CN1763021A - Method for purifying orlistat - Google Patents
Method for purifying orlistat Download PDFInfo
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- CN1763021A CN1763021A CN 200510094601 CN200510094601A CN1763021A CN 1763021 A CN1763021 A CN 1763021A CN 200510094601 CN200510094601 CN 200510094601 CN 200510094601 A CN200510094601 A CN 200510094601A CN 1763021 A CN1763021 A CN 1763021A
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- Prior art keywords
- orlistat
- solvent
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- purifying
- crystallization
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 title claims abstract description 70
- 229960001243 orlistat Drugs 0.000 title claims abstract description 70
- 238000000034 method Methods 0.000 title claims abstract description 28
- 238000002425 crystallisation Methods 0.000 claims abstract description 29
- 230000008025 crystallization Effects 0.000 claims abstract description 28
- 239000002904 solvent Substances 0.000 claims abstract description 24
- 239000012454 non-polar solvent Substances 0.000 claims abstract description 12
- 238000001953 recrystallisation Methods 0.000 claims abstract description 4
- 238000001914 filtration Methods 0.000 claims abstract description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000000706 filtrate Substances 0.000 claims description 4
- 239000012535 impurity Substances 0.000 abstract description 18
- 238000000746 purification Methods 0.000 abstract description 13
- 238000009776 industrial production Methods 0.000 abstract description 2
- SIKWOTFNWURSAY-UHFFFAOYSA-N Lipstatin Natural products CCCCCCC1C(CC(CC=CCC=CCCCCC)C(=O)OC(CC(C)C)NC=O)OC1=O SIKWOTFNWURSAY-UHFFFAOYSA-N 0.000 description 13
- OQMAKWGYQLJJIA-CUOOPAIESA-N lipstatin Chemical compound CCCCCC[C@H]1[C@H](C[C@H](C\C=C/C\C=C/CCCCC)OC(=O)[C@H](CC(C)C)NC=O)OC1=O OQMAKWGYQLJJIA-CUOOPAIESA-N 0.000 description 13
- 239000000356 contaminant Substances 0.000 description 11
- 238000004519 manufacturing process Methods 0.000 description 11
- 238000005984 hydrogenation reaction Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- 238000000855 fermentation Methods 0.000 description 7
- 230000004151 fermentation Effects 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000000605 extraction Methods 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- 230000002950 deficient Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 241000187747 Streptomyces Species 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
- 229940086609 Lipase inhibitor Drugs 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 150000002613 leucine derivatives Chemical class 0.000 description 1
- 229960004232 linoleic acid Drugs 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The present invention discloses orlistat purifying method, which includes dissolving coarse orlistate product in medium polarity solvent, filtering, eliminating impurity, crystallization, dissolving in non-polar solvent, recrystallization, and repeating some steps until reaching the medicinal purity standard. The said method is suitable for purifying coarse orlistate product with purity of 50-85 %, and has the advantages of high yield, short purification period, simple purification process and being suitable for industrial production.
Description
Technical field
The present invention relates to a kind of method of purification of organic compound, particularly, the present invention relates to a kind of method for preparing the high purity orlistat.
Background technology
Orlistat (Orlistat), be the derivative of natural product lipstatin (Buddhist nun moors Si Tating) after hydrogenation of streptomyces, chemical name (S)-2-formamido group-4-methyl-valerate (S)-1-[[(2S, 3S)-3-hexyl-4-oxygen-2-oxetanyl]-methyl]-dodecyl ester.Orlistat is a specific specificity gi tract lipase inhibitor, is used for prevention and treatment and obesity diseases associated.
