- 229960002268 triflusal Drugs 0.000 title abstract description 5
- 230000015572 biosynthetic process Effects 0.000 title description 3
- 238000003786 synthesis reaction Methods 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 57
- 230000008569 process Effects 0.000 claims abstract description 28
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 15
- 239000011630 iodine Substances 0.000 claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 88
- 239000008213 purified water Substances 0.000 claims description 62
- 238000003756 stirring Methods 0.000 claims description 54
- 238000006243 chemical reaction Methods 0.000 claims description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- 238000001035 drying Methods 0.000 claims description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- 238000011010 flushing procedure Methods 0.000 claims description 33
- 238000010907 mechanical stirring Methods 0.000 claims description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 239000000463 material Substances 0.000 claims description 25
- 238000005406 washing Methods 0.000 claims description 25
- 239000012065 filter cake Substances 0.000 claims description 24
- 238000001914 filtration Methods 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 21
- 206010013786 Dry skin Diseases 0.000 claims description 17
- 239000000706 filtrate Substances 0.000 claims description 17
- 239000007787 solid Substances 0.000 claims description 17
- -1 trifluoromethyl Whitfield's ointment Chemical compound 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 11
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 9
- 230000008025 crystallization Effects 0.000 claims description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 7
- 239000012467 final product Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000005457 ice water Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 238000004383 yellowing Methods 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 5
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 5
- 239000012346 acetyl chloride Substances 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- 238000013019 agitation Methods 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 50
- 238000004128 high performance liquid chromatography Methods 0.000 description 28
- 238000000746 purification Methods 0.000 description 21
- 239000000356 contaminant Substances 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 210000001772 blood platelet Anatomy 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 3
- 208000032843 Hemorrhage Diseases 0.000 description 3
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 3
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 208000007536 Thrombosis Diseases 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 3
- 239000004299 sodium benzoate Substances 0.000 description 3
- 235000010234 sodium benzoate Nutrition 0.000 description 3
- 206010008190 Cerebrovascular accident Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 208000005189 Embolism Diseases 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 208000001435 Thromboembolism Diseases 0.000 description 2
- 230000000702 anti-platelet effect Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 230000007797 corrosion Effects 0.000 description 2
- 238000005260 corrosion Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 230000009863 secondary prevention Effects 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 241000218998 Salicaceae Species 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 210000003725 endotheliocyte Anatomy 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 239000013037 reversible inhibitor Substances 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
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- 230000009466 transformation Effects 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention aims to provide a method for synthesizing and refining triflusal, wherein iodine is selected as a catalyst in the process of preparing the triflusal.
Description
Technical field:
The present invention relates to the pharmaceutical chemistry field, particularly the preparation method of UR-1501 and process for purification thereof.
Background technology:
Popular name: UR-1501, English name: triflusal, chinesization formal name used at school: 2-acetyl oxygen-4-[trifluoromethyl] phenylformic acid, its molecular formula: C
10H
7F
3O
4, molecular weight: 248.1553, CAS RN:322-79-2,
Its chemical structural formula is following:
Pharmacological action: this medicine forms through the biology that the irreversible inhibition to the thrombocyte cyclooxygenase reduces thrombus; Its major metabolite HTB (3-hydroxyl-4-trifluoro-benzoic acid) is the reversible inhibitor of thrombocyte cyclooxygenase; And its transformation period very long (about 34 hours), this just helps the anti-platelet activity of UR-1501; Also can pass through to suppress cAMP content in the thrombocyte phosphodiesterase platelet increasing, thereby produce antiplatelet aggregative activity with its meta-bolites HTB.Its effect of restraining the endotheliocyte cyclooxygenase is atomic; Do not influence the synthetic of prostaglandin(PG); But the anti-freezing of its meta-bolites platelet increasing gathers effect; This medicine is applied to human body does not increase the bleeding time, even clinical trial confirms to use simultaneously at thromboembolism treatment, does not increase cardiovascular hemorrhage incidence yet; Validity to UA, coronary artery urethroptasty and the disease of short circuit operation, Acute Stage of Myocardial Infarction, peripheral vascular disease and thromboembolism is identical with Asprin; But hemorrhage complication seldom, is used for the clinical study of cerebro-vascular diseases secondary prevention, and particularly the research of TAPIRSS confirms the secondary prevention of TIA (transient ischemic attack) and transient apoplexy is superior to Asprin in South America.
Indication: the thrombosis of prevention myocardial infarction, stable or UA, TIAS or apoplexy; Thrombosis after the minimizing CABG.
At present, prior art mainly utilizes the vitriol oil as the synthetic UR-1501 of catalyzer, but the vitriol oil has following shortcoming as catalyzer:
(1) utilize the vitriol oil as the synthetic UR-1501 of catalyzer; The UR-1501 that obtains, bullion yield≤85%, single maximum contaminant>=4%; Carry out twice refining difficulty that all compares and obtain salable product (need make with extra care through three times and just might obtain salable product, at this moment total recovery≤60%).
