CN102030689A - Refining method of ibutilide fumarate - Google Patents
Refining method of ibutilide fumarate Download PDFInfo
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- CN102030689A CN102030689A CN2009101909951A CN200910190995A CN102030689A CN 102030689 A CN102030689 A CN 102030689A CN 2009101909951 A CN2009101909951 A CN 2009101909951A CN 200910190995 A CN200910190995 A CN 200910190995A CN 102030689 A CN102030689 A CN 102030689A
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Abstract
The invention relates to a refining method of ibutilide fumarate raw material medicine capable of resisting arrhythmia. The method comprises the following steps of: dissolving a crude ibutilide fumarate product into a solvent with stronger polarity or medium polarity, decoloring with activated carbon and filtering; then adding a solvent with smaller polarity to an obtained filter liquor, stirring, standing still and removing the supernate; adding a solvent with medium polarity to an obtained residue; and recrystallizing to obtain high-purity ibutilide fumarate. In the invention, impurities in the crude ibutilide fumarate product are effectively removed by adopting a mixed solvent eluting method, which improves the product purity, ensures that the product conforms to the medicinal requirement and guarantees the safety of clinical medication. The invention has the advantages of stable product quality and simple process operation and is suitable for mass industrial production.
Description
Technical field
The invention belongs to medical technical field, relate to the process for purification of anti-arrhythmic U-70226E bulk drug.
Background technology
U-70226E (Ibutilide Fumarate), chemistry (±)-N-[4-[4-(second heptyl amice base) by name-1-hydroxyl butyl] phenyl] Toluidrin-2-butylene diacid salt is by (the Pharmacia of U.S. Pharmacia S.P.A.; Upjohn) a kind of III class anti-arrhythmic of Yan Zhikaifaing with novel ion channel activity.Obtain the FDA approval December nineteen ninety-five, go on the market trade(brand)name Convert in April, 1996 in the U.S..Now having become atrial fibrillation and the first-selected medicine again that changes of auricular flutter that treatment takes place recently, also is the at present unique III class antiarrhythmic drug that changes multiple atrial fibrillation and auricular flutter that is approved for of the U.S..Its curative effect of this product is better than amiodarone, general sieve is pounced on anti-arrhythmics such as ketone, pronestyl, sotalol, atlansil.The U-70226E chemical formula is as follows:
U-70226E
The preparation method of U-70226E is at Chinese patent CN1733714, CN101381332, Chinese Journal of Pharmaceuticals .2003, and 34 (5): 209-211 and J.Med.Chem, 1991,34 (1): open among the 308-315.According to Chinese Journal of Pharmaceuticals .2003, it is synthetic that disclosed route carries out U-70226E among 34 (5) .209-211, the finished product for preparing passes through repeatedly acetone recrystallization, and purity is the highest can only to reach 98.5%, and exists a kind of peculiar impurity about 1.2% not remove in the product all the time.At Chinese Journal of Pharmaceuticals .2003, the disclosed synthesis technique of 34 (5) .209-211 makes the U-70226E crude product, makes with extra care according to the method among the CN101381332, also can not reach effective purifying, receives high quality, the qualified medicine of high yield.
Summary of the invention
The technical problem to be solved in the present invention provides a kind of process for purification of U-70226E bulk drug.This method can significantly reduce the remaining impurity in the U-70226E crude product, improves finished product purity, reduces the number of times of crude product recrystallization, reduces production costs.
For solving the problems of the technologies described above, technical scheme of the present invention is: at first the U-70226E crude product is joined the solvent (organic solvent 1) of a certain amount of polarity than strong or middle polarity, reflux, stirring and dissolving; Added an amount of activated carbon decolorizing then 20～30 minutes, filtered while hot; Add the less organic solvent (organic solvent 2) of a certain amount of polarity in the filtrate under keeping reflux state then, stir, cooling is left standstill, and divides and removes supernatant liquor; In resistates, add a certain amount of medium polar solvent (organic solvent 3) again, the heating fusion, crystallisation by cooling filters then, and drying gets U-70226E, carries out purity detecting with high performance liquid chromatography.
The weightmeasurement ratio of U-70226E crude product of the present invention and organic solvent 1 is 1g: 5～15ml, preferred 1g: 10～12ml.
