CN103601715B - A kind of separating and purifying method of 2-(4-fluorophenyl) thiophene - Google Patents

A kind of separating and purifying method of 2-(4-fluorophenyl) thiophene Download PDF

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CN103601715B
CN103601715B CN201310592895.8A CN201310592895A CN103601715B CN 103601715 B CN103601715 B CN 103601715B CN 201310592895 A CN201310592895 A CN 201310592895A CN 103601715 B CN103601715 B CN 103601715B
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fluorophenyl
thiophene
separating
suction filtration
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CN103601715A (en
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孟艳秋
刘文虎
丁一
杨哲
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Shenyang University of Chemical Technology
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Shenyang University of Chemical Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/12—Radicals substituted by halogen atoms or nitro or nitroso radicals

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Abstract

A kind of separating and purifying method of 2-(4-fluorophenyl) thiophene, relates to a kind of separating and purifying method of compound, and comprise reaction gained mixture organic solvent A and extract, anhydrous sodium sulfate drying is for subsequent use; Suction filtration mixed solution, vacuum fractionation under certain temperature B; Heat oil ether is to 60 DEG C, and the residuum added, until do not dissolve, then adds a small amount of sherwood oil, and residue major part is dissolved, and suction filtration, is down to room temperature, obtains the pure substance of 2-(4-fluorophenyl) thiophene; 2-(4-fluorophenyl) thiophene is the important intermediate of synthesis antidiabetic medicine Canagliflozin, the invention provides a kind of method of 2-(4-fluorophenyl) thiophene of being purified by means re-crystallization, the method is easy and simple to handle, and yield is higher, is very applicable to suitability for industrialized production.