When (2) utilizing the vitriol oil as the synthetic UR-1501 of catalyzer, after reaction finished, when adding the entry termination reaction, temperature rose very violent, particularly during industrial production, used vitriol oil amount big, the temperature more violent also more difficult control of rising.
(3) vitriol oil industry usage quantity is bigger, and is more serious to equipment corrosion.
(4) learn through experiment: utilize the vitriol oil as the synthetic UR-1501 of catalyzer, along with the prolongation in reaction times and the raising of temperature of reaction, all can increase product clearly in the generation of impurity.
We are through constantly making great efforts and many times test, work out a kind of preparation method and process for purification of new UR-1501 finally, have not only overcome above-mentionedly with the whole shortcomings of the vitriol oil as catalyzer, have also improved its stability and output.Reference: us 3052603 us4096252 CA 58; 479c CA 56; The acetysalicylic process for catalytic synthesis of the improvement Yunnan Institute for nationalities journal of 11722e catalysis of iodine synthesis of acetyl Whitfield's ointment research and development forward position volume 21 days the 16 May in 2008 the 10th phase Xaxa synthesis condition the 12 volume a kind of 4-trifluoromethyl of the 3rd phase July in 2003, one Chinese patent application number: the method one Chinese patent application of 200510042319.1 1 kinds of refining trifluoro willows number: 200710191190.X
Summary of the invention:
The object of the present invention is to provide a kind of preparation method of UR-1501.
Another object of the present invention is to provide the process for purification of UR-1501.
UR-1501 synthetic route of the present invention is following:
Step is following:
Trifluoromethyl Whitfield's ointment and diacetyl oxide, or trifluoromethyl Whitfield's ointment and Acetyl Chloride 98Min. react, and make catalyzer with iodine in the reaction, wherein the trifluoromethyl Whitfield's ointment: diacetyl oxide or Acetyl Chloride 98Min.: the mol ratio of iodine is=1: 2-10: 0.002-0.1; 50 ℃-120 ℃ of temperature of reaction, 10 minutes-180 minutes reaction times; Reaction is under agitation carried out, 50～1000 rev/mins of stirring velocitys, and reaction finishes, and stops heating, and cooling adds frozen water, mechanical stirring crystallization 0.5-4 hour, the dry UR-1501 that gets.
React whole process with nitrogen protection in the reaction, monitor reaction solution with TLC, developping agent is an ethanol: acetonitrile=1: 3, and reaction finishes; Temperature was in the use ice-water bath was reduced to :-10 ℃-0 ℃, slowly add ice purified water 80ml, water temperature: 0 ℃-15 ℃, and the thick oily matter of system yellowing;-10 ℃-8 ℃ abundant stirring and crystallizing 0.5h-4h hour, crystallization is complete, filters, and drains; Filter cake is drained with X4 drip washing of ice purified water 25ml, and article must wet; Wet article are placed ambient temperature overnight earlier and are dried naturally, 20 ℃ of-70 ℃ of normal pressures of material placement or drying under reduced pressure 2-8 hour are got final product in second day.
The most preferred preparation method of the present invention in an embodiment.
Catalyzer of the present invention gets through screening, has used soda ash light, Sodium Benzoate, the vitriol oil, iodine as the synthetic UR-1501 of catalyzer respectively, and the mol ratio of preparation method and raw material is with embodiment 1.
Use the vitriol oil as catalyzer, the bullion yield: 80%, purity: 95%, content: 82%, single maximum contaminant: 4.48%;
Use Sodium Benzoate as catalyzer, the bullion yield: 89.9%, purity: 86%, content: 88%, single maximum contaminant: 12.8%;
Use soda ash light as catalyzer, the bullion yield: 81.4%, purity: 96%, content: 81%, single maximum contaminant: 3.8%;
Through experiment showed, that soda ash light or Sodium Benzoate or the vitriol oil obtain the UR-1501 quality product as catalyst reaction, purity is all not as good as the UR-1501 that catalyst reaction obtains with iodine.
Among the preparation method of UR-1501 of the present invention, select for use iodine also to have following beneficial effects as catalyzer:
1. utilize iodine as the synthetic UR-1501 of catalyzer, along with the prolongation in reaction times and the raising of temperature of reaction, react all very stable, almost the not generation of newly-increased impurity.
2. utilize iodine as the synthetic UR-1501 of catalyzer, reaction conditions is gentle, easily control.
3. production unit there is not corrosion.
The process for purification of UR-1501 of the present invention, step is following:
The UR-1501 bullion is dissolved in the organic solvent, after the dissolving, filters; Filtrating adds another kind of solvent, after the dissolving through mechanical stirring in filtrating; Filtration is drained; Slow stirring and crystallizing, drying, wherein said organic solvent is selected from: methyl alcohol, ethanol, acetone, propyl alcohol, Virahol, butanols, methylene dichloride, trichloromethane, acetonitrile, THF or ETHYLE ACETATE; Another kind of solvent is selected from: water, hexanaphthene, normal hexane or sherwood oil, and the bulking value ratio of bullion and organic solvent is 1: 2-10; The volume ratio of said organic solvent and another kind of solvent 1: 2～10.
