CN103992296A - Preparation method of orlistat - Google Patents
Preparation method of orlistat Download PDFInfo
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- CN103992296A CN103992296A CN201410249734.3A CN201410249734A CN103992296A CN 103992296 A CN103992296 A CN 103992296A CN 201410249734 A CN201410249734 A CN 201410249734A CN 103992296 A CN103992296 A CN 103992296A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D305/10—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having one or more double bonds between ring members or between ring members and non-ring members
- C07D305/12—Beta-lactones
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Abstract
The invention belongs to the technical field of medicines, and in particular relates to a preparation method of orlistat, which specifically comprises the steps of pre-processing a fermentation solution, extracting through a filter cake, concentrating, extracting through a non-polar solvent, concentrating, extracting through a polar solvent, freezing to remove impurity, concentrating, crystallizing through a non-polar solvent, hydrogenating, backwashing, crystallizing and re-crystallizing. The content of orlistat prepared by adopting the preparation method disclosed by the invention is above 99%; the maximum individual impurity is within 0.1% and is higher than medicine standard; the preparation method disclosed by the invention is short in route, good in quality, convenient to operate, low in equipment investment and low in solvent use amount; furthermore, all solvents can be recycled and reused; and the production cost and the environmental pollution of orlistat are greatly reduced.
Description
Technical field
The invention belongs to medical technical field, particularly a kind of preparation method of orlistat.
Background technology
Orlistat (orlistat) is the novel slimming medicine that Roche Holding Ag develops the earliest, also be unique a kind of non-nervus centralis diet pill, it is long-acting and potent specificity gi tract lipase inhibitor, by being combined with the active ser position of stomach and enteral gastric lipase enzyme and steapsase, form covalent linkage, lipase is lost activity, stop steatolysis, absorption and utilization in food, thereby reach the object of fat-reducing.
At present, domestic production orlistat has two kinds of methods: a kind of is that chemistry is complete synthesis, and reactions steps is many, and yield is low, and environment compatibility is poor; Another kind is that microorganism fermentation obtains orlistat intermediate, and then intermediate is through the synthetic orlistat of a step hydrogenation, and the orlistat that second method is produced is occupied an leading position.Each pharmacy corporation is continued to optimize through bacterial screening, fermentation control and downstream extraction purifying process, can progressively improve the fermentation titer of orlistat intermediate and the quality of the finished product and yield.Therefore,, from cost and environmental angle, microorganism fermentation has significant superiority.
Chinese patent application CN 102010387A discloses a kind of method of purifying orlistat, has described the method for utilizing dynamic axial compression (DAC) technology separation and purification orlistat.
Chinese patent application CN 101948450A discloses a kind of method of manufacture orlistat, and intermediate extracts the purifying of the orlistat after the absorption of stage resin post, wash-out and hydrogenation through silica gel column chromatography, obtains orlistat.
Chinese patent application CN 102304105A discloses a kind of method of preparing orlistat, this invention purification of intermediate stage has been introduced silica gel column chromatography, after hydrogenation, use the middle grade solvent crystallizations such as ethanol, acetone, with non-polar solvents such as heptane, sherwood oil, normal hexanes, turn brilliant again, obtain high purity orlistat.
Summary of the invention
In order to solve the technical barrier that orlistat is purified to the high quality standards of ICH requirement, overcome in prior art investment of production equipment high, production cost is high, the shortcomings such as yield is low, contriver is through a large amount of tests, optimized a kind of preparation method of orlistat, comprise the pre-treatment of fermented liquid, lixiviate, concentrated, non-polar solvent extraction, concentrated, middle grade solvent extraction, concentrated, obtain the above orlistat intermediate of content 80%, and then dissolve with non-polar solvent, hydrogenation, filter to obtain hydride, in hydride, add the aqueous solutions of organic solvent of middle grade to carry out backwash removal of impurities, then carry out non-polar solvent crystallization and recrystallization, until product content is more than 99%, in maximum single assorted 0.1%.
