CN101177398B - Method for refining trifluoro willow - Google Patents
Method for refining trifluoro willow Download PDFInfo
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- CN101177398B CN101177398B CN200710191190XA CN200710191190A CN101177398B CN 101177398 B CN101177398 B CN 101177398B CN 200710191190X A CN200710191190X A CN 200710191190XA CN 200710191190 A CN200710191190 A CN 200710191190A CN 101177398 B CN101177398 B CN 101177398B
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- tetrahydrofuran
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Abstract
The invention provides a method for refining triflusal capable of improving the productivity, safety and reliability, which comprises the following steps: firstly, the crude triflusal is dissolved in the weak lye at low temperature; solid insoluble impurity is rapidly filtered, then the weak lye is acidized to separate out the triflusal crystal; solid is filtered and dried in vacuum at low temperature; secondly, the solid obtained in the first step is added in the higher temperature reflowing solution of tetrahydrofuran and cyclohexane for dissolution, cooling, crystallization,filtering and drying, and triflusal refines with larger content than 99.5% of triflusal are obtained.
Description
Technical field
Invention relates to a kind of process for purification of Triflusal, belongs to medical technical field.
Background technology
Triflusal has another name called Triflusal (Fig. 1), is the analog of Asprin, has replaced methyl on the original Asprin phenyl ring by trifluoromethyl, chemistry trifluoromethyl acetylsalicylic acid by name, and structure is suc as formula shown in one.Triflusal is by Spain Uriach company development product the earliest, as the anti-platelet aggregation agent, has more specifically effect than acetylsalicylic acid (Asprin) on prevention and treatment thromboembolic disorders and complication.Its action time is longer and danger of bleeding is littler.Formula one is as follows:
Triflusal (Triflusal)
The present disclosed Triflusal synthetic method of patent US4096252, wherein the synthetic method of final step acid esterification reaction has two kinds, is respectively to carry out esterification and carry out esterification with Acetyl Chloride 98Min. with the sulphuric acid catalysis diacetyl oxide.Since reaction raw materials trifluoromethyl Whitfield's ointment be one not only had hydroxyl and but also have the compound of carboxyl, so esterification under acidic conditions, the esterification self-polymeric reaction can take place in itself, suc as formula two, shown in the formula three.So no matter use the sort of esterification process, in the product of gained, all contain about autohemagglutination product 5-10%.Behind recrystallization of result of study demonstration, the content of these autohemagglutination products is still up to 2-3%.The product that conforms with medicinal standard that obtains generally needs recrystallization 2 times.To remove these impurity with sherwood oils and ether system recrystallization 2 times by the treatment process of former patent, the calculation of yield with each 70%, the productive rate that obtains purified product is only about 50%.
Formula two is as follows:
Formula three is as follows:
Used sherwood oil is the uncertain mixture of content in the recrystallization system of former patent in addition, the poor repeatability of producing between causing batch; The boiling point of used ether only has 36 ℃, has limited the solvent temperature of Triflusal, causes the difference between solvent temperature and the cooling temperature to diminish, and the recrystallization productive rate is low, just must be and will obtain higher productive rate to solution concentration, and the mixed system solvent evaporation is restive again.And use ether as recrystallization solvent,, should use less under the big working condition as far as possible because its volatile inflammable and explosive characteristic is unfavorable for industrialization.For fear of above unfavorable factor, the invention goes out a kind of process for purification that the self-polymeric reaction by product carries out recrystallization again of removing earlier, significantly improving productive rate, and makes the security of operating process increase.
Summary of the invention
The object of the present invention is to provide a kind of process for purification that can improve productive efficiency, more safe and reliable Triflusal crude product.
Technical scheme of the present invention is as follows:
The method of refining trifluoro willow, the first step will be dissolved in the weakly alkaline aqueous solution under the Triflusal crude product low temperature, filters rapidly and removes solid insoluble impurities (mainly being the autohemagglutination product), again solution is carried out acidifying Triflusal is separated out with crystal again, filter out solid, low-temperature vacuum drying; Second step was added in the reflux mixing solutions of tetrahydrofuran (THF) down and hexanaphthene of comparatively high temps to the resulting solid of the first step and dissolves, wherein the volume ratio of tetrahydrofuran (THF) and hexanaphthene be preferably 1: 6～1: 12, cooling crystallization then, filter, the dry Triflusal elaboration that gets, gained Triflusal content is greater than 99.5%.