During mechanical stirring, be under 5 ℃ of-60 ℃ of temperature condition, to add entry or hexanaphthene or sherwood oil (explaining: be water or hexanaphthene or normal hexane or the sherwood oil that just in organic solvent, adds 2～10ml according to the every use of above-mentioned organic solvent 1ml) wherein according to volume ratio 1ml: 2～10ml.
The solvent for use proportioning includes, but are not limited to following several kinds: methanol-water (1: 2-10), alcohol-water (1: 2-10), acetone---water (1: 2-10), propyl alcohol-water (1: 2-10), Virahol-water (1: 2-10), methylene dichloride-sherwood oil (1: 2-10), acetonitrile-water (1: 2-10), methylene dichloride-hexanaphthene (1: 2-10)
The process for purification of the most preferred UR-1501 of the present invention in an embodiment.
The process for purification of UR-1501 of the present invention has plurality of advantages, and productive rate is high, and purification efficiency is high, purity height, good stability, simple, with low cost, the suitable scale operation of technology.
Embodiment:
Through following examples the present invention is described further, but not as restriction of the present invention.
Embodiment 1: the preparation method of UR-1501
Three mouthfuls of round-bottomed flasks of the good anhydrous 250ml of drying under nitrogen atmosphere, are installed mechanical stirring, spherical condensation tube, TM (0-200 ℃), added oil bath, add to trifluoromethyl Whitfield's ointment (10g 0.0485mol), diacetyl oxide (14.9g 0.1456mol), iodine (0.048g) mechanical stirring (stirring velocity: 450 rev/mins) successively; Nitrogen protection reaction whole process, 120 ℃ of reactions of temperature in oil bath slowly is warming up to, timing insulated and stirred reaction 60min monitors reaction solution (TLC system: silica GF254 thin layer plate with TLC; Developping agent, ethanol: acetonitrile=1: 3), reaction finishes, and stops heating; Remove oil bath, temperature was room temperature in stirring at room was reduced to naturally, used ice-water bath to reduce to interior temperature again to be :-10 ℃-0 ℃, slowly add ice purified water (water temperature: 0 ℃～10 ℃) 80ml; The thick oily matter of system yellowing ,-5 ℃ of-0 ℃ of abundant stirring and crystallizing 2 hours, crystallization is complete; Filter, drain, filter cake is with X4 drip washing of ice purified water 25ml; Drain, article 14 grams that must wet, wet article are placed ambient temperature overnight earlier and are dried naturally; Material placed 40 ℃ of constant pressure and dry casees dry 8 hours in second day, dry product: 10.62 grams, bullion yield: 88.2%; Purity: 98%, content: 95%, single maximum contaminant: 0.9%
The preparation method of embodiment 2, UR-1501
Three mouthfuls of round-bottomed flasks of the good anhydrous 250ml of drying under nitrogen atmosphere, are installed mechanical stirring, spherical condensation tube, TM (0-200 ℃), added oil bath, add to trifluoromethyl Whitfield's ointment (10g 0.0485mol), Acetyl Chloride 98Min. (11.43g 0.1456mol), iodine (0.048g 0.00038mol) mechanical stirring (stirring velocity: 450 rev/mins) successively; Nitrogen protection reaction whole process, 120 ℃ of reactions of temperature in oil bath slowly is warming up to, timing insulated and stirred reaction 60min monitors reaction solution (TLC system: silica GF254 thin layer plate with TLC; Developping agent, ethanol: acetonitrile=1: 3), reaction finishes, and stops heating; Remove oil bath, temperature was room temperature in stirring at room was reduced to naturally, used ice-water bath to reduce to interior temperature again to be :-10 ℃～0 ℃, slowly add ice purified water (water temperature: 0 ℃～10 ℃) 80ml; The thick oily matter of system yellowing ,-5 ℃ of-0 ℃ of abundant stirring and crystallizing 2 hours, crystallization is complete; Filter, drain, filter cake is with X4 drip washing of ice purified water 25ml; Drain, article 13.9 grams that must wet, wet article are placed ambient temperature overnight earlier and are dried naturally; Material placed 60 ℃ of constant pressure and dry casees dry 8 hours in second day, dry product: 10.61 grams, bullion yield: 88%; Purity: 97.8%, content: 94.8%, single maximum contaminant: 0.9%
The preparation method of embodiment 3, UR-1501