Creative non-polar solvent and polar solvent two steps of adopting of contriver extract phase inversion, cryogenic freezing removal of impurities and crystallizations, obtain high-quality orlistat intermediate, after hydrogenation, add middle grade aqueous solutions of organic solvent to carry out backwash, can preferentially remove a large amount of polar impurities, improve orlistat content and purity, then utilize orlistat Tc in non-polar solvent high, content promotes the fast feature of amplitude, repeatedly carry out non-polar solvent crystallization, can effectively remove most of non polar impurities, reduce the content of related substance
Technical scheme of the present invention is specially, and a kind of preparation method of orlistat, comprises the steps:
1) fermentation liquor pretreatment:
In fermented liquid, add flocculating aids, with acid, adjust pH4.0-5.0, stir, filter, obtain filter cake;
2) lixiviate:
By step 1) in gained filter cake with polar solvent, soak, stir, filter, must be containing the solution of orlistat intermediate;
3) concentrated, tune solvent volume concentration:
By step 2) in filter gained orlistat midbody solution to be concentrated into orlistat intermediate concentration be 15～30g/L, with tap water, regulating the volumetric concentration of aqueous solutions of organic solvent is 50～80%;
4) non-polar solvent extraction:
To step 3) in add with the immiscible non-polar solvent of system in gained orlistat intermediate aqueous organic solvent solution and extract, phase-splitting obtains the nonpolar extraction liquid containing orlistat intermediate;
5) concentrated, polar solvent extract:
By step 4) the nonpolar extraction solution of extraction gained orlistat intermediate, being concentrated into concentration is 100～200g/L, adds polar solvent extract, phase-splitting obtains the polarity extraction solution of orlistat intermediate;
6) freezing removal of impurities:
By step 5) the polarity extraction liquid of gained orlistat intermediate stirs, and is cooled to below 5 ℃, and insulation, then removes by filter insolubles, obtains the clear filtrate of orlistat intermediate, is concentrated into dryly, obtains orlistat intermediate oily matter;
7) intermediate crystallization:
With solvent by step 6) gained orlistat intermediate oily matter dilutes, making its concentration is 50～100g/L, adopts falling temperature method, stirring and crystallizing, filters to obtain white orlistat intermediate crystal;
8) hydrogenation:
By step 7) with non-polar solvent, to be dissolved into concentration be 10～80g/L to crystallization orlistat intermediate crystal, adds the palladium charcoal that is equivalent to orlistat intermediate weight 5～10%, logical hydrogen reacts under 30～40 ℃ of temperature, pressure 0.3～1Mpa; After hydrogenation finishes, filter to obtain hydride;
9) backwash:
To add in hydride volume be equivalent to hydride volume 1-3 doubly, the aqueous solutions of organic solvent of middle grade, stir, standing, phase-splitting, phase in collection;
10) crystallization:
It is 10～100g/L that phase solution on gained after orlistat backwash is diluted to orlistat concentration with non-polar solvent, adopts falling temperature method to carry out stirred crystallization, filters to obtain orlistat crystal.
Step 10) crystallisation step in can repeat 0-4 time according to HPLC gained orlistat content and single assorted situation, to guarantee that assorted being controlled at of orlistat list is less than 0.1%; Repeating step is to be dissolved in non-polar solvent by orlistat crystal, and preferred concentration is 10～100g/L, adopts falling temperature method to carry out stirred crystallization, filters to obtain orlistat crystal.
Wherein, step 1) described fermented liquid can be but be not limited to the disclosed fermented liquid of CN102304105A; Described flocculating aids can be at least one in diatomite, perlite, Mierocrystalline cellulose, Graphite Powder 99, sawdust, magnesium oxide, gypsum, gac, acidic white earth; Preferred flocculating aids is any in diatomite, magnesium oxide, perlite; Add-on is 3～10% of fermented liquid weight.Described acid is preferably at least one in hydrochloric acid, acetic acid, sulfuric acid, oxalic acid.
The present invention is to step 2) in the polar organic solvent of lixiviate carried out preferably, preferably solvent is a kind of in methyl alcohol, acetone, acetonitrile or ethanol; The envelope-bulk to weight ratio of polar organic solvent and filter cake is (5～10): 1.
The present invention is to step 3) in the volumetric concentration of aqueous solutions of organic solvent carried out preferably, preferably the volumetric concentration with tap water adjusting aqueous solutions of organic solvent is 60～70%.
The present invention is to step 4) in the non-polar organic solvent that adds carried out preferably, preferred any in sherwood oil, heptane or normal hexane, its consumption is equivalent to 0.5～1.5 times of orlistat intermediate aqueous organic solvent solution volume.
The present invention is to step 5) in the polar solvent that adds carried out preferably, being preferably acetonitrile or methyl alcohol; It adds volume and the volume ratio of the front orlistat intermediate nonpolar phase of extraction is (1～3): 1.
The present invention is to step 6) in freezing removal of impurities condition carried out preferably, be preferably cooled to-5～5 ℃, insulation 1～3h, remove by filter insoluble impurity.