The described weak base of the first step dissolving crude product is weak mineral alkali or organic bases, or is the salt of alkalescence.Described weak mineral alkali or organic bases are selected weak ammonia, triethylamine or trimethylpyridine for use; The described salt that is alkalescence is selected yellow soda ash, sodium bicarbonate, sodium hydrogen phosphate or Sodium phosphate dibasic for use.Each link temperature control is 0～10 ℃ in the first step.
Utilize the poly-trifluoromethyl Whitfield's ointment of reaction by-product to be insoluble to character in the weakly alkaline water among the present invention, isolate these impurity.Because this is unstable in protonated solvent for Triflusal, can hydrolysis slowly, so this step separated and dissolved again acidifying overall time of process of separating out unsuitable long, temperature is unsuitable too high, finishes in the preferred 30 minutes time, preferred temperature is controlled at the 0-30 degree.The mass ratio of second mixing solutions of step described in the recrystallization and Triflusal is preferably 6: 1～and 12: 1.
It is as follows that tetrahydrofuran (THF) that the present invention was adopted in second step and hexanaphthene system are carried out the embodiment of recrystallization advantage, and the boiling point of tetrahydrofuran (THF) is 65.40 ℃, about high 30 degree of boiling point than ether.Tetrahydrofuran (THF) steam is condensed easily during backflow, guarantee stablizing between each composition of solvent system under the backflow situation, confirmatory experiment shows under tetrahydrofuran (THF) and hexanaphthene volume ratio are 1: 8 condition, 70 ℃ were refluxed 3 hours, and the component volume ratio in the gas chromatographic analysis mixed solvent still maintains about 1: 8.2; Sherwood oil and ether system are under 40 ℃ situation only by contrast, and ether just begins a large amount of evaporations, is difficult to keep the proportioning unanimity of each component in the solvent, technology instability under the big working condition.And the boiling point raising that tetrahydrofuran (THF) and hexanaphthene cooperatively interact and can make mixed solvent, too big change can not take place in the proportioning of long-time reflux solvent, the recovery set that is well suited for solvent is used, and the proportioning in solution has better response to the solubleness of Triflusal for tetrahydrofuran (THF) and hexanaphthene under this solvent system, can reconcile solubleness as required, with at the crude product of different content and improve crystalline rate.
Embodiment:
Experimental example one:
The first step is dissolved in the aqueous solution that 150mL concentration is the 1M sodium bicarbonate under 5 ℃ of the 25g Triflusal crude products, by the time solid almost dissolves, after filtering removal solid insoluble impurities rapidly, add excessive acetic acid neutralization, the Triflusal crystal is separated out again, filter out crystal, about 4 hours of 10 ℃ of vacuum-drying is lower than 0.3% to water content; The mixing solutions 150g that second step sample that drying is good is put into 70 ℃ of tetrahydrofuran (THF)s and hexanaphthene (tetrahydrofuran (THF) and hexanaphthene volume ratio 1: 9) dissolves, behind the backflow 10min, place 10 ℃ of environment cooling crystallizations, filter, 30 ℃ of drying under reduced pressure get the Triflusal elaboration.Gained Triflusal content is made with extra care overall yield 78% greater than 99.5%.
Experimental example two:
The first step is dissolved in the aqueous solution that 100mL concentration is the 1N triethylamine under 5 ℃ of the 25g Triflusal crude products, by the time solid almost dissolves, after filtering removal solid insoluble impurities rapidly, add excessive acetic acid neutralization, the Triflusal crystal is separated out again, filter out crystal, about 4 hours of 10 ℃ of vacuum-drying is lower than 0.3% to water content; The mixing solutions 200g that second step sample that drying is good is put into 70 ℃ of tetrahydrofuran (THF)s and hexanaphthene (tetrahydrofuran (THF) and hexanaphthene volume ratio 1: 9) dissolves, and behind the backflow 10min, places 0 ℃ of environment cooling crystallization, filters, and 30 ℃ of drying under reduced pressure get the Triflusal elaboration.Gained Triflusal content is made with extra care overall yield 81% greater than 99.5%.
