CN102070567A - Method for preparing high-purity orlistat by using reverse phase high-performance liquid chromatogram - Google Patents
Method for preparing high-purity orlistat by using reverse phase high-performance liquid chromatogram Download PDFInfo
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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 72
- 229960001243 orlistat Drugs 0.000 title claims abstract description 72
- 238000000034 method Methods 0.000 title claims abstract description 26
- 239000007788 liquid Substances 0.000 title claims abstract description 14
- 239000012535 impurity Substances 0.000 claims abstract description 36
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 23
- 238000002360 preparation method Methods 0.000 claims abstract description 18
- 238000001914 filtration Methods 0.000 claims abstract description 17
- 239000000243 solution Substances 0.000 claims abstract description 17
- 239000007864 aqueous solution Substances 0.000 claims abstract description 10
- 238000001035 drying Methods 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- 239000003495 polar organic solvent Substances 0.000 claims abstract description 7
- 238000007670 refining Methods 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- 238000002425 crystallisation Methods 0.000 claims description 18
- 230000008025 crystallization Effects 0.000 claims description 18
- 238000004366 reverse phase liquid chromatography Methods 0.000 claims description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 239000000945 filler Substances 0.000 claims description 9
- 239000003480 eluent Substances 0.000 claims description 8
- 238000005984 hydrogenation reaction Methods 0.000 claims description 8
- 238000012856 packing Methods 0.000 claims description 7
- 238000000746 purification Methods 0.000 claims description 7
- 238000000855 fermentation Methods 0.000 claims description 6
- 230000004151 fermentation Effects 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 3
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 3
- 238000005070 sampling Methods 0.000 abstract description 9
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 239000006228 supernatant Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 10
- 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 4
- 239000003814 drug Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 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 4
- 239000002245 particle Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 238000005374 membrane filtration Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 241000946767 Streptomyces toxytricini Species 0.000 description 1
- 241001655322 Streptomycetales Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000000547 structure data Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing high-purity orlistat by using a reverse phase high-performance liquid chromatogram. The method comprises the following steps of: (1) preparing liquid supernatant: dissolving an orlistat sample into an organic solvent, filtering out impurities through micropores to obtain clear solution; (2) sampling the solution obtained in the step (1) into a reverse phase high-performance liquid chromatogram preparation column, eluting by using aqueous solution, as an eluting agent, of the organic solvent, collecting target components, and performing high performance liquid chromatography (HPLC) test, wherein the chromatographic purity is over 99.5 percent and the single impurity is below 0.1 percent; and (3) refining: concentrating the collected target components to dry under the vacuum condition, adding a non-polar organic solvent, crystallizing at the temperature of 0 to 5 DEG C, filtering and drying to obtain the orlistat with the purity over 99.5 percent. The method for preparing high-purity orlistat has the advantages that: the orlistat is high in purity and yield rate; the process is simple; and continuous sampling can be realized. The disposable investment of equipment is a little high, but the running cost is low; therefore, the method is suitable for industrialized production.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of preparation method of high purity orlistat.
Background technology
Orlistat (Orlistat) is that product Lipstatin (Lipstatin) after poison three plain streptomycetes (Streptomyces toxytricini) fermentation culture is after hydrogenation and make.Be the fat-reducing medication of unique permission of FDA approval in U.S.'s listing.
Chinese patent " method of purification of a lipstatin " (application number: 00101172.3), disclose double-current extraction and separated Lipstatin with counter-current extraction, after the hydrogenation with hexane or heptane crystallization orlistat.Chinese patent " a kind of method of purifying orlistat " (application number: 200510094601.4), disclose the middle polarity solvent and be used for the orlistat crystallization, carried out recrystallization with nonpolar solvent again.The method of these disclosed purifying orlistats, can obtain to meet the orlistat of medicinal standard, but prepared orlistat chromatographic purity is mostly at 98.0-98.5%, maximum single impurity (the relative retention time RT=0.95 place that HPLC detects) at 0.2-0.6%, is difficult to further improve the purity and the quality of medicine orlistat.
Present bulk drug market, especially American-European market for the single impurity that surpasses 0.1%, requires to provide the analysis of the molecular structure data.Announce that and the related impurities of orlistat is never formal if single impurity surpasses 0.1% in the product, then make troubles to products export, price differs greatly especially.Want to enter high-end drug market, must preparation purity more than 99.5%, single impurity is at the high purity orlistat below 0.1%.The orlistat product that domestic production producer provides, purity concentrates on 98.0-98.5%, during HPLC detected, RT0.95, RT1.24, RT1.27 three place's impurity were mostly at 0.2-0.6% (Fig. 1), and especially this impurity at RT0.95 place adopts technology such as solvent crystal, silica gel column chromatography to be difficult to remove.