Chinese patent " method of purification of a lipstatin " (publication number: CN1266058A, on September 13rd, 2000 is open), the method of purification of orlistat is disclosed, the lipatatin that is about to streptomyces fermentation back generation carries out the double fluid extraction with heptane and aqueous acetic acid, and selects for use hexane or heptane to come hydrogenation and crystallization.United States Patent (USP) leucine derivatives (patent No. US4598089, in July, 1986 is open) disclose and a kind ofly concentrated and purifying obtains the method for orlistat with chromatographic process, that is: fermented product lipstatin is soaked to concentrate and go up spectrum post wash-out, concentrate, use the heptane crystallization after the hydrogenation.Though the method for the disclosed purifying orlistat of these technology is fairly simple, and also can obtain to meet the orlistat of medicinal standard, but these technology are very high to the purity requirement of the lipstatin in the fermented liquid, and require after the hydrogenation purity of orlistat sample itself higher.As the disclosed purifying technique of CN1266058A patent, very high to the purity requirement of the intermediate lipstain in the fermented liquid: weight content obtains the orlistat of purity that can be medicinal up to 90% otherwise can't purify at all.And also existing with heptane purifying or crystallization of mentioning among the US4598089 can not be removed impurity completely effectively, defectives such as solvent large usage quantity.Concentrate with purifying with chromatography simultaneously and also have following defective: defectives such as yield is low, the cycle is long, intermediate Lipstatin is difficult for preserving, easy oxidation.
At present, domestic fermentation also only is in the junior stage with the production of substratum, and the industrial culture medium raw material suitable with external quality can't be provided.Such as used linolic acid in the fermenting process of orlistat, domestic best product content also only reaches 54%, and external standard is 60%.Just because of the culture medium raw material of domestic fermentation usefulness and external different and some other reasons can cause that in actual production the lipstatin purity after the fermentation is very low, weight content approximately has only 20-45%.Because the not production domesticization of substratum makes that also the price of import substratum is very high, consider simultaneously, can't be applied in the industrial production at all from the production cost angle.
Because the purity of lipstatin is low, bring in the orlistat sample after the hydrogenation and except containing orlistat, also contain other plurality of impurities, and orlistat content is very low, weight content has only 50-70%, and impurities is many, the composition of impurity also with prior art in disclosed different, under this practical situation, can't use prior art to carry out purification process, if use the prior art purifying, the finished product of gained does not reach medicinal purity requirement far away at all.
Summary of the invention
The present invention has overcome the defective that the orlistat of low-purity can't be purified in the prior art, provides a kind of and the orlistat of low-purity can have been purified to the method for purification that meets medicinal standard and be suitable for industrial application.
The objective of the invention is to overcome and be difficult to purify this technical problem of low-purity orlistat in the prior art, provide a kind of and can remove impurity, yield height effectively, the cycle is short and be suitable for the technology of the purifying orlistat of suitability for industrialized production.
Through discovering, the dissolving selectivity of the solvent of middle polarity is stronger, orlistat is easy to be dissolved in the solvent of middle polarity, and contained impurity is insoluble in the solvent of middle polarity in the orlistat sample, and nonpolar solvent such as heptane are bigger to impurity solubleness more in the orlistat sample, can not remove impurity, as long as just can reach the purpose of removing impurity, thereby obtain the method for highly purified orlistat by the repeatedly alternate repetition ground dissolving of several solvents, crystallization.The contriver utilizes this characteristics, by with the solvent of orlistat sample dissolution in middle polarity, in ethanol, acetonitrile, acetone, Virahol, butanone, butanols etc., orlistat is dissolved in the solvent, thus and the insoluble impurity of removing effectively of impurity.
The invention provides a kind of method of purifying orlistat, can remove impurity effectively, obtain meeting the product of medicinal standard with this method.
After technology extraction concentrated routinely, hydrogenation, heptane crystallization gets the orlistat sample with fermented liquid, the content that records orlistat with HPLC was very low, and content approximately has only 50-85% (w/w), even lower, and the medicinal standard of distance 98% is very big.