Experimental example three:
The first step is dissolved in the aqueous solution that 150mL concentration is 0.5M yellow soda ash under 5 ℃ of the 25g Triflusal crude products, by the time solid almost dissolves, after filtering removal solid insoluble impurities rapidly, add excessive acetic acid neutralization, the Triflusal crystal is separated out again, filter out crystal, about 4 hours of 10 ℃ of vacuum-drying is lower than 0.3% to water content; The mixing solutions 250g that second step sample that drying is good is put into 50 ℃ of tetrahydrofuran (THF)s and hexanaphthene (tetrahydrofuran (THF) and hexanaphthene volume ratio 1: 12) dissolves, behind the backflow 10min, suitably evaporating solvent places 0 ℃ of environment cooling crystallization, filter, 30 ℃ of drying under reduced pressure get the Triflusal elaboration.Gained Triflusal content is made with extra care overall yield 71% greater than 99.5%.
Experimental example four:
The first step is dissolved in the aqueous solution that 100mL concentration is the 1N Sodium phosphate dibasic under 5 ℃ of the 25g Triflusal crude products, by the time solid almost dissolves, after filtering removal solid insoluble impurities rapidly, add excessive acetic acid neutralization, the Triflusal crystal is separated out again, filter out crystal, about 4 hours of 10 ℃ of vacuum-drying is lower than 0.3% to water content; The mixing solutions 300g that second step sample that drying is good is put into 50 ℃ of tetrahydrofuran (THF)s and hexanaphthene (tetrahydrofuran (THF) and hexanaphthene volume ratio 1: 12) dissolves, behind the backflow 10min, suitably evaporating solvent places 0 ℃ of environment cooling crystallization, filter, 30 ℃ of drying under reduced pressure get the Triflusal elaboration.Gained Triflusal content is made with extra care overall yield 69% greater than 99.5%.
Experimental example five:
The first step is dissolved in the aqueous solution that 100mL concentration is the 1M trimethylpyridine under 1 ℃ of the 25g Triflusal crude product, by the time solid almost dissolves, after filtering removal solid insoluble impurities rapidly, add excessive acetic acid neutralization, the Triflusal crystal is separated out again, filter out crystal, about 4 hours of 2 ℃ of vacuum-drying is lower than 0.3% to water content; The mixing solutions 200g that second step sample that drying is good is put into 60 ℃ of tetrahydrofuran (THF)s and hexanaphthene (tetrahydrofuran (THF) and hexanaphthene volume ratio 1: 6) dissolves, behind the backflow 10min, suitably evaporating solvent places 0 ℃ of environment cooling crystallization, filter, 20 ℃ of drying under reduced pressure get the Triflusal elaboration.Gained Triflusal content is made with extra care overall yield 58% greater than 99%.
Experimental example six:
The first step is dissolved in the aqueous solution that 100mL concentration is the 0.5M sodium hydrogen phosphate under 10 ℃ of the 25g Triflusal crude products, by the time solid almost dissolves, after filtering removal solid insoluble impurities rapidly, add excessive acetic acid neutralization, the Triflusal crystal is separated out again, filter out crystal, about 4 hours of 8 ℃ of vacuum-drying is lower than 0.3% to water content; The mixing solutions 150g that second step sample that drying is good is put into 80 ℃ of tetrahydrofuran (THF)s and hexanaphthene (volume ratio of tetrahydrofuran (THF) and hexanaphthene 1: 12) dissolves, behind the backflow 10min, suitably evaporating solvent places 0 ℃ of environment cooling crystallization, filter, 15 ℃ of drying under reduced pressure get the Triflusal elaboration.Gained Triflusal content is made with extra care overall yield 74% greater than 99.5%.