Three mouthfuls of round-bottomed flasks of the good anhydrous 250ml of drying under nitrogen atmosphere, are installed mechanical stirring, spherical condensation tube, TM (0-100 ℃), added oil bath, add to trifluoromethyl Whitfield's ointment (0.1mol), diacetyl oxide (0.2mol), iodine (0.0002mol) mechanical stirring (stirring velocity: 50 rev/mins) successively; Nitrogen protection reaction whole process, 50 ℃ of reactions of temperature in oil bath slowly is warming up to, timing insulated and stirred reaction 10min monitors reaction solution (TLC system: silica GF254 thin layer plate with TLC; Developping agent, ethanol: acetonitrile=1: 3), reaction finishes, and stops heating; Remove oil bath, temperature was room temperature in stirring at room was reduced to naturally, used ice-water bath to reduce to interior temperature again to be :-10 ℃-0 ℃, slowly add ice purified water (water temperature: 0 ℃-10 ℃) 80ml; The thick oily matter of system yellowing, 4 ℃ of-8 ℃ of abundant stirring and crystallizing 0.5 hour, crystallization is complete; Filter, drain, filter cake is with X4 drip washing of ice purified water 25ml; Drain, article 14 grams that must wet, wet article are placed ambient temperature overnight earlier and are dried naturally; Material placed 40 ℃ of constant pressure and dry casees dry 8 hours in second day, dry product: 21.8 grams, bullion yield: 87.8%; Purity: 97.8%, content: 93.8%, single maximum contaminant: 0.92%
The preparation method of embodiment 4, UR-1501
Three mouthfuls of round-bottomed flasks of the good anhydrous 250ml of drying under nitrogen atmosphere, are installed mechanical stirring, spherical condensation tube, TM (0-200 ℃), added oil bath, add to trifluoromethyl Whitfield's ointment (0.01mol), diacetyl oxide (0.1mol), iodine (0.01mol) mechanical stirring (stirring velocity: 1000 rev/mins) successively; Nitrogen protection reaction whole process, 120 ℃ of reactions of temperature in oil bath slowly is warming up to, timing insulated and stirred reaction 180min monitors reaction solution (developping agent with TLC; Ethanol: acetonitrile=1: 3), reaction finishes, and stops heating, removes oil bath; Temperature was room temperature in stirring at room was reduced to naturally, used ice-water bath to reduce to interior temperature again to be :-10 ℃-0 ℃, slowly add ice purified water (water temperature: 0 ℃-10 ℃) 80ml, the thick oily matter of system yellowing;-10 ℃ of-0 ℃ of abundant stirring and crystallizing 4 hours, crystallization is complete, filters, and drains; Filter cake is drained with 4 drip washing of ice purified water 25ml X, article 14 grams that must wet, and wet article are placed ambient temperature overnight earlier and are dried naturally; Material placed 70 ℃ of constant pressure and dry casees dry 6 hours in second day, dry product: 2.19 grams, bullion yield: 88%; Purity: 97.3%, content: 93.8%, single maximum contaminant: 0.95%
The process for purification of embodiment 5, UR-1501
UR-1501 bullion 5 grams, 95% ethanol 15ml to the anhydrous flask adding of drying the foregoing description 1 makes fully stir, and 50 ℃ of solids are molten entirely clear, and filtration is drained; With 95% ethanol 3ml flushing flask and funnel, drain, pour filtrating into dry anhydrous 250ml three mouthfuls of round-bottomed flasks, again with 95% ethanol 2ml flushing filter flask; Merging filtrate, mechanical stirring (stirring velocity: 500 rev/mins) slowly adds purified water 50ml and slowly stirred one hour; And then add purified water 30ml (adding purified water 80ml altogether), and slowly stirred 50 ℃ of crystallizatioies again two hours, filter; Drain, filter cake is drained with 3 drip washing of purified water 25ml X; The article that must wet, wet article are placed ambient temperature overnight earlier and are dried naturally, material are placed 40 ℃ of constant pressure and dry casees dryings 8 hours in second day; Get dry product: 4.34 grams, refining yield: 86.8%, highly finished product content: 103% (HPLC method), purity: 99.5% (HPLC method) gets salable product.
The process for purification of embodiment 6, UR-1501
UR-1501 bullion 5 grams, 95% ethanol 10ml to the anhydrous flask adding of drying the foregoing description 1 makes fully stir, and 45 ℃ of solids are molten entirely clear, and filtration is drained; With 95% ethanol 3ml flushing flask and funnel, drain, pour filtrating into dry anhydrous 250ml three mouthfuls of round-bottomed flasks, again with 95% methyl alcohol 2ml flushing filter flask; Merging filtrate, mechanical stirring (stirring velocity: 50 rev/mins) slowly adds purified water 10ml and slowly stirred one hour; Add purified water 10ml (adding purified water 20ml altogether) again, slowly stirred 45 ℃ of crystallizatioies 0.5 hour, filter; Drain, filter cake is drained with 25mlX3 drip washing of purified water; The article that must wet, wet article are placed ambient temperature overnight earlier and are dried naturally, material are placed 20 ℃ of constant pressure and dry casees dryings 3 hours in second day; Get dry product: 4.28 grams, refining yield: 85.6%, highly finished product content: 102% (HPLC method), purity: 99.4% (HPLC method) gets salable product.