Step 7) solvent in is preferably a kind of in sherwood oil, heptane, normal hexane; Tc is-10～-15 ℃.
Step 8) non-polar solvent in is preferably a kind of in normal hexane, heptane, sherwood oil.
Step 9) in, organic solvent is preferably a kind of in methyl alcohol, ethanol or acetonitrile, and in aqueous solutions of organic solvent, the volumetric concentration of organic solvent is 60～80%.
Step 10) non-polar solvent in is preferably a kind of in normal hexane, heptane, sherwood oil; Tc is-5～5 ℃.
Find after deliberation, orlistat intermediate is very easily dissolved in polar organic solvent, also be dissolved in non-polar organic solvent, alternately extraction by two kinds of solvents is used, both removed the polar impurity being mixed in product, also remove some non polar impurities, and then by the polar solvent removal of impurities of lowering the temperature, improved the product content before the crystallization of orlistat intermediate.Afterwards, orlistat intermediate, by decrease temperature crystalline in non-polar solvent, is further removed the low-pole impurity that some extraction processs cannot be eliminated, and orlistat intermediate crystalline content is reached more than 80%.After hydrogenation, utilize the aqueous solution of medium polar solvent to carry out backwash, can remove a large amount of polar impurities.Then adopt non-polar solvent to repeatedly kick into row crystallization to orlistat, can obtain highly purified orlistat product.
Wherein, described underpressure distillation and vacuum-drying are this area common technology means, and unless stated otherwise, vacuum tightness and temperature are not particularly limited.
The present invention compared with prior art has advantages of following outstanding:
1) in technical solution of the present invention, the extraction of product and intermediate, purifying do not need resin column and silicagel column, and operational path is short, easy and simple to handle, reproducible.
2) to have overcome existing explained hereafter cost high in the present invention, complex operation step, and facility investment is large, the defect of inefficiency of production, the orlistat intermediate content that the method is produced is high, and extract yield is more than 80%, there is significant cost and quality-advantage, be applicable to very much industrial-scale production.
3) the present invention is by orlistat intermediate fermented liquid is alternately extracted in polarity, non-polar organic solvent, and in conjunction with crystallization in cooling removal of impurities, non-polar solvent, gained orlistat intermediate product content reaches more than 80%; Hydrogenation and aftertreatment are simple, can obtain content more than 99%, maximum single assorted orlistat of 0.1% that is not more than.
4) adopt technique of the present invention to prepare orlistat intermediate, facility investment is few, and yield is high, and solvent for use is recyclable applying mechanically all, low in the pollution of the environment, meets the requirement of cleaner production.
Embodiment
For better explanation the present invention, by embodiment, set forth, but therefore do not limit the present invention in described embodiment.In the embodiment of the present invention, other unexposed item, is prior art.
Embodiment 1
1) fermentation liquor pretreatment: to 1.5m
3in fermented liquid (fermentation unit 8.5g/L), add 45kg diatomite, with hydrochloric acid, adjusting pH is 4.5, stirs 1h, and filter press is collected filter cake 360kg;
2) lixiviate: use 2.88m
3industrial acetone is to step 1) filter cake that obtains carries out lixiviate, and lixiviate 3h, filters, must be containing the transparent filtrate 3.2m of clarification, incarnadine of orlistat intermediate
3;
3) concentrated, tune solvent volume concentration: by step 2) gained orlistat intermediate acetone soln carries out concentrating under reduced pressure with falling-film evaporator, at 30 ℃ of temperature, be concentrated into product concentration 20g/L, the volumetric concentration that adds 150L tap water adjusting aqueous acetone solution is 65%;
4) non-polar solvent extraction: to step 3), in the acetone/water solution of deployed orlistat intermediate, add 480L sherwood oil, stir 60min, extraction, after standing 2h, phase in collection, obtains the petroleum ether solution 520L containing orlistat intermediate;
5) petroleum ether solution of the orlistat intermediate that concentrated, polar solvent extract: by step 4), phase-splitting obtains concentrates with scraper evaporator, under temperature 50 C, while being evaporated to concentration 200g/L, add 60L acetonitrile, stir 30min extraction, after standing 1h, collect lower phase, obtain the acetonitrile phase solution 70L of orlistat intermediate;
6) freezing removal of impurities: to crystallization kettle, chuck passes into-10 ℃ of chilled water cooling stir process by the acetonitrile phase transition containing orlistat intermediate, when temperature is down to 0 ℃, insulation 1h, filtering and impurity removing, obtains orlistat intermediate filtrate.