Summary of the invention
The objective of the invention is to overcome being difficult to that prior art exists controls single impurity in the technical problem below 0.1%, be difficult to remove the problem of RT0.95, RT1.24, RT1.27 impurity such as (HPLC analyses), provide a kind of can effectively remove various impurity, with general purity (70-99.5%) orlistat purify to more than 99.5%, yield is high and the RPLC that is suitable for industrialized production prepares the method for high purity orlistat.
Technical scheme of the present invention is summarized as follows:
A kind of RPLC prepares the method for high purity orlistat, comprises the steps:
(1) preparation of upper prop liquid: will be dissolved in the organic solvent through fermentation and the orlistat sample that obtains through separation and purification, hydrogenation, crystallization ratio in 1g: 10-50ml, through the millipore filtration removal of impurities, settled solution;
(2) RPLC preparative column on the solution sample introduction that step (1) is obtained, with concentration expressed in percentage by volume is that the aqueous solution of the organic solvent of 50-98% is made eluent, at wash-out pressure 3.0-10.0MPa, wash-out under the temperature 10-35 ℃ of condition, collect target components, carry out HPLC and measure, chromatographic purity is more than 99.5%, and single impurity is below 0.1%;
(3) refining: the target components vacuum concentration of collecting is extremely done, and in the ratio adding non-polar organic solvent of 1g: 15-50ml, in 0-5 ℃ of crystallization, filtration drying obtains purity at the orlistat more than 99.5%.
The chromatographic purity of raw material orlistat sample is 70.0-99.5%.
Described organic solvent of step (1) or the described organic solvent of step (2) are C
1-C
4Alcohols, C
3-C
4Ketone, ethyl acetate, acetonitrile, propionitrile and tetrahydrofuran (THF) at least a.
C
1-C
4Alcohols be methyl alcohol, ethanol, Virahol or butanols.
C
3-C
4Ketone be acetone, 2-butanone.
Filler is C18, C8, C4 or C6H5 in the RPLC preparative column, and packing material size is 5-250 μ m.
The described non-polar organic solvent of step (3) is heptane, hexane or sherwood oil.
Repeating said steps (2) or step (3) make the purity of orlistat reach more than 99.5%, single impurity is below 0.1%.
Advantage of the present invention is:
Adopt method of the present invention to prepare the high purity orlistat, total recovery is at 75-90%, and productive rate is in 360-720kg product/100kg filler/moon.Adopt HPLC to measure the orlistat of the present invention's preparation, purity can reach more than 99.5%, and single impurity far above medicinal standard, belongs to high-end product below 0.1%.
But technology purifying orlistat disclosed by the invention has advantages such as purity height, yield height, the simple continuous sample introduction of technology, and the equipment one-time investment is high slightly, but running cost is not high, is suitable for suitability for industrialized production.
Description of drawings
Fig. 1 is raw material orlistat sample HPLC figure.
Fig. 2 is the reversed-phase preparative chromatography figure of embodiment 1.
Fig. 3 is the orlistat finished product HPLC figure of method preparation of the present invention.
Embodiment
The invention will be further described below in conjunction with specific embodiment.
The orlistat material sample can detect with HPLC available from Hunan Biology Pharmacy Co., Ltd of big nation, and purity is at 95.0-99.5%, and the single impurity above 0.1% is at 3-5; Can also be by our company's prepared in laboratory.
Get orlistat sample 1.5g, be dissolved in 60ml methyl alcohol, through 0.45 μ m membrane filtration, solution sampling carrying out HPLC detects, chromatographic purity is seen Fig. 1, and orlistat purity is 98.46%, and RT0.95 place impurity is 0.51%, RT1.24 impurity 0.27%, RT1.27 place impurity are 0.34%.
Column size is 4.6 * 250mm, the particle diameter 5 μ m of filler C18, orlistat solution sample introduction, flow velocity 1.0ml/min, 80% methanol aqueous solution carries out wash-out, flow velocity 0.8ml/min, 23 ℃ of working temperatures, pressure 3.0MPa, it is 195nm that the UV of employing detects wavelength, collect target components (Fig. 2) in 38.7-43.7min, the productive rate of preparative column is 5.8g product/kg filler/h.
Collect liquid and contain orlistat 1.4g, vacuum concentration evaporates solvent, adds the dissolving of 45ml heptane, is cooled to 0 ℃ of crystallization, and filtration drying gets the pure product 1.2g of orlistat, analyzes (Fig. 3) through HPLC, orlistat purity 99.8%, maximum single assorted 0.10%.