The weight ratio of U-70226E crude product of the present invention and gac is 1: 0.01～0.1, preferred 1: 0.05～0.1.
The volume ratio of organic solvent 2 of the present invention and organic solvent 1 is 1～3: 1, preferred 1～2: 1.
The weightmeasurement ratio of U-70226E crude product of the present invention and organic solvent 3 is 1g: 10～12ml.
Organic solvent 1 of the present invention is a kind of in acetone, methylene dichloride, Virahol, the dimethyl formamide, preferred acetone.
Organic solvent 2 of the present invention is a kind of in ether, isopropyl ether, sherwood oil, hexanaphthene, the normal hexane, preferred ether, sherwood oil.
Organic solvent 3 of the present invention is a kind of in acetone and the Virahol.
U-70226E after adopting the inventive method refining, its HPLC purity can reach more than 99.7%.
U-70226E crude product of the present invention can pass through Chinese Journal of Pharmaceuticals .2003, and 34 (5) .209-211 disclosed methods prepare and get.
The present invention adopts the method for mixed solvent wash-out, can effectively remove the impurity in the extraordinarily thick product of fumaric acid Yi Buli, and the purity of highly finished product is reached more than 99.7%, and single impurity meets medicinal requirements less than 0.1%, has guaranteed clinical application safety.Technological operation of the present invention is simple, has significantly reduced the number of times of recrystallization, has reduced production cost.The constant product quality that the present invention makes is suitable for industrialized production.
Embodiment
Come further the present invention to be made an explanation below by embodiment, but be not appreciated that it is that the scope of the invention is construed as limiting.
Embodiment 1
With HPLC purity be 96.8% U-70226E crude product 10g add be equipped with stir and three mouthfuls of reaction flasks of reflux exchanger in, add acetone 100ml stirring heating and reflux, treat that complete molten back adds the gac 0.5g 20min that decolours, filtered while hot; Slowly add the 100ml ether in the filtrate under keeping reflux state, vigorous stirring is even, is cooled to 5 ℃ and leaves standstill; Tell supernatant liquor; After adding 100ml acetone heating for dissolving in the resistates, be cooled to 5 ℃ of crystallizatioies, filter, 50 ℃ of drying under reduced pressure promptly get U-70226E.Get product 8.7g after the drying, yield 87.0%, HPLC purity is 99.9%.
Embodiment 2
With HPLC purity be 96.8% U-70226E crude product 10g add be equipped with stir and three mouthfuls of reaction flasks of reflux exchanger in, add methylene dichloride 120ml stirring heating and reflux, treat that complete molten back adds the gac 0.5g 20min that decolours, filtered while hot; Slowly add the 120ml ether in the filtrate under keeping reflux state, vigorous stirring is even, is cooled to 5 ℃ and leaves standstill; Tell supernatant liquor; After adding 100ml acetone heating for dissolving in the resistates, be cooled to 5 ℃ of crystallizatioies, filter, 50 ℃ of drying under reduced pressure promptly get U-70226E.Get product 8.1g after the drying, yield 81.0%, HPLC purity is 99.7%.
Embodiment 3
With HPLC purity be 95.6% U-70226E crude product 10g add be equipped with stir and three mouthfuls of reaction flasks of reflux exchanger in, add acetone 120ml stirring heating and reflux, treat that complete molten back adds the gac 1g 30min that decolours, filtered while hot; Slowly add the 200ml ether in the filtrate under keeping reflux state, vigorous stirring is even, is cooled to 5 ℃ and leaves standstill; Tell supernatant liquor; After adding 120ml acetone heating for dissolving in the resistates, be cooled to 5 ℃ of crystallizatioies, filter, 50 ℃ of drying under reduced pressure promptly get U-70226E.Get product 8.3g after the drying, yield 83.0%, HPLC purity is 99.7%.