The process for purification of embodiment 7, UR-1501
UR-1501 bullion 5 grams, 95% ethanol 40ml to the anhydrous flask adding of drying the foregoing description 1 makes fully stir, and 40 ℃ of solids are molten entirely clear, and filtration is drained; With 95% ethanol 5ml flushing flask and funnel, drain, pour filtrating into dry anhydrous 250ml three mouthfuls of round-bottomed flasks, again with 95% ethanol 5ml flushing filter flask; Merging filtrate, mechanical stirring (stirring velocity: 800 rev/mins) slowly adds purified water 500ml and slowly stirred one hour; Add purified water 300ml (adding purified water 800ml altogether) again, slowly stirred 40 ℃ of crystallizatioies 4 hours, filter; Drain, filter cake is drained with 3 drip washing of purified water 25mlX; The article that must wet, wet article are placed ambient temperature overnight earlier and are dried naturally, material are placed 70 ℃ of constant pressure and dry casees dryings 24 hours in second day; Get dry product: 4.31 grams, refining yield: 86.2%, highly finished product content: 102.8% (HPLC method), purity: 99.3% (HPLC method) gets salable product.
The process for purification of embodiment 8, UR-1501
UR-1501 bullion 5 grams, propyl alcohol 15ml to the anhydrous flask adding of drying the foregoing description 1 makes fully stir, and 50 ℃ of solids are molten entirely clear, and filtration is drained; With propyl alcohol 3ml flushing flask and funnel, drain, pour filtrating into dry anhydrous 250ml three mouthfuls of round-bottomed flasks, again with propyl alcohol 2ml flushing filter flask; Merging filtrate, mechanical stirring (stirring velocity: 500 rev/mins) slowly adds purified water 50ml and slowly stirred one hour; Add purified water 30ml (adding purified water 80ml altogether) again, slowly stirred 50 ℃ of crystallizatioies two hours, filter; Drain, filter cake is drained with X3 drip washing of purified water 25ml; The article that must wet, wet article are placed ambient temperature overnight earlier and are dried naturally, material are placed 40 ℃ of constant pressure and dry casees dryings 8 hours in second day; Get dry product: 4.29 grams, refining yield: 85.8%, highly finished product content: 102.2% (HPLC method), purity: 99.6% (HPLC method) gets salable product.
The process for purification of embodiment 9, UR-1501
UR-1501 bullion 5 grams, acetone 15ml to the anhydrous flask adding of drying the foregoing description 1 makes fully stir, and 45 ℃ of solids are molten entirely clear, and filtration is drained; With acetone 3ml flushing flask and funnel, drain, pour filtrating into dry anhydrous 250ml three mouthfuls of round-bottomed flasks, again with acetone 2ml flushing filter flask; Merging filtrate, mechanical stirring (stirring velocity: 500 rev/mins) slowly adds purified water 50ml and slowly stirred one hour; Add purified water 30ml (adding purified water 80ml altogether) again, slowly stirred 45 ℃ of crystallizatioies two hours, filter; Drain, filter cake is drained with 25mlX3 drip washing of purified water; The article that must wet, wet article are placed ambient temperature overnight earlier and are dried naturally, material are placed 40 ℃ of constant pressure and dry casees dryings 8 hours in second day; Get dry product: 4.18 grams, refining yield: 83.6%, highly finished product content: 102.3% (HPLC method), purity: 99.2% (HPLC method) gets salable product.
The process for purification of embodiment 10, UR-1501
To the anhydrous flask adding of drying UR-1501 bullion 5 grams, Virahol 15ml, fully stir, 50 ℃ of solids are molten entirely clear, and filtration is drained; With Virahol 3ml flushing flask and funnel, drain, pour filtrating into dry anhydrous 250ml three mouthfuls of round-bottomed flasks, again with Virahol 2ml flushing filter flask; Merging filtrate, mechanical stirring slowly adds purified water 50ml and slowly stirred one hour, adds purified water 30ml (adding purified water 80ml altogether) again; Slowly stirred 50 ℃ of crystallizatioies two hours, filter, drain, filter cake is with 25mlX3 drip washing of purified water; Drain, the article that must wet, wet article are placed ambient temperature overnight earlier and are dried naturally, material are placed 40 ℃ of constant pressure and dry casees dryings 8 hours in second day; Get dry product: 3.9 grams, refining yield: 78%, highly finished product content: 96% (HPLC method), purity: 95% (HPLC method) gets salable product.
The process for purification of embodiment 11, UR-1501
UR-1501 bullion 5 grams, methylene dichloride 15ml to the anhydrous flask adding of drying the foregoing description 1 makes fully stir, and 30 ℃ of solids are molten entirely clear, and filtration is drained; With methylene dichloride 3ml flushing flask and funnel, drain, pour filtrating into dry anhydrous 250ml three mouthfuls of round-bottomed flasks, again with methylene dichloride 2ml flushing filter flask; Merging filtrate, mechanical stirring (stirring velocity: 500 rev/mins) slowly adds sherwood oil 50ml and slowly stirred one hour; Add sherwood oil 30ml (adding sherwood oil 80ml altogether) again, slowly stirred 30 ℃ of crystallizatioies two hours, filter; Drain, filter cake is drained with mixed solution [methylene dichloride: sherwood oil=1: 4 (V/V)] X3 drip washing of 25ml; The article that must wet, wet article are placed ambient temperature overnight earlier and are dried naturally, material are placed 40 ℃ of constant pressure and dry casees dryings 8 hours in second day; Get dry product: 4.26 grams, refining yield: 85.2%, highly finished product content: 102% (HPLC method), purity: 99.4% (HPLC method) gets salable product.