Get orlistat sample 1.5g, be dissolved in 60ml methyl alcohol, through 0.45 μ m membrane filtration, sampling HPLC analyzes, and orlistat purity is 81.3%.
COSMOSIL 5C18 chromatographic column (4.6 * 250mm), C18 particle diameter 5 μ m, moving phase is methyl alcohol: water=83: 17 (v/v), 23 ℃ of working temperatures, operating pressure 3.0MPa, the detection wavelength is 195nm.The one-level preparation: sample introduction flow velocity 1.0ml/min, elution flow rate 0.8ml/min, 39.5-43.1min collects target components, and HPLC is surveyed in sampling, purity 97.3%, maximum single assorted (isomer) 0.4%.The secondary preparation: the collection component of one-level preparation ,-0.1MPa, 70 ℃ of vacuum concentration are to concentration 20-30mg/ml.By similarity condition sample introduction, wash-out, the collection target components of one-level preparation, HPLC is surveyed in sampling, purity 99.6%, maximum single assorted 0.1%.
The collection component of secondary preparation contains orlistat 1.35g, collect liquid in-0.1MPa, 70 ℃ of vacuum concentration to doing, add the dissolving of 40ml heptane, 0 ℃ of crystallization, filtration drying gets the pure product 1.1g of orlistat, sampling HPLC analyzes, orlistat purity 99.7%, maximum single assorted 0.06%.
Get orlistat sample 30kg, be dissolved in 1000L methyl alcohol, through 0.45 μ m membrane filtration, solution sampling carrying out HPLC detects, and orlistat purity is 98.1%, and RT0.95 place impurity is 0.35%.
Main column physical dimension 1500 * 1500 * 3800mm, chromatographic column internal diameter 800mm, height 800mm, effective packing height 450mm, packing quality 150kg, C18 particle diameter 10-15 μ m.The preparation work temperature is 20 ℃, operating pressure≤10.0MPa, and 83% methanol aqueous solution is made eluent, sample introduction flow velocity 20L/min, elution flow rate 40L/min, 6 components of fraction collection.The vacuum concentration target components contains orlistat 29.5kg, evaporates solvent, adds 900L heptane dissolving, is cooled to 0 ℃ of crystallization, filter, dry, beat powder, must the pure product 25.1kg of orlistat, total recovery is 83.7%.Sampling is carried out HPLC and is analyzed orlistat purity 99.9%, maximum single assorted 0.08%.
A kind of RPLC prepares the method for high purity orlistat, comprises the steps:
(1) preparation of upper prop liquid: with fermented liquid in the chromatographic purity that separation and purification, hydrogenation, crystallization obtain to be 99.5% orlistat sample in the ratio of 1g: 40ml be dissolved in volume ratio is methyl alcohol-ethanol of 1: 1, through the millipore filtration removal of impurities, settled solution;
(2) RPLC preparative column on the solution sample introduction that step (1) is obtained, column size 4.6 * 150mm, filler C18 particle diameter 100-120 μ m is that the aqueous solution of methyl alcohol-alcohol mixed solvent of 75% is made eluent with concentration expressed in percentage by volume, described methyl alcohol-alcoholic acid volume ratio is 1: 1, at wash-out pressure 5.0MPa, wash-out under 25 ℃ of conditions of temperature, flow velocity 1.0ml/min, collect target components, carry out HPLC and measure, chromatographic purity is more than 99.5%, and single impurity is below 0.1%;
(3) refining: the target components vacuum concentration of collecting is extremely done, and in the ratio adding sherwood oil of 1g: 50ml, in 0-5 ℃ of crystallization, filtration drying obtains purity at the orlistat more than 99.5%.
A kind of RPLC prepares the method for high purity orlistat, comprises the steps:
(1) preparation of upper prop liquid: will and be 90.0% orlistat sample through the chromatographic purity that separation and purification, hydrogenation, crystallization obtain through fermentation be dissolved in the acetone in the ratio of 1g: 20ml, through the millipore filtration removal of impurities, settled solution;
(2) RPLC preparative column (4.6 * 250mm) on the solution sample introduction that step (1) is obtained, filler is C8 in the preparative column, packing material size is 10 μ m, is that the aqueous solution of 95% acetone is made eluent with concentration expressed in percentage by volume, at wash-out pressure 3.0MPa, wash-out under 20 ℃ of conditions of temperature, flow velocity 1.0ml/min collects target components, carries out HPLC and measures, chromatographic purity is more than 99.5%, and single impurity is below 0.1%;
(3) refining: the target components vacuum concentration of collecting is extremely done, and in the ratio adding hexane of 1g: 15ml, in 0-5 ℃ of crystallization, filtration drying obtains purity at the orlistat more than 99.5%.
