CN103012396A - Transfer method for isomers of palonosetron hydrochloride - Google Patents
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Abstract
The invention provides a transfer method for isomers of palonosetron hydrochloride. The method comprises the following steps of: carrying out primary refining on a crude product of the palonosetron hydrochloride, dissolving recycled solids, and carrying out hydrogen pressure displacement, nitrogen pressure displacement, impurity removing and recrystallization on the dissolved recycled solids, thus obtaining the high-purity palonosetron hydrochloride. According to the transfer method, the inactive isomers of the palonosetron hydrochloride can be transferred into active isomers, so that the waste is avoided, the yield of the active isomers is improved, and the recycling is implemented. The method is suitable for industrial application.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, be specifically related to a kind of conversion process of antiemetic PalonosetronHydrochloride isomer.
Background technology
PalonosetronHydrochloride, chemistry 2-[1-azabicyclo [2,2,2] suffering by name-3S-yl]-2,3,3aS, 4,5,6-, six hydrogen-1H-benzo [de] isoquinoline-1-ketone hydrochloride, structural formula is suc as formula shown in the I.PalonosetronHydrochloride is the stronger 5-HT3 selective receptor antagonist of affinity, developed by Switzerland Hellsin company, went on the market in the U.S. in 2003, now more than ten country's listings in the whole world, acute or the retardance that is used for preventing and treat chemotherapy to cause is felt sick, is vomitted, and also is used for preventing and treating postoperative nausea, vomiting.
Can find out from the structural formula of PalonosetronHydrochloride, it has two chiral centres, i.e. four optical isomer: S.S, S.R, R.R, R.S type isomer, and wherein S.S type isomer has biological effect; Other three isomer non-activities.In order to guarantee that isomer quantity is minimum in the finished product, present existing technique all can use chiral raw material, just only has a kind of non-activity isomer in the product for preparing like this, i.e. R.S type isomer.Prior art (such as US7737280, US8093391) generally can adopt the repeatedly recrystallization such as alcoholic solvent or toluene in order to remove this isomer, has greatly affected the yield of product, and R.