The process for purification of embodiment 12, UR-1501
UR-1501 bullion 5 grams, acetonitrile 15ml to the anhydrous flask adding of drying the foregoing description 1 makes fully stir, and 40 ℃ of solids are molten entirely clear, and filtration is drained; With acetonitrile 3ml flushing flask and funnel, drain, pour filtrating into dry anhydrous 250ml three mouthfuls of round-bottomed flasks, again with acetonitrile 2ml flushing filter flask; Merging filtrate, mechanical stirring (stirring velocity: 500 rev/mins) slowly adds purified water 50ml and slowly stirred one hour; Add purified water 30ml (adding purified water 80ml altogether) again, slowly stirred 40 ℃ of crystallizatioies two hours, filter; Drain, filter cake is drained with X3 drip washing of purified water 25ml; The article that must wet, wet article are placed ambient temperature overnight earlier and are dried naturally, material are placed 40 ℃ of constant pressure and dry casees dryings 8 hours in second day; Get dry product: 4.22 grams, refining yield: 84.4%, highly finished product content: 102% (HPLC method), purity: 98% (HPLC method) gets salable product.
The process for purification of embodiment 13, UR-1501
UR-1501 bullion 5 grams, methylene dichloride 15ml to the anhydrous flask adding of drying the foregoing description 1 makes fully stir, and 50 ℃ of solids are molten entirely clear, and filtration is drained; With methylene dichloride 3ml flushing flask and funnel, drain, pour filtrating into dry anhydrous 250ml three mouthfuls of round-bottomed flasks, again with methylene dichloride 2ml flushing filter flask; Merging filtrate, mechanical stirring (stirring velocity: 500 rev/mins) slowly adds hexanaphthene 50ml and slowly stirred one hour; Add hexanaphthene 30ml (adding hexanaphthene 80ml altogether) again, slowly stirred 50 ℃ of crystallizatioies two hours, filter; Drain, filter cake is drained with 25mlX3 drip washing of mixed solution [methylene dichloride: hexanaphthene=1: 4 (V/V)]; The article that must wet, wet article are placed ambient temperature overnight earlier and are dried naturally, material are placed 40 ℃ of constant pressure and dry casees dryings 8 hours in second day; Get dry product: 4.27 grams, refining yield: 85.4%, highly finished product content: 102.4% (HPLC method), purity: 99.5% (HPLC method) gets salable product.
The process for purification of embodiment 14, UR-1501
UR-1501 bullion 5 grams, butanols 15ml to the anhydrous flask adding of drying the foregoing description 1 makes fully stir, and 50 ℃ of solids are molten entirely clear, and filtration is drained; With butanols 3ml flushing flask and funnel, drain, pour filtrating into dry anhydrous 250ml three mouthfuls of round-bottomed flasks, again with butanols 2ml flushing filter flask; Merging filtrate, mechanical stirring (stirring velocity: 500 rev/mins) slowly adds purified water 50ml and slowly stirred one hour; Add purified water 30ml (adding purified water 80ml altogether) again, slowly stirred 50 ℃ of crystallizatioies two hours, filter; Drain, filter cake is drained with 25mlX3 drip washing of purified water; The article that must wet, wet article are placed ambient temperature overnight earlier and are dried naturally, material are placed 40 ℃ of constant pressure and dry casees dryings 8 hours in second day; Get dry product: 4.28 grams, refining yield: 85.6%, highly finished product content: 102.3% (HPLC method), purity: 99.4% (HPLC method) gets salable product.
The process for purification of embodiment 15, UR-1501
UR-1501 bullion 5 grams, THF 15ml to the anhydrous flask adding of drying the foregoing description 1 makes fully stir, and 50 ℃ of solids are molten entirely clear, and filtration is drained; With THF 3ml flushing flask and funnel, drain, pour filtrating into dry anhydrous 250ml three mouthfuls of round-bottomed flasks, again with THF 2ml flushing filter flask; Merging filtrate, mechanical stirring (stirring velocity: 500 rev/mins) slowly adds purified water 50ml and slowly stirred one hour; Add purified water 30ml (adding purified water 80ml altogether) again, slowly stirred 50 ℃ of crystallizatioies two hours, filter; Drain, filter cake is drained with 25mlX3 drip washing of purified water; The article that must wet, wet article are placed ambient temperature overnight earlier and are dried naturally, material are placed 40 ℃ of constant pressure and dry casees dryings 8 hours in second day; Get dry product: 4.27 grams, refining yield: 85.4%, highly finished product content: 102.7% (HPLC method), purity: 99.3% (HPLC method) gets salable product.