Claims (6)
1. the method for a refining trifluoro willow, it is characterized in that: the first step had been dissolved in the Triflusal crude product in 1: 1～1: 1.5 in the weakly alkaline aqueous solution of a kind of pH value between 7～11 by equivalence ratio under 0～10 ℃ of temperature condition, after filtering removal solid insoluble impurities rapidly, add in the excessive acetic acid and after Triflusal is separated out again, filter out crystal, vacuum-drying under 0～10 ℃ of temperature condition; Second step was dissolved in the desciccate of the first step mixing solutions of tetrahydrofuran (THF) and hexanaphthene under 50～80 ℃ of temperature, cooling crystallization under 0～20 ℃ of temperature, filter, the dry Triflusal elaboration that gets, wherein the volume ratio of tetrahydrofuran (THF) and hexanaphthene is 1: 6～1: 12.
2. Triflusal process for purification according to claim 1 is characterized in that: the used weakly alkaline aqueous solution of the first step dissolving crude product is the weak mineral alkali or the aqueous solution of organic bases, or is the aqueous solution of the salt of alkalescence.
3. Triflusal process for purification according to claim 2 is characterized in that: described weak mineral alkali or organic bases are selected weak ammonia, triethylamine or trimethylpyridine for use; The described salt that is alkalescence is selected yellow soda ash, sodium bicarbonate, sodium hydrogen phosphate or Sodium phosphate dibasic for use.
4. Triflusal process for purification according to claim 1 is characterized in that each link temperature is controlled 0～10 ℃ in the first step.
5. Triflusal process for purification according to claim 1 is characterized in that the first step entire operation process begins only to filter to acidifying from dissolving, and time control was finished in 30 minutes.
6. Triflusal process for purification according to claim 1 is characterized in that the mixing solutions described in the second step recrystallization and the mass ratio of Triflusal are 6: 1～12: 1.
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| CN200710191190XA CN101177398B (en) | 2007-12-11 | 2007-12-11 | Method for refining trifluoro willow |
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| CN200710191190XA CN101177398B (en) | 2007-12-11 | 2007-12-11 | Method for refining trifluoro willow |
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| CN101177398B true CN101177398B (en) | 2010-11-03 |
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| CN101503355B (en) * | 2009-01-21 | 2012-05-09 | 吉林天强制药有限公司 | Synthesis and refining of triflusal |
| CN103709183B (en) * | 2013-12-06 | 2016-01-06 | 辽宁师范大学 | The synthetic method of triflusal-metal compound |
| CN103665012B (en) * | 2013-12-06 | 2016-06-22 | 辽宁师范大学 | Novel triflusal inorganic drug compound and synthetic method |
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Effective date of registration: 20110228 Address after: The streets of Qixia District of Nanjing City, Jiangsu province 210049 Tsing Ma No. 18 North Street Co-patentee after: Jiangsu Haici Biological Pharmaceutical Co., Ltd. of Yangtze River Pharmaceutical Group Patentee after: Nanjing Hailing Chinese Medicine Pharmaceutical Technology Research Co., Ltd. Address before: The streets of Qixia District of Nanjing City, Jiangsu province 210049 Tsing Ma No. 18 North Street Patentee before: Nanjing Hailing Chinese Medicine Pharmaceutical Technology Research Co., Ltd. |
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Effective date of registration: 20120106 Address after: 225321 No. 8, Tai Tay Road, Binjiang Industrial Park, Taizhou Economic Development Zone, Jiangsu, Taizhou Patentee after: Jiangsu Haici Biological Pharmaceutical Co., Ltd. of Yangtze River Pharmaceutical Group Address before: The streets of Qixia District of Nanjing City, Jiangsu province 210049 Tsing Ma No. 18 North Street Co-patentee before: Jiangsu Haici Biological Pharmaceutical Co., Ltd. of Yangtze River Pharmaceutical Group Patentee before: Nanjing Hailing Chinese Medicine Pharmaceutical Technology Research Co., Ltd. |