7) intermediate crystallization: concentrating under reduced pressure orlistat intermediate filtrate, to dry, obtains incarnadine orlistat intermediate oily matter.Oily matter is dissolved completely with 210L sherwood oil, and to be diluted to orlistat intermediate concentration be 50g/L, the stirred crystallization of lowering the temperature ,-15 ℃ of filtrations, obtain white orlistat intermediate crystal.Through HPLC, detect, crystallization rear center body content is 84.3%, and purity is 95.2%, and extracting total recovery is 83.2%.
8) hydrogenation: orlistat intermediate crystallization crystal all dissolves with 200L sherwood oil, and compound concentration is 50g/L, adds 1kg palladium charcoal to carry out hydrogenation, and 40 ℃ of temperature, pressure 0.5MPa, after reaction 5h, remove by filter palladium charcoal, obtain hydride 210L.
9) backwash: to the methanol aqueous solution 420L that adds 70% in hydride, stir 30min, after standing 30min, phase-splitting, collects to obtain sherwood oil phase 201L.
10) crystallization and recrystallization: the petroleum ether solution that is 48g/L by orlistat concentration under whipped state, decrease temperature crystalline ,-1 ℃ of filtration, and by cold petroleum ether, obtain orlistat crystal.Repeat above-mentioned steps, sherwood oil recrystallization 3 times, finally white orlistat crystal.30 ℃ of vacuum-dryings, detect through HPLC, and orlistat content is 99.1%, and it is 0.1% that maximum is singly mixed, and purity is 99.3%.As calculated, total recovery is 41.7%.
Embodiment 2
1) fermentation liquor pretreatment: to 1.45m
3in fermented liquid (fermentation unit 9.2g/L), add 70kg perlite, with oxalic acid, adjusting pH is 4.7, stirs 2h, and filter press is collected filter cake 350kg;
2) lixiviate: use 3.5m
3industrial methanol is to step 1) gained filter cake carries out lixiviate, lixiviate 5h, filter press, must be containing clarification, the incarnadine clear solution 4m of orlistat intermediate
3;
3) concentrated, tune solvent volume concentration: by step 2) gained orlistat intermediate methanol solution carries out concentrating under reduced pressure with falling-film evaporator, at temperature is controlled 30 ℃, be concentrated into product concentration 20g/L, the volumetric concentration that adds 170L tap water adjusting methanol aqueous solution is 62%;
4) non-polar solvent extraction: in the methanol/water solution of orlistat intermediate, add 670L heptane, stir 60min, extraction, after standing 2h, phase in collection, obtains the n-heptane solution 730L containing orlistat intermediate;
5) concentrated, polar solvent extract: with the scraper evaporator enrichment step 4) n-heptane solution of the orlistat intermediate that extracts, under temperature 50 C, while being evaporated to concentration 150g/L, add 160L acetonitrile, stir 30min extraction, phase-splitting after standing 1h, collects lower phase, obtains the acetonitrile solution 175L of orlistat intermediate;
6) freezing removal of impurities, concentrated: to crystallization kettle, chuck passes into-10 ℃ of chilled water cooling stir process by the acetonitrile phase transition containing orlistat intermediate, when temperature is down to-5 ℃, insulation 2h, filtering and impurity removing, obtains orlistat intermediate filtrate.
7) crystallization: concentrating under reduced pressure orlistat intermediate filtrate, to dry, obtains incarnadine orlistat intermediate oily matter.Oily matter is dissolved completely with 140L heptane, and release to orlistat intermediate concentration be 80g/L, the stirred crystallization of lowering the temperature ,-13 ℃ of filtrations, obtain white orlistat intermediate crystal.Through HPLC, detect, crystallization rear center body content is 85.3%, and purity is 96.5%, and extracting total recovery is 85.1%.
8) hydrogenation: orlistat intermediate crystallization crystal all dissolves with 130L heptane, and compound concentration is 80g/L, adds 0.9kg palladium charcoal to carry out hydrogenation, and 40 ℃ of temperature, pressure 0.35MPa, after reaction 5h, remove by filter palladium charcoal, obtain hydride 135L.
9) backwash: to the aqueous ethanolic solution 270L that adds 65% in hydride, stir 30min, after standing 30min, phase-splitting, collects to obtain heptane phase 139L.