The process for purification of embodiment 16, UR-1501
UR-1501 bullion 5 grams, ETHYLE ACETATE 15ml to the anhydrous flask adding of drying the foregoing description 1 makes fully stir, and 60 ℃ of solids are molten entirely clear, and filtration is drained; With ETHYLE ACETATE 3ml flushing flask and funnel, drain, pour filtrating into dry anhydrous 250ml three mouthfuls of round-bottomed flasks, again with ETHYLE ACETATE 2ml flushing filter flask; Merging filtrate, mechanical stirring (stirring velocity: 500 rev/mins) slowly adds sherwood oil 50ml and slowly stirred one hour; Add sherwood oil 30ml (adding sherwood oil 80ml altogether) again, slowly stirred 60 ℃ of crystallizatioies two hours, filter; Drain, filter cake is drained with mixed solution [acetate stone ethyl ester: oily ether=1: 4 (V/V)] X3 drip washing of 25ml; The article that must wet, wet article are placed ambient temperature overnight earlier and are dried naturally, material are placed 70 ℃ of constant pressure and dry casees dryings 12 hours in second day; Get dry product: 4.31 grams, refining yield: 86.2%, highly finished product content: 102.9% (HPLC method), purity: 99% (HPLC method) gets salable product.
The process for purification of embodiment 17, UR-1501
To the anhydrous flask adding of drying UR-1501 bullion 5 grams, methyl alcohol 15ml, fully stir, 40 ℃ of solids are molten entirely clear, and filtration is drained; With methyl alcohol 3ml flushing flask and funnel, drain, pour filtrating into dry anhydrous 250ml three mouthfuls of round-bottomed flasks, again with methyl alcohol 2ml flushing filter flask; Merging filtrate, mechanical stirring slowly adds purified water 50ml and slowly stirred one hour, adds purified water 30ml (adding purified water 80ml altogether) again; Slowly stirred 40 ℃ of crystallizatioies two hours, filter, drain, filter cake is with 25mlX3 drip washing of purified water; Drain, the article that must wet, wet article are placed ambient temperature overnight earlier and are dried naturally, material are placed 40 ℃ of constant pressure and dry casees dryings 8 hours in second day; Get dry product: 4.1 grams, refining yield: 82%, highly finished product content: 95% (HPLC method), purity: 99% (HPLC method) gets salable product.
The process for purification of embodiment 18, UR-1501
To the anhydrous flask adding of drying UR-1501 bullion 5 grams, methylene dichloride 20ml, fully stir, 30 ℃ of solids are molten entirely clear, and filtration is drained; With methylene dichloride 3ml flushing flask and funnel, drain, pour filtrating into dry anhydrous 250ml three mouthfuls of round-bottomed flasks, again with methylene dichloride 2ml flushing filter flask; Merging filtrate, mechanical stirring slowly adds hexanaphthene (or sherwood oil) 50ml and slowly stirred one hour; Add hexanaphthene (or sherwood oil) 30ml [adding hexanaphthene (or sherwood oil) 80ml altogether] again, slowly stirred 30 ℃ of crystallizatioies two hours, filter; Drain, filter cake is drained with 25mlX3 drip washing of mixed solution [methylene dichloride: hexanaphthene=1: 4 (V/V)]; The article that must wet, wet article are placed ambient temperature overnight earlier and are dried naturally, material are placed 50 ℃ of constant pressure and dry casees dryings 8 hours in second day; Get dry product: 3.8 grams, refining yield: 76%, highly finished product content: 95% (HPLC method), purity: 96% (HPLC method) gets salable product.
Claims (9)
1. the preparation method of a UR-1501 is characterized in that, step is following:
(1) preparation of UR-1501 bullion: trifluoromethyl Whitfield's ointment and diacetyl oxide; Or trifluoromethyl Whitfield's ointment and Acetyl Chloride 98Min. react; Make catalyzer with iodine, wherein the trifluoromethyl Whitfield's ointment: diacetyl oxide or Acetyl Chloride 98Min.: the mol ratio of iodine is=1: 2-10: 0.002-0.1; 50 ℃-120 ℃ of temperature of reaction, 10 minutes-180 minutes reaction times; Reaction is under agitation carried out, and stirring velocity 50-1000 rev/min, reaction finishes, and stops heating, and cooling adds frozen water, mechanical stirring crystallization 0.5-4 hour, the dry UR-1501 that gets;
(2) UR-1501 is refining: step 1 gained UR-1501 bullion is dissolved in the organic solvent, after the dissolving, filters; Filtrating is stirred through machine, in filtrating, adds another kind of solvent, after the dissolving; Filtration is drained; Slow stirring and crystallizing, drying, wherein said organic solvent is selected from: methyl alcohol, ethanol, acetone, propyl alcohol, Virahol, butanols, methylene dichloride, trichloromethane, acetonitrile, THF or ETHYLE ACETATE; Another kind of solvent is selected from: water, hexanaphthene, normal hexane or sherwood oil, and wherein the bulking value ratio of UR-1501 bullion and organic solvent is: 1: 2-10; The volume ratio of said organic solvent and another kind of solvent 1: 2～10.