A kind of RPLC prepares the method for high purity orlistat, comprises the steps:
(1) preparation of upper prop liquid: will and be 80.0% orlistat sample through the chromatographic purity that separation and purification, hydrogenation, crystallization obtain through fermentation be dissolved in the Virahol in the ratio of 1g: 10ml, through the millipore filtration removal of impurities, settled solution;
(2) RPLC preparative column (4.6 * 150mm) on the solution sample introduction that step (1) is obtained, filler is C4 in the preparative column, packing material size is 200-250 μ m, the aqueous solution that with concentration expressed in percentage by volume is 98% Virahol is made eluent, at wash-out pressure 10.0MPa, and wash-out under 35 ℃ of conditions of temperature, flow velocity 0.7ml/min, collect target components, carry out HPLC and measure chromatographic purity 97.0%;
(3) step (2) is collected target components and carry out the secondary preparation by similarity condition, collect target components, carry out HPLC and measure, chromatographic purity is more than 99.5%, and single impurity is below 0.1%;
(4) refining: the target components vacuum concentration of collecting is extremely done, and in the ratio adding sherwood oil of 1g: 50ml, in 0-5 ℃ of crystallization, filtration drying obtains purity at the orlistat more than 99.5%.
A kind of RPLC prepares the method for high purity orlistat, comprises the steps:
(1) preparation of upper prop liquid: will and be 70.0% orlistat sample through the chromatographic purity that separation and purification, hydrogenation, crystallization obtain through fermentation be dissolved in the ethyl acetate in the ratio of 1g: 50ml, through the millipore filtration removal of impurities, settled solution;
(2) RPLC preparative column (4.6 * 150mm) on the solution sample introduction that step (1) is obtained, filler is C6H5 in the RPLC preparative column, packing material size is 10 μ m, is that the aqueous solution of 50% ethyl acetate is made eluent with concentration expressed in percentage by volume, at wash-out pressure 7.0MPa, wash-out under 10 ℃ of conditions of temperature, flow velocity 0.8ml/min collects target components, carries out HPLC and measures, chromatographic purity is 99.2%, and single impurity is below 0.15%;
(3) refining: the target components vacuum concentration of collecting is extremely done, and in the ratio adding sherwood oil of 1g: 20ml, in 0-5 ℃ of crystallization, filtration drying, chromatographic purity are more than 99.4%, and single impurity is below 0.1%;
(4) with the ratio adding sherwood oil of dry thing in 1g: 40ml, in 0-5 ℃ of crystallization, filtration drying obtains purity at the orlistat more than 99.5%.
With the acetone in the acetonitrile alternate embodiment 5, other obtains purity at the orlistat more than 99.5% with embodiment 5.
Embodiment 9
With the acetone in the propionitrile alternate embodiment 5, other obtains purity at the orlistat more than 99.5% with embodiment 5.
With the acetone in the tetrahydrofuran (THF) alternate embodiment 5, other obtains purity at the orlistat more than 99.5% with embodiment 5.
Embodiment 11
With the acetone in the butanols alternate embodiment 5, other obtains purity at the orlistat more than 99.5% with embodiment 5.
With the acetone in the 2-butanone alternate embodiment 5, other obtains purity at the orlistat more than 99.5% with embodiment 5.
Discover, with polar organic solvent dissolving orlistat sample, be carried on non-polar stationary phases such as C18, with the polar organic solvent aqueous solution as eluent, separate with reversed-phased high performace liquid chromatographic, distillate order (Fig. 2), collect target components according to the difference of impurity, orlistat, impurity, effectively remove impurity, single impurity can be controlled at below 0.1%.
Claims (8)
1. a RPLC prepares the method for high purity orlistat, it is characterized in that comprising the steps:
(1) preparation of upper prop liquid: will be dissolved in the organic solvent through fermentation and the orlistat sample that obtains through separation and purification, hydrogenation, crystallization ratio in 1g: 10-50ml, through the millipore filtration removal of impurities, settled solution;
(2) RPLC preparative column on the solution sample introduction that step (1) is obtained, with concentration expressed in percentage by volume is that the aqueous solution of the organic solvent of 50-98% is made eluent, at wash-out pressure 3.0-10.0MPa, wash-out under the temperature 10-35 ℃ of condition, collect target components, carry out HPLC and measure, chromatographic purity is more than 99.5%, and single impurity is below 0.1%;
(3) refining: the target components vacuum concentration of collecting is extremely done, and in the ratio adding non-polar organic solvent of 1g: 15-50ml, in 0-5 ℃ of crystallization, filtration drying obtains purity at the orlistat more than 99.5%.
2. method according to claim 1 is characterized in that: the chromatographic purity of described orlistat sample is 70.0-99.5%.
3. method according to claim 1 is characterized in that described organic solvent of described step (1) or the described organic solvent of step (2) are C
1-C
4Alcohols, C
3-C
4Ketone, ethyl acetate, acetonitrile, propionitrile and tetrahydrofuran (THF) at least a.
4. method according to claim 3 is characterized in that described C
1-C
4Alcohols be methyl alcohol, ethanol, Virahol or butanols.
5. method according to claim 3 is characterized in that described C
3-C
4Ketone be acetone, 2-butanone.
6. method according to claim 1 is characterized in that filler is C18, C8, C4 or C6H5 in the described RPLC preparative column, and packing material size is 5-250 μ m.
7. method according to claim 1 is characterized in that the described non-polar organic solvent of described step (3) is heptane, hexane or sherwood oil.
8. method according to claim 1 is characterized in that repeating said steps (2) or step (3), and the purity of orlistat is reached more than 99.5%.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102304105A (en) * | 2011-07-15 | 2012-01-04 | 鲁南新时代生物技术有限公司 | Method for preparing high-purity Orlistat |
| CN102993135A (en) * | 2012-12-31 | 2013-03-27 | 山东新时代药业有限公司 | Method for purifying orlistat |
| WO2014060445A1 (en) | 2012-10-19 | 2014-04-24 | Akzo Nobel Chemicals International B.V. | Method for preparing high purity orlistat |
| CN106543109A (en) * | 2016-10-21 | 2017-03-29 | 大邦(湖南)生物制药有限公司 | A kind of orlistat purifying process |
| CN108658900A (en) * | 2017-03-31 | 2018-10-16 | 江苏汉邦科技有限公司 | A method of isolating and purifying orlistat |
| CN109651301A (en) * | 2019-01-16 | 2019-04-19 | 苏州纳微科技股份有限公司 | A kind of purification process of orlistat |
| CN111458431A (en) * | 2020-04-13 | 2020-07-28 | 中山奕安泰医药科技有限公司 | Method for detecting isomer of orlistat intermediate |
| CN113834714A (en) * | 2021-11-09 | 2021-12-24 | 广东江门中医药职业学院 | Method for detecting pharmaceutical ingredients of orlistat illegally added in traditional Chinese medicine weight-losing health-care product |
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| CN102304105B (en) * | 2011-07-15 | 2013-07-10 | 鲁南新时代生物技术有限公司 | A method for preparing high-purity orlistat |
| CN102304105A (en) * | 2011-07-15 | 2012-01-04 | 鲁南新时代生物技术有限公司 | Method for preparing high-purity Orlistat |
| WO2014060445A1 (en) | 2012-10-19 | 2014-04-24 | Akzo Nobel Chemicals International B.V. | Method for preparing high purity 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 |
| CN106543109B (en) * | 2016-10-21 | 2019-02-12 | 大邦(湖南)生物制药有限公司 | A kind of orlistat purifying process |
| CN106543109A (en) * | 2016-10-21 | 2017-03-29 | 大邦(湖南)生物制药有限公司 | A kind of orlistat purifying process |
| CN108658900A (en) * | 2017-03-31 | 2018-10-16 | 江苏汉邦科技有限公司 | A method of isolating and purifying orlistat |
| CN109651301A (en) * | 2019-01-16 | 2019-04-19 | 苏州纳微科技股份有限公司 | A kind of purification process of orlistat |
| CN109651301B (en) * | 2019-01-16 | 2023-05-12 | 苏州纳微科技股份有限公司 | Purification method of orlistat |
| CN111458431A (en) * | 2020-04-13 | 2020-07-28 | 中山奕安泰医药科技有限公司 | Method for detecting isomer of orlistat intermediate |
| CN113834714A (en) * | 2021-11-09 | 2021-12-24 | 广东江门中医药职业学院 | Method for detecting pharmaceutical ingredients of orlistat illegally added in traditional Chinese medicine weight-losing health-care product |
| CN113834714B (en) * | 2021-11-09 | 2024-03-08 | 广东江门中医药职业学院 | Detection method for illegally adding orlistat medicine components into traditional Chinese medicine weight-losing health-care products |
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