10) crystallization and recrystallization: the heptane that is 75g/L by orlistat concentration is diluted to concentration 30g/L with heptane, under whipped state, decrease temperature crystalline ,-3 ℃ of filtrations, and by cold heptane wash, obtain orlistat crystal.Repeat above-mentioned steps, heptane recrystallization 3 times, finally white orlistat crystal.30 ℃ of vacuum-dryings, detect through HPLC, and orlistat content is 99.3%, and it is 0.080% that maximum is singly mixed, and purity is 99.3%.
As calculated, total recovery is 42.8%.
Embodiment 3
1) fermentation liquor pretreatment: to 1.5m
3in fermented liquid (fermentation unit 8.8g/L), add 60kg magnesium oxide, with oxalic acid, adjusting pH is 5.0, stirs 3h, filters, and collects filter cake 375kg;
2) lixiviate: use 1.88m
3industrial alcohol is to step 1) in filter gained filter cake and carry out lixiviate, lixiviate 3h, filter press, must be containing clarification, the incarnadine clear solution 2.1m of orlistat intermediate
3;
3) concentrated, adjust solvent volume concentration: with falling-film evaporator by step 2) gained orlistat intermediate ethanolic soln carries out concentrating under reduced pressure, at 30 ℃ of temperature, be concentrated into product concentration 25g/L, the volumetric concentration that adds 200L tap water adjusting aqueous ethanolic solution is 67%;
4) non-polar solvent extraction: add 840L normal hexane in the ethanol/water solution of orlistat intermediate, stir 60min extraction, after standing 2h, phase in collection, obtains the hexane solution 900L containing orlistat intermediate;
5) concentrated, polar solvent extract: the hexane solution with the concentrated orlistat intermediate of scraper evaporator, while being evaporated to concentration 100g/L under temperature 50 C, adds 250L methyl alcohol, stir 30min extraction, phase-splitting after 1h, collects lower phase, obtains the methanol solution 290L of orlistat intermediate;
6) freezing, filtration, concentrated: to crystallization kettle, chuck passes into-10 ℃ of chilled waters cooling stir process by the methyl alcohol phase transition containing orlistat intermediate, when temperature is down to-5 ℃, insulation 1h, filtering and impurity removing, obtains orlistat intermediate filtrate.
7) crystallization: concentrating under reduced pressure orlistat intermediate filtrate, to dry, obtains incarnadine orlistat intermediate oily matter.Oily matter is dissolved completely with 100L normal hexane, and to be diluted to orlistat intermediate concentration be 100g/L, the stirred crystallization of lowering the temperature ,-13 ℃ of filtrations, obtain white orlistat intermediate crystal.Through HPLC, detect, crystallization rear center body content is 84.4%, and purity is 95.6%, and extracting total recovery is 82.5%.
8) hydrogenation: orlistat intermediate crystallization crystal all dissolves with 88L normal hexane, and compound concentration is 100g/L, adds 1kg palladium charcoal to carry out hydrogenation, and 40 ℃ of temperature, pressure 0.4MPa, after reaction 5h, remove by filter palladium charcoal, obtain hydride 95L.
9) backwash: to the acetonitrile solution 190L that adds 75% in hydride, stir 30min, after standing 30min, phase-splitting, collects to obtain normal hexane phase 98L.
10) crystallization and recrystallization: the normal hexane that is 95g/L by orlistat concentration is diluted to 60g/L with normal hexane, under whipped state, decrease temperature crystalline, 0 ℃ of filtration, and with cold normal hexane washing, obtain orlistat crystal.With heptane, replace normal hexane to repeat above-mentioned steps, recrystallization 4 times, finally white orlistat crystal.30 ℃ of vacuum-dryings, detect through HPLC, and orlistat content is 99.1%, and it is 0.085% that maximum is singly mixed, and purity is 99.3%.As calculated, total recovery is 40%.
