CN102584791A - Method for refining pantoprazole optical enantiomer - Google Patents
Method for refining pantoprazole optical enantiomer Download PDFInfo
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- CN102584791A CN102584791A CN2012100004319A CN201210000431A CN102584791A CN 102584791 A CN102584791 A CN 102584791A CN 2012100004319 A CN2012100004319 A CN 2012100004319A CN 201210000431 A CN201210000431 A CN 201210000431A CN 102584791 A CN102584791 A CN 102584791A
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- pantoprazole
- acetate
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- white color
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Abstract
The invention relates to a method for refining a pantoprazole optical enantiomer. The method is characterized by comprising the following steps of: adding acetic alkyl ester into a crude product of the pantoprazole optical enantiomer, stirring until the crude product is dissolved completely, adding active carbon, stirring, filtering while a solution is hot, freezing the solution for crystallizing, performing suction filtration until crystals are dried, leaching a filter cake by using the acetic alkyl ester, performing suction filtration until the filter cake is dried to obtain an off-white solid, and drying under reduced pressure to obtain a refined product of the pantoprazole optical enantiomer. The method is simple and convenient and high in refined yield; and the pantoprazole by refining is high in purity, so the method is suitable for industrial production.
Description
Technical field:
The present invention relates to a kind of process for purification of pantoprazole optical antipode.
Technical background:
S-pantoprazole sodium (Levpantoprazole Sodium); Chemical name S-(-)-5-difluoro-methoxy-2-(((3; 4-dimethoxy-2-pyridyl) sulfinyl methyl))-1H-benzoglyoxaline sodium; Being the third generation proton pump inhibitor after omeprazole (omeprazole), lansoprazole (lansoprazole), is the sodium salt that has been applied to single corresponding isomer S-(-)-pantoprazole of clinical pantoprazole at present.This medical instrument has higher selective synthesizing bioavailability, and the security with height in clinical treatment receives doctor and patient's approval, thereby has promoted the growth of produce market.
In the anti-peptic ulcer medication of sample hospital, occupy second in 2006, and occupied the share in proton pump preparation market 23.62%, the medication amount of money is gone up on year-on-year basis and was increased by 31.71% in 1 year.Pantoprazole is in October, 1994 by pause medicine of (BykGulden) big pharmaceutical factory Initial Public Offering in South Africa of German hectogram.At present, the pantoprazole whole world seven big drug market before sales the last 500 medicines of being shortlisted for, 2005 annual sales amounts add up to 35.46 hundred million dollars, have gone up an average annual growth rate on year-on-year basis 10.74%.
These medicine characteristics are in metabolic process, to be difficult for cytopigment p450 effect and oxidation deactivation; Bioavailability improves 7 times than omeprazole; Security and validity all are higher than omeprazole and lansoprazole with the other medicines adapted time, and is also stable than omeprazole and lansoprazole under weak acid environment.This medicine is mainly used in treatment and the disorderly diseases associated of gastric acid secretion, like stomach ulcer, duodenal ulcer, reflux esophagitis and assistant-Emhorn syndromes etc.Proved the pantoprazole than racemic modification and R-configuration clinically, good effect, the toxic side effect of S-configuration pantoprazole are low.
Summary of the invention
It is high to the purpose of this invention is to provide a kind of refining yield, and the preparation method is easy, operation easily, and purity is high and be applicable to the process for purification of the pantoprazole optical antipode that large-scale industrialization is effectively produced.
Technical scheme of the present invention provides a kind of process for purification of pantoprazole optical antipode, and this method steps is:
Get 1 equivalent pantoprazole optical antipode bullion and add 8～50 equivalent alkyl acetates, 40 ℃～80 ℃ are stirred to whole dissolvings, add 0.01%～1% (W/V) gac; Continue to stir 3～30 minutes, filtered while hot was placed-15 ℃～5 ℃ crystallizatioies 2～24 hours with solution; Suction filtration is to doing; Filter cake is drained with 1～10 normal-10 ℃～10 ℃ alkyl acetate drip washing, obtains the off-white color solid; With the off-white color solid that obtains 40 ℃～50 ℃ drying under reduced pressure 3～12 hours in the drying under reduced pressure case, promptly get pantoprazole optical antipode highly finished product.
Alkyl in the wherein said alkyl acetate comprises the straight or branched alkyl of carbon containing 1～4, specifically as a kind of extremely several kinds in methyl acetate, ETHYLE ACETATE, propyl acetate, isopropyl acetate, butylacetate, the isobutyl acetate.Ethyl acetate, propyl acetate.
Recrystallization temperature described in the above-mentioned technology is-10 ℃～10 ℃, and preferred TR is-10 ℃～0 ℃.
The present invention is easy, and refining yield is high, and the pantoprazole impurity of refining gained is few.
Embodiment
Below in conjunction with embodiment the present invention is done further explain, but should understand the non-scope that only limits to these embodiment of scope of the present invention.
Embodiment:
Embodiment 1: S-pantoprazole refining
Get S-pantoprazole bullion 100g, sample quality: total impurities, 0.71%, single assorted 0.37%.Use the 2000ml acetic acid ethyl dissolution, temperature is 60 ℃, is stirred to whole dissolvings.
Under 60 ℃ of conditions, add the 1g gac, stirred 15 minutes, filtered while hot is placed on solution-10 ℃ refrigeration chamber then, crystallization 12 hours, suction filtration is to doing, and filter cake is extremely dried with 10 ℃ ETHYLE ACETATE 100ml drip washing, obtains the off-white color solid;
At last with the off-white color solid that obtains (93kpa) 40 ℃～50 ℃ dryings 5 hours in the drying under reduced pressure case.Promptly get exsiccant off-white color S-pantoprazole highly finished product 73g.Yield is 73%; Quality: color is an off-white color; Total impurities is 0.15%, and single mixing is 0.07%.