The invention discloses a kind of method of purifying orlistat, comprise following step:
1) dissolving, crystallization: with the orlistat sample with the dissolving of the solvent of middle polarity, volume ratio meter by weight, the add-on of solvent is 2-5 with the ratio of orlistat sample: 1, filter, decon, the solvent of adding middle polarity in the filtrate of gained are to 10-15: 1, crystallization gets crystallized sample;
2) heavily dissolving, recrystallization: with 1) crystallized sample of gained dissolves with nonpolar solvent, volume ratio meter by weight, the add-on of nonpolar solvent is 15-25 with the ratio of crystallized sample: 1, filtration, decon; In the filtrate of gained, add nonpolar solvent, to 2545: 1, crystallization.
The weight content of wherein said orlistat sample be about 50-85% or below.If content is higher than 85% even up to the orlistat sample more than 90%, can purify with the technology of prior art.Purifying technique of the present invention is for the orlistat that purification is higher than 85%, and compared with prior art superiority is not very remarkable.And be lower than 50% orlistat sample for content, the present invention also can purify, just repetition that will be repeatedly in purification process, this can extend manufacture cycle, reaching increases production cost widely, from the industrialization angle, from be lower than 50% orlistat sample, be purified to the pure product that meet medicinal standard and do not meet suitability for industrialized production and require.
Wherein in step 1), the add-on of solvent and the weightmeasurement ratio of orlistat sample are 2-5 when dissolving: 1, be preferably 3-4: 1.If the solvent amount that adds very little, soltion viscosity is excessive, and orlistat can not be dissolved in the solvent fully, is difficult to filter.If the solvent add-on is too much, impurity also can be added in the solvent and mix with orlistat, does not have the effect of removing impurity.When crystallization, the add-on of middle polarity solvent is also very important, preferred about 10: 1.If add very little, crystallization velocity is too fast, impurity also can be tied together; And add too much, and orlistat dissolves in solvent too much, and crystallization is bad, and yield is too low.
Wherein in described step 2) in, when heavily dissolving, the add-on of nonpolar solvent is preferably about 20: 1 with weightmeasurement ratio.In recrystallization, the add-on of nonpolar solvent is also very important, can select 25-45: 1 amount, but when selecting 30-40: during 1 amount, the crystallization of orlistat is comparatively complete, and crystalline form is also relatively good.
In the wherein said step 1), the middle polarity solvent is ethanol, acetonitrile, acetone, propylene glycol, Virahol, butanone, butanols etc., preferred acetonitrile.
Wherein said step 2) in, nonpolar solvent is heptane, hexane, tetracol phenixin, chloroform or sherwood oil etc., preferred heptane because with heptane not the dawn can remove impurity behind the main peak, and can improve the weight content of orlistat.
In the purification process of orlistat, behind crystallisation step, crystallized sample is carried out high performance liquid chromatography (HPLC) detect, look the particular case of impurity, repeat step 1) or step 2) or repeat step 1) and 2), and it is carried out HPLC detect, up to the purity that meets medicinal standard.
In the purification process of orlistat, the industrial ordinary method of used solvent such as Rotary Evaporators, can reclaim or apply mechanically.Save production cost on the one hand, can not cause industrial pollution on the one hand.Be suitable for industrialized big production.
In whole purification process, filter used filter membrane aperture and can select 0.8 μ m, 0.45 μ m, 0.22 μ m, consider flow velocity and impurity-eliminating effect, preferred 0.45 μ m.
The method of the disclosed purifying orlistat of the present invention is not high for the purity requirement that fermented liquid extracts spissated lipstatin, and approximately 20-45% gets final product.And the lipstatin purity among the patent CN1266058A is 90%.Therefore the present invention mainly provides the orlistat (important content 50-85%, even lower) of the low-purity of gained after the intermediate lipstatin hydrogenation that purity is lower to carry out the method that purification process obtains salable product.
Through behind the purifying technique disclosed by the invention, adopt high effective liquid chromatography for measuring orlistat content, the weight content of orlistat can reach more than 98%, meets medicinal standard.
The technology of purifying orlistat disclosed by the invention is simple, convenient, and production cost is low, is suitable for industrialization.
Embodiment
The invention will be further described below by example.