2. the preparation method of claim 1 is characterized in that, step 1 adopts nitrogen protection reaction whole process, monitors reaction solution with TLC; Developping agent is an ethanol: acetonitrile=1: 3, and reaction finishes, and uses ice-water bath to reduce to interior temperature to be :-10 ℃-0 ℃, slowly add ice purified water 80ml; Water temperature: 0 ℃-15 ℃, the thick oily matter of system yellowing ,-10 ℃-8 ℃ abundant stirring and crystallizing 0.5h-4h hour, crystallization is complete; Filter, drain, filter cake is drained with 25mlX4 drip washing of ice purified water; The article that must wet, wet article are placed ambient temperature overnight earlier and are dried naturally, 20 ℃ of-70 ℃ of normal pressures of material placement or drying under reduced pressure 2-8 hour are got final product in second day.
3. the preparation method of claim 1 is characterized in that, step 1 reaction raw materials consumption is: trifluoromethyl Whitfield's ointment consumption 10g, diacetyl oxide consumption 14.9g, iodine consumption 0.048g.
4. the preparation method of claim 1 is characterized in that, the said extraction temperature of step 2 is 5 ℃-60 ℃, slow stirring and crystallizing 0.5h-4h, crystallization after-filtration, material place 20-70 ℃ constant pressure and dry 3-24 hour, get final product.
5. the preparation method of claim 1 is characterized in that, under said 5 ℃ of-60 ℃ of temperature condition of step 2, and said slow stirring and crystallizing, machine mixing speed: 50-800 rev/min.
6. the preparation method of claim 1 is characterized in that step 2: the UR-1501 bullion, use organic solvent, and filtration is drained; Stir filtrating, stirring velocity: 50-800 rev/min, added another kind of stirring solvent one hour, stirring and crystallizing 0.5h-4h; Filter, drain, filter cake is drained with 25mlX3 drip washing of purified water; The article that must wet, wet article placement ambient temperature overnight earlier dry naturally, material are placed 20-70 ℃ of constant pressure and dry 3-24 hour in second day, get final product.
7. the preparation method of claim 1 is characterized in that step 2: UR-1501 bullion 5 grams, dissolve shake well with 95% ethanol 15ml; Solid dissolves clear entirely, and filtration is drained, and with 95% ethanol 3ml washing bottle and funnel, drains; Pour filtrating into dry anhydrous 250ml bottle, again with 95% ethanol 2ml flushing filter flask, merging filtrate, mechanical stirring; Stirring velocity: 500 rev/mins, slowly add purified water 50ml and slowly stirred one hour, add purified water 30ml again, slowly stirring and crystallizing is two hours; Filter, drain, filter cake is drained with 25mlX3 drip washing of purified water; The article that must wet, wet article are placed ambient temperature overnight earlier and are dried naturally, material are placed 40 ℃ of constant pressure and dry casees dryings 8 hours in second day, get final product.
8. the preparation method of claim 1 is characterized in that step 2: UR-1501 bullion 5 grams, 95% methyl alcohol 15ml, shake well; Solid dissolves clear entirely, and filtration is drained, and with 95% methyl alcohol 3ml flushing Erlenmeyer flask and funnel, drains; Pour filtrating into dry anhydrous 250ml three mouthfuls of round-bottomed flasks, again with 95% methyl alcohol 2ml flushing filter flask, merging filtrate, mechanical stirring; Slowly add purified water 50ml and slowly stirred one hour, add purified water 30ml again, slowly stirring and crystallizing is two hours, filters; Drain, filter cake is drained with 25mlX3 drip washing of purified water, and article must wet; Wet article are placed ambient temperature overnight earlier and are dried naturally, material are placed 40 ℃ of constant pressure and dry casees dryings 8 hours in second day, get final product.
9. the preparation method of claim 1 is characterized in that step 2: UR-1501 bullion 5 grams, 95% ETHYLE ACETATE 15ml, shake well; Solid dissolves clear entirely, and filtration is drained, and with 95% ETHYLE ACETATE 3ml flushing Erlenmeyer flask and funnel, drains; Pour filtrating into dry anhydrous 250ml three mouthfuls of round-bottomed flasks, again with 95% ETHYLE ACETATE 2ml flushing filter flask, merging filtrate, mechanical stirring; Stirring velocity: 500 rev/mins, slowly add purified water 50ml and slowly stirred one hour, add purified water 30ml again, slowly stirring and crystallizing is two hours; Filter, drain, filter cake is drained with 25mlX3 drip washing of purified water; The article that must wet, wet article are placed ambient temperature overnight earlier and are dried naturally, material are placed 70 ℃ of constant pressure and dry casees dryings 12 hours in second day, get final product.
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| CN1680266A (en) * | 2005-01-11 | 2005-10-12 | 山东师范大学 | Catalytic synthesis of 4-trifluoromethylvinyl salicylic acid |
| CN101177398A (en) * | 2007-12-11 | 2008-05-14 | 南京海陵中药制药工艺技术研究有限公司 | Method for refining trifluoro willow |
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| CN1680266A (en) * | 2005-01-11 | 2005-10-12 | 山东师范大学 | Catalytic synthesis of 4-trifluoromethylvinyl salicylic acid |
| CN101177398A (en) * | 2007-12-11 | 2008-05-14 | 南京海陵中药制药工艺技术研究有限公司 | Method for refining trifluoro willow |
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