Embodiment 2: S-pantoprazole refining
Get S-pantoprazole bullion 100g, sample quality: total impurities, 0.78%, single assorted 0.39%.With the dissolving of 2000ml propyl acetate, temperature is 60 ℃, is stirred to whole dissolvings.
Under 60 ℃ of conditions, add the 1g gac, stirred 15 minutes, filtered while hot is placed on solution-10 ℃ refrigeration chamber then, crystallization 12 hours, suction filtration is to doing, and filter cake is extremely dried with 10 ℃ propyl acetate 100ml drip washing, obtains the off-white color solid;
At last with the off-white color solid that obtains (93kpa) 40 ℃～50 ℃ dryings 5 hours in the drying under reduced pressure case.Promptly get exsiccant off-white color S-pantoprazole highly finished product 71g.Yield is 71%; Quality: color is an off-white color; Total impurities is 0.17%, and single mixing is 0.08%.
Embodiment 3: S-pantoprazole refining
Get S-pantoprazole bullion 100g, sample quality: total impurities, 0.81%, single assorted 0.43%.With the dissolving of 2000ml butylacetate, temperature is 60 ℃, is stirred to whole dissolvings.
Under 60 ℃ of conditions, add the 1g gac, stirred 15 minutes, filtered while hot is placed on solution-10 ℃ refrigeration chamber then, crystallization 12 hours, suction filtration is to doing, and filter cake is extremely dried with 10 ℃ butylacetate 100ml drip washing, obtains the off-white color solid;
At last with the off-white color solid that obtains (93kpa) 40 ℃～50 ℃ dryings 5 hours in the drying under reduced pressure case.Promptly get exsiccant off-white color S-pantoprazole highly finished product 74g.Yield is 74%; Quality: color is an off-white color; Total impurities is 0.18%, and single mixing is 0.06%.
Embodiment 4: dextral-pantoprazole refining
Get dextral-pantoprazole bullion 100g, sample quality: total impurities, 0.83%, single assorted 0.41%.Use the 2000ml acetic acid ethyl dissolution, temperature is 60 ℃, is stirred to whole dissolvings.
Under 60 ℃ of conditions, add the 1g gac, stirred 15 minutes, filtered while hot is placed on solution-10 ℃ refrigeration chamber then, crystallization 15 hours, suction filtration is to doing, and filter cake is extremely dried with 10 ℃ ETHYLE ACETATE 120ml drip washing, obtains the off-white color solid;
At last with the off-white color solid that obtains (93kpa) 40 ℃～50 ℃ dryings 5 hours in the drying under reduced pressure case.Promptly get exsiccant off-white color dextral-pantoprazole highly finished product 76g.Yield is 76%; Quality: color is an off-white color; Total impurities is 0.13%, and single mixing is 0.06%.
Claims (6)
1. the process for purification of a pantoprazole optical antipode, its method is:
Get 1 equivalent pantoprazole optical antipode bullion and add 8～50 equivalent alkyl acetates, 40 ℃～80 ℃ are stirred to whole dissolvings, add 0.01%～1% (W/V) gac; Continue to stir 3～30 minutes, filtered while hot was placed-15 ℃～5 ℃ crystallizatioies 2～24 hours with solution; Suction filtration is to doing; Filter cake is drained with 1～10 normal-10 ℃～10 ℃ alkyl acetate drip washing, obtains the off-white color solid; With the off-white color solid that obtains 40 ℃～50 ℃ drying under reduced pressure 3～12 hours in the drying under reduced pressure case, promptly get pantoprazole optical antipode highly finished product.
2. process for purification according to claim 1; It is characterized in that alkyl in the described alkyl acetate comprises the straight or branched alkyl of carbon containing 1～4, specifically comprise a kind of in methyl acetate, ETHYLE ACETATE, propyl acetate, isopropyl acetate, butylacetate, the isobutyl acetate to several kinds.
3. process for purification according to claim 1 is characterized in that solvent temperature is 40 ℃～60 ℃.
4. process for purification according to claim 1 is characterized in that the gac add-on is 0.05%～0.5% (W/V).
5. process for purification according to claim 1 is characterized in that recrystallization temperature is-10 ℃～0 ℃.
6. process for purification according to claim 1 is characterized in that drying temperature is 40 ℃～50 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100004319A CN102584791A (en) | 2012-01-04 | 2012-01-04 | Method for refining pantoprazole optical enantiomer |
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| CN2012100004319A CN102584791A (en) | 2012-01-04 | 2012-01-04 | Method for refining pantoprazole optical enantiomer |
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| CN2012100004319A Pending CN102584791A (en) | 2012-01-04 | 2012-01-04 | Method for refining pantoprazole optical enantiomer |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101289443A (en) * | 2008-06-10 | 2008-10-22 | 上海慈瑞医药科技有限公司 | Method for refining lansoprazole bulk drug |
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- 2012-01-04 CN CN2012100004319A patent/CN102584791A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101289443A (en) * | 2008-06-10 | 2008-10-22 | 上海慈瑞医药科技有限公司 | Method for refining lansoprazole bulk drug |
Non-Patent Citations (1)
| Title |
|---|
| 王庆河等: "泮托拉唑钠的合成研究", 《中国药学杂志》, vol. 34, no. 8, 31 August 1999 (1999-08-31), pages 564 - 565 * |
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Application publication date: 20120718 |