Embodiment 1
The fermentation, extraction concentrated solution contains lipstatin 30% (w/w) 120ml, gets sample after the hydrogenation, contains orlistat sample 46g, content 52%, sample look ash adds acetone 150ml dissolving, filters approximately, adds acetone to 600ml, crystallization, suction filtration gets the 30g crystallization, off-white color, HPLC detection level 96% (W/W), maximum contaminant 0.52%.Add acetone 120ml again, dissolving is filtered, and adds acetone to 400ml, low temperature crystallization, and suction filtration gets the 25g crystallization, off-white color, HPLC detects, content 97%, maximum contaminant 0.4%.Add the 500ml heptane and dissolve again, filter, add heptane to 900ml, crystallization obtains the pure product 20g of orlistat, content 98.8%, maximum contaminant 0.4%.
Embodiment 2
Fermentation, extraction concentrated solution Lipstatin purity 40% (w/w) 90ml, HPLC purity 74% (pressing the peak area normalization method calculates), get orlistat sample 52g after the hydrogenation, content 68.9%, maximum contaminant 2.0% adds ethanol 110ml and dissolves, filters, adds ethanol to 530ml, crystallization, obtain orlistat sample 35g, purity 83.1%, maximum contaminant 0.9%.Add heptane 550ml and heavily dissolve, filter, add heptane to 1300ml, crystallization obtains orlistat sample 34g, purity 88.1%, maximum contaminant 0.9%.Add heptane 700ml and heavily dissolve, filter, add heptane to 1000ml, crystallization obtains the pure product 14g of orlistat, purity 98.5%, and maximum contaminant is lower than 0.5%.
Embodiment 3
The fermentation, extraction concentrated solution contains lipstatin 35% (w/w) 100ml, HPLC purity 71% (pressing the peak area normalization method calculates) gets the about 51g of orlistat sample, content 70% after the hydrogenation, sample look ash, add acetonitrile 150ml dissolving, filter, add acetonitrile to 750ml, crystallization, get orlistat sample 32g, off-white color, purity 91.1%, maximum contaminant 0.92%; Add hexane 750ml and heavily dissolve, filter, add hexane to 1400ml, crystallization obtains orlistat sample 31g, purity 93.5%, maximum contaminant 0.92%.Add acetonitrile 65mi dissolving, filter, add acetonitrile to 310mi, crystallization gets orlistat sample 18g, off-white color, purity 95.1%, maximum contaminant 0.53%; Add hexane 270ml and heavily dissolve, filter, add hexane to 420ml, crystallization obtains the pure product 16g of orlistat, purity 98.6%, and maximum contaminant is below 0.5%.
Claims (5)
1. the method for a purifying orlistat comprises following step:
1) dissolving, crystallization: with the orlistat sample with the dissolving of the solvent of middle polarity, volume ratio meter by weight, the add-on of solvent is 2-5 with the ratio of orlistat sample: 1, filter, decon, the solvent of adding middle polarity in the filtrate of gained are to 10-15: 1, crystallization gets crystallized sample;
2) dissolving, recrystallization: with 1) crystallized sample of gained dissolves with nonpolar solvent, volume ratio meter by weight, the add-on of nonpolar solvent is 15-25 with the ratio of crystallized sample: 1, filtration, decon; In the filtrate of gained, add nonpolar solvent, to 25-45: 1, crystallization.
2. the method for purifying orlistat according to claim 1, the weight content that it is characterized in that described orlistat sample is 50-85%.
3. the method for purifying orlistat according to claim 1 is characterized in that described middle polarity solvent is ethanol, acetonitrile, acetone.
4. the method for purifying orlistat according to claim 1 is characterized in that described nonpolar solvent is heptane, hexane or sherwood oil.