Description

A kind of separating and purifying method of 2-(4-fluorophenyl) thiophene
Technical field
The present invention relates to a kind of separating and purifying method of compound, particularly relate to the separating and purifying method of a kind of 2-(4-fluorophenyl) thiophene.
Background technology
Canagliflozin is one of Novel antidiabetic that clinical effectiveness is best in recent years.2-(4-fluorophenyl) thiophene is the important intermediate in this compou nd synthesis process.2-(4-fluorophenyl) thiophene is the important intermediate of synthesis antidiabetic medicine Canagliflozin, so need to carry out purifying to thick product 2-(4-fluorophenyl) thiophene.This compound physical property is special, is white solid under normal temperature, is liquid under heating condition.Therefore, separating-purifying is difficult to.Traditional column chromatography separation method, complex operation, consuming time longer, and be unfavorable for suitability for industrialized production.At present, only mention in the document both at home and abroad about this compound of synthesis and utilize this compound of column chromatography for separation, but the method complex operation, not easily suitability for industrialized production.At present, the specific considerations that this compound separation is purified is not had in pertinent literature both domestic and external.
Summary of the invention
The object of the present invention is to provide the separating and purifying method of a kind of 2-(4-fluorophenyl) thiophene, the method take sherwood oil as solvent, and obtain pure 2-(4-fluorophenyl) thiophene by recrystallization, it is easy and simple to handle, yield is higher, is very applicable to suitability for industrialized production.
The object of the invention is to be achieved through the following technical solutions:
A kind of separating and purifying method of 2-(4-fluorophenyl) thiophene, described method comprises reaction gained mixture organic solvent A and extracts, and anhydrous sodium sulfate drying is for subsequent use; Suction filtration mixed solution, vacuum fractionation under certain temperature B; Heat oil ether is to 60 DEG C, and the residuum added, until do not dissolve, then adds a small amount of sherwood oil, and residue major part is dissolved, and suction filtration, is down to room temperature, obtains the pure substance of 2-(4-fluorophenyl) thiophene;
Its concrete steps are as follows:
First the synthesis of 2-(4-fluorophenyl) thiophene: at Ar 2under protection, add in round-bottomed flask and be dissolved in toluene: ethanol: Na 2cO 3for the 4-fluorobenzoic boric acid of the mixing solutions of 2:1:1, at room temperature add Pd (PPh 3) 4, stir, add 2-bromothiophene, 80 DEG C of oil bath backflows, induction stirring 24h;
The separating-purifying of 2-(4-fluorophenyl) thiophene: react to obtain mixture dichloromethane extraction organic phase, anhydrous sodium sulfate drying is for subsequent use; Suction filtration mixed solution, vacuum fractionation at 90 DEG C; Heat oil ether, to 60 DEG C, adds residuum, until do not dissolve, then adds a small amount of sherwood oil, and residue major part is dissolved, and suction filtration, is down to room temperature, obtains the pure substance of 2-(4-fluorophenyl) thiophene.
The separating and purifying method of described a kind of 2-(4-fluorophenyl) thiophene, described organic solvent A comprises methylene dichloride or ethyl acetate or chloroform or methyl alcohol or ethanol.
The separating and purifying method of described a kind of 2-(4-fluorophenyl) thiophene, described temperature B is 82-90 DEG C.
The separating and purifying method of described a kind of 2-(4-fluorophenyl) thiophene, the temperature of described recrystallization is the applicable temperature being applicable to 2-(4-fluorophenyl) thiophene recrystallization, and this temperature is generally 60 DEG C.
Embodiment
Below in conjunction with embodiment, the invention will be further described.
The present invention reacts gained mixture organic solvent extraction, and anhydrous sodium sulfate drying is for subsequent use; Suction filtration mixed solution, at a certain temperature vacuum fractionation; Heat oil ether, to 60 DEG C, adds step residuum 2., until do not dissolve, then adds a small amount of sherwood oil, and residue major part is dissolved.Suction filtration, is down to room temperature, obtains the pure substance of 2-(4-fluorophenyl) thiophene.
Embodiment 1
(1) synthesis of 2-(4-fluorophenyl) thiophene:
At Ar 2under protection, add in the round-bottomed flask of 250mL and be dissolved in toluene: ethanol: Na 2cO 3for 0.139g (1mmol) the 4-fluorobenzoic boric acid of the mixing solutions of 2:1:1.At room temperature add 0.023g Pd (PPh 3) 4, stir 5 minutes, add 0.163g 2-bromothiophene, 80 DEG C of oil bath backflows, induction stirring 24h.
(2) separating-purifying of 2-(4-fluorophenyl) thiophene:
1. react to obtain mixture dichloromethane extraction organic phase, anhydrous sodium sulfate drying is for subsequent use;
2. suction filtration mixed solution, vacuum fractionation at 90 DEG C.
3. heat oil ether is to 60 DEG C, adds step residuum 2., until do not dissolve, then adds a small amount of sherwood oil, and residue major part is dissolved.Suction filtration, is down to room temperature, obtains the pure substance of 2-(4-fluorophenyl) thiophene.
Embodiment 2
(1) synthesis of 2-(4-fluorophenyl) thiophene:
At Ar 2under protection, add in the round-bottomed flask of 250mL and be dissolved in toluene: ethanol: Na 2cO 3for 0.139g (1mmol) the 4-fluorobenzoic boric acid of the mixing solutions of 2:1:1.At room temperature add 0.023g Pd (PPh 3) 4, stir 5 minutes, add 0.163g 2-bromothiophene, 80 DEG C of oil bath backflows, induction stirring 24h.
(2) separating-purifying of 2-(4-fluorophenyl) thiophene:
1. react mixture ethyl acetate extracts organic phase, anhydrous sodium sulfate drying is for subsequent use;
2. suction filtration mixed solution, vacuum fractionation at 84 DEG C.
3. heat oil ether is to 60 DEG C, adds step residuum 2., until do not dissolve, then adds a small amount of sherwood oil, and residue major part is dissolved.Suction filtration, is down to room temperature, obtains the pure substance of 2-(4-fluorophenyl) thiophene.
Embodiment 3
(1) synthesis of 2-(4-fluorophenyl) thiophene:
At Ar 2under protection, add in the round-bottomed flask of 250mL and be dissolved in toluene: ethanol: Na 2cO 3for 0.139g (1mmol) the 4-fluorobenzoic boric acid of the mixing solutions of 2:1:1.At room temperature add 0.023g Pd (PPh 3) 4, stir 5 minutes, add the 2-bromothiophene of 0.163g, 80 DEG C of oil bath backflows, induction stirring 24h.
(2) separating-purifying of 2-(4-fluorophenyl) thiophene:
1. react gained mixture chloroform extraction organic phase, anhydrous sodium sulfate drying is for subsequent use;
2. suction filtration mixed solution, vacuum fractionation at 90 DEG C.
3. heat oil ether is to 60 DEG C, adds step residuum 2., until do not dissolve, then adds a small amount of sherwood oil, and residue major part is dissolved.Suction filtration, is down to room temperature, obtains the pure substance of 2-(4-fluorophenyl) thiophene.

Claims (3)

1. a separating and purifying method for 2-(4-fluorophenyl) thiophene, is characterized in that, described method comprises reaction gained mixture organic solvent A and extracts, and anhydrous sodium sulfate drying is for subsequent use; Suction filtration mixed solution, at B temperature, vacuum fractionation obtains residuum, and heat oil ether, to 60 DEG C, adds residuum, until do not dissolve, then add a small amount of sherwood oil, residue major part is dissolved, suction filtration, is down to room temperature, obtains the pure substance of 2-(4-fluorophenyl) thiophene;
Its concrete steps are as follows:
First the synthesis of 2-(4-fluorophenyl) thiophene: at Ar 2under protection, add in round-bottomed flask and be dissolved in toluene: ethanol: Na 2cO 3for the 4-fluorobenzoic boric acid of the mixing solutions of 2:1:1, at room temperature add Pd (PPh 3) 4, stir, add 2-bromothiophene, 80 DEG C of oil bath backflows, induction stirring 24h;
The separating-purifying of 2-(4-fluorophenyl) thiophene: react mixture organic solvent A extracts organic phase, anhydrous sodium sulfate drying is for subsequent use; Suction filtration mixed solution, vacuum fractionation at B temperature; Heat oil ether, to 60 DEG C, adds residuum, until do not dissolve, then adds a small amount of sherwood oil, and residue major part is dissolved, and suction filtration, is down to room temperature, obtains the pure substance of 2-(4-fluorophenyl) thiophene.
2. the separating and purifying method of a kind of 2-according to claim 1 (4-fluorophenyl) thiophene, is characterized in that, described organic solvent A comprises methylene dichloride or ethyl acetate or chloroform or methyl alcohol or ethanol.
3. the separating and purifying method of a kind of 2-according to claim 1 (4-fluorophenyl) thiophene, is characterized in that, described temperature B is 82-90 DEG C.
CN201310592895.8A 2013-11-22 2013-11-22 A kind of separating and purifying method of 2-(4-fluorophenyl) thiophene Active CN103601715B (en)

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WO2016098016A1 (en) * 2014-12-17 2016-06-23 Dr. Reddy’S Laboratories Limited Process for the preparation of sglt2 inhibitors
WO2017093949A1 (en) * 2015-12-04 2017-06-08 Dr. Reddy's Laboratories Limited Substantially pure canagliflozin
CN105753835B (en) * 2016-04-11 2018-06-12 黑龙江鑫创生物科技开发有限公司 A kind of method for synthesizing 2- (4- fluorophenyls) thiophene
CN113372326A (en) * 2021-06-23 2021-09-10 江苏法安德医药科技有限公司 Separation and purification method of 2- (4-fluorophenyl) thiophene

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CN102264714A (en) * 2008-10-17 2011-11-30 詹森药业有限公司 Process for the preparation of compounds useful as inhibitors of sglt
CN102827122A (en) * 2011-06-17 2012-12-19 山东亨利医药科技有限责任公司 Glucoside derivate

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EP0948489A1 (en) * 1996-12-17 1999-10-13 Fujisawa Pharmaceutical Co., Ltd. Piperazine compounds as inhibitors of mmp or tnf
WO2002026706A2 (en) * 2000-09-29 2002-04-04 Bayer Pharmaceuticals Corporation 17-beta-hydroxysteroid dehydrogenase-ii inhibitors

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102264714A (en) * 2008-10-17 2011-11-30 詹森药业有限公司 Process for the preparation of compounds useful as inhibitors of sglt
CN102827122A (en) * 2011-06-17 2012-12-19 山东亨利医药科技有限责任公司 Glucoside derivate

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