Embodiment 4
With HPLC purity be 96.3% U-70226E crude product 10g add be equipped with stir and three mouthfuls of reaction flasks of reflux exchanger in, add acetone 100ml stirring heating and reflux, treat that complete molten back adds the gac 0.8g 30min that decolours, filtered while hot; Slowly add the 200ml sherwood oil in the filtrate under keeping reflux state, vigorous stirring is even, is cooled to 5 ℃ and leaves standstill; Tell supernatant liquor; After adding 100ml acetone heating for dissolving in the resistates, be cooled to 5 ℃ of crystallizatioies, filter, 50 ℃ of drying under reduced pressure promptly get U-70226E.Get product 7.8g after the drying, yield 78.0%, HPLC purity is 99.8%.
Embodiment 5
With HPLC purity be 96.3% U-70226E crude product 10g add be equipped with stir and three mouthfuls of reaction flasks of reflux exchanger in, add acetone 100ml stirring heating and reflux, treat that complete molten back adds the gac 0.5g 20min that decolours, filtered while hot; Slowly add the 200ml hexanaphthene in the filtrate under keeping reflux state, vigorous stirring is even, is cooled to 5 ℃ and leaves standstill; Tell supernatant liquor; After adding 100ml Virahol heating for dissolving in the resistates, be cooled to 5 ℃ of crystallizatioies, filter, 50 ℃ of drying under reduced pressure promptly get U-70226E.Get product 7.9g after the drying, yield 79.0%, HPLC purity is 99.7%.
Claims (7)
1. the process for purification of a U-70226E is characterized in that: earlier the U-70226E crude product is dissolved in organic solvent 1, activated carbon decolorizing, filtration; Add organic solvent 2 then in the filtrate, leave standstill after stirring, divide and remove supernatant liquor; Add organic solvent 3 again in resistates, recrystallization gets the pure product of U-70226E; Wherein organic solvent 1 is selected from acetone, methylene dichloride, Virahol, dimethyl formamide, and organic solvent 2 is selected from ether, isopropyl ether, sherwood oil, hexanaphthene, normal hexane, and organic solvent 3 is selected from acetone, Virahol.
2. process for purification according to claim 1 is characterized in that: the weightmeasurement ratio of U-70226E crude product and organic solvent 1 is 1g: 5～15ml.
3. process for purification according to claim 1 is characterized in that: the weight ratio of the gac of U-70226E crude product and adding is 1: 0.01～0.1.
4. process for purification according to claim 1 is characterized in that: organic solvent 2 is 1～3: 1 with the volume ratio of organic solvent 1.
5. process for purification according to claim 1 is characterized in that: the weightmeasurement ratio of U-70226E crude product and organic solvent 3 is 1g: 6～12ml.
6. according to each described process for purification of claim 1～5, it is characterized in that: organic solvent 1 is acetone.
7. according to each described process for purification of claim 1～5, it is characterized in that: organic solvent 2 is selected from ether, sherwood oil.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2009101909951A CN102030689A (en) | 2009-09-28 | 2009-09-28 | Refining method of ibutilide fumarate |
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| CN2009101909951A CN102030689A (en) | 2009-09-28 | 2009-09-28 | Refining method of ibutilide fumarate |
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| CN2009101909951A Pending CN102030689A (en) | 2009-09-28 | 2009-09-28 | Refining method of ibutilide fumarate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111138293A (en) * | 2020-01-10 | 2020-05-12 | 蚌埠丰原医药科技发展有限公司 | Method for synthesizing ibutilide fumarate intermediate by using microchannel reactor |
| CN115043710A (en) * | 2022-05-31 | 2022-09-13 | 武汉华尔生物科技有限公司 | Method for purifying high-purity hydroquinone |
-
2009
- 2009-09-28 CN CN2009101909951A patent/CN102030689A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111138293A (en) * | 2020-01-10 | 2020-05-12 | 蚌埠丰原医药科技发展有限公司 | Method for synthesizing ibutilide fumarate intermediate by using microchannel reactor |
| CN111138293B (en) * | 2020-01-10 | 2023-07-07 | 蚌埠丰原医药科技发展有限公司 | Method for synthesizing ibutilide fumarate intermediate by using microchannel reactor |
| CN115043710A (en) * | 2022-05-31 | 2022-09-13 | 武汉华尔生物科技有限公司 | Method for purifying high-purity hydroquinone |
| CN115043710B (en) * | 2022-05-31 | 2024-03-12 | 武汉华尔生物科技有限公司 | Purification method of high-purity hydroquinone |
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Application publication date: 20110427 |