5. the method for purifying orlistat according to claim 1 is characterized in that repeating a wherein any step or two steps, up to the purity that meets medicinal standard.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2005100946014A CN1763021B (en) | 2005-09-29 | 2005-09-29 | Method for purifying orlistat |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2005100946014A CN1763021B (en) | 2005-09-29 | 2005-09-29 | Method for purifying orlistat |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1763021A true CN1763021A (en) | 2006-04-26 |
| CN1763021B CN1763021B (en) | 2010-08-11 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2005100946014A Active CN1763021B (en) | 2005-09-29 | 2005-09-29 | Method for purifying orlistat |
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| Country | Link |
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| CN (1) | CN1763021B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102070567A (en) * | 2011-01-21 | 2011-05-25 | 天津市海德安科医药科技发展有限公司 | Method for preparing high-purity orlistat by using reverse phase high-performance liquid chromatogram |
| CN102070568A (en) * | 2011-02-28 | 2011-05-25 | 珠海联邦制药股份有限公司 | Preparation method of orlistat |
| CN102558103A (en) * | 2010-12-13 | 2012-07-11 | 山东新时代药业有限公司 | Method for separating and purifying Orlistat |
| CN102993135A (en) * | 2012-12-31 | 2013-03-27 | 山东新时代药业有限公司 | Method for purifying orlistat |
| CN103739572A (en) * | 2014-01-09 | 2014-04-23 | 山东新时代药业有限公司 | Process for recovering orlistat crystallization mother solution |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK1028115T3 (en) * | 1999-01-29 | 2003-03-17 | Hoffmann La Roche | Purification of lipstatin |
| EP1470116A4 (en) * | 2001-12-04 | 2005-04-06 | Biogal Gyogyszergyar | Preparation of orlistat and orlistat crystalline forms |
| WO2005007639A1 (en) * | 2003-07-17 | 2005-01-27 | Biocon Limited | Preparation of tetrahydrolipstatin by hydrogenation of lipstatin, solvent extraction and purification |
| ES2329474T3 (en) * | 2003-09-12 | 2009-11-26 | Ranbaxy Laboratories Limited | PROCESS FOR THE PREPARATION OF ORLISTAT CRYSTAL FORMS. |
-
2005
- 2005-09-29 CN CN2005100946014A patent/CN1763021B/en active Active
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558103A (en) * | 2010-12-13 | 2012-07-11 | 山东新时代药业有限公司 | Method for separating and purifying Orlistat |
| CN102558103B (en) * | 2010-12-13 | 2015-01-14 | 山东新时代药业有限公司 | Method for separating and purifying Orlistat |
| CN102070567A (en) * | 2011-01-21 | 2011-05-25 | 天津市海德安科医药科技发展有限公司 | Method for preparing high-purity orlistat by using reverse phase high-performance liquid chromatogram |
| CN102070568A (en) * | 2011-02-28 | 2011-05-25 | 珠海联邦制药股份有限公司 | Preparation method of orlistat |
| WO2012116520A1 (en) * | 2011-02-28 | 2012-09-07 | 珠海联邦制药股份有限公司 | Method for preparing orlistat |
| CN102070568B (en) * | 2011-02-28 | 2012-09-26 | 珠海联邦制药股份有限公司 | Preparation method of orlistat |
| CN102993135A (en) * | 2012-12-31 | 2013-03-27 | 山东新时代药业有限公司 | Method for purifying orlistat |
| CN102993135B (en) * | 2012-12-31 | 2015-09-09 | 山东新时代药业有限公司 | A kind of purification process of orlistat |
| CN103739572A (en) * | 2014-01-09 | 2014-04-23 | 山东新时代药业有限公司 | Process for recovering orlistat crystallization mother solution |
| CN103739572B (en) * | 2014-01-09 | 2016-01-27 | 山东新时代药业有限公司 | A kind of orlistat crystalline mother solution recovery process |
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| Publication number | Publication date |
|---|---|
| CN1763021B (en) | 2010-08-11 |
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Application publication date: 20060426 Assignee: Hangzhou Huadi Pharmaceutical Technology Co.,Ltd. Assignor: Hangzhou Huadong Medicine Group Biopharmaceutical Co.,Ltd. Contract record no.: X2021330000100 Denomination of invention: A method for purifying orlistat Granted publication date: 20100811 License type: Common License Record date: 20210820 |