Claims (10)
1. a preparation method for orlistat, specifically comprises the following steps:
1) fermentation liquor pretreatment:
In fermented liquid, add flocculating aids, with acid, adjust pH4.0-5.0, stir, filter, obtain filter cake;
2) lixiviate:
By step 1) in gained filter cake with polar solvent, carry out lixiviate, stir, filter, must be containing the solution of orlistat intermediate;
3) concentrated, tune solvent volume concentration:
By step 2) in filter gained orlistat midbody solution to be concentrated into orlistat intermediate concentration be 15～30g/L, with tap water, regulating the volumetric concentration of aqueous solutions of organic solvent is 50～80%;
4) non-polar solvent extraction:
To step 3) in add with the immiscible non-polar solvent of system in gained orlistat intermediate aqueous organic solvent solution and extract, phase-splitting obtains the nonpolar extraction liquid containing orlistat intermediate;
5) concentrated, polar solvent extract:
By step 4) the nonpolar extraction solution of extraction gained orlistat intermediate, being concentrated into concentration is 100～200g/L, adds polar solvent extract, phase-splitting obtains the polarity extraction solution of orlistat intermediate;
6) freezing removal of impurities:
By step 5) the polarity extraction liquid of gained orlistat intermediate stirs, and is cooled to below 5 ℃, and insulation, then removes by filter insoluble impurities, obtains the clear filtrate of orlistat intermediate, is concentrated into dryly, obtains orlistat intermediate oily matter;
7) crystallization:
With solvent by step 6) gained orlistat intermediate oily matter dilutes, making concentration is 50～100g/L, adopts falling temperature method, stirring and crystallizing, filters to obtain orlistat intermediate white crystal;
8) hydrogenation:
By step 7) with non-polar solvent, to be dissolved into concentration be 10-80g/L to crystallization orlistat intermediate crystal, the palladium charcoal that adds product weight 5～10%, pass into hydrogen and react under 30～40 ℃ of temperature, pressure 0.3～1Mpa, after hydrogenation finishes, filter to obtain hydride;
9) backwash:
To the aqueous solutions of organic solvent that adds 2 times of volumes, middle grade in hydride, stir, standing, phase-splitting, phase in collection;
10) crystallization:
It is 30～50g/L that phase solution on gained after orlistat backwash is diluted to concentration with non-polar solvent, adopts falling temperature method to carry out stirred crystallization, obtains orlistat crystal after filtration.
2. a kind of preparation method of orlistat according to claim 1, it is characterized in that, step 1) described flocculating aids is any in diatomite, perlite, Mierocrystalline cellulose, Graphite Powder 99, sawdust, magnesium oxide, gypsum, gac, acidic white earth, and add-on is 3～10% of fermented liquid weight; Described acid is a kind of in hydrochloric acid, oxalic acid, acetic acid, sulfuric acid.
3. the preparation method of a kind of orlistat according to claim 1, is characterized in that step 2) in the polar organic solvent of lixiviate be a kind of in methyl alcohol, acetone, acetonitrile or ethanol; The envelope-bulk to weight ratio of polar organic solvent and filter cake is (5～10): 1; Step 3) in, with tap water, regulating the volumetric concentration of aqueous solutions of organic solvent is 60～70%.
4. the preparation method of a kind of orlistat according to claim 1, it is characterized in that, step 4) non-polar organic solvent adding in is any in sherwood oil, heptane or normal hexane, and its consumption is equivalent to 0.5～1.5 times of orlistat intermediate aqueous organic solvent solution volume; Step 5) polar extraction solvent in is a kind of in acetonitrile or methyl alcohol, and it adds the volume ratio of orlistat intermediate nonpolar phase before volume and extraction is (1～3): 1.
5. the preparation method of a kind of orlistat according to claim 1, is characterized in that step 6) in be cooled to-5～5 ℃ during freezing removal of impurities, insulation 1～3h, removes by filter insoluble impurity; Step 7) in, solvent is a kind of in sherwood oil, heptane, normal hexane, and Tc is-10～-15 ℃.
6. the preparation method of a kind of orlistat according to claim 1, is characterized in that step 8) in non-polar solvent be a kind of in normal hexane, heptane, sherwood oil.
7. according to the preparation method of a kind of orlistat described in the arbitrary claim of claim 1-6, it is characterized in that step 9) in organic solvent be a kind of in the aqueous solution of methyl alcohol, ethanol or acetonitrile.
8. according to the preparation method of a kind of orlistat described in the arbitrary claim of claim 1-6, it is characterized in that step 9) in aqueous solutions of organic solvent in the volumetric concentration of organic solvent be 60～80%.
9. according to the preparation method of a kind of orlistat described in the arbitrary claim of claim 1-6, it is characterized in that step 10) in non-polar solvent be a kind of in normal hexane, heptane, sherwood oil.
10. according to the preparation method of a kind of orlistat described in the arbitrary claim of claim 1-6, it is characterized in that step 10) in Tc be-5～5 ℃.
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| CN107266395A (en) * | 2017-08-08 | 2017-10-20 | 中山万远新药研发有限公司 | A kind of preparation method of the crystal formation of orlistat I |
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| CN103992296B (en) | 2015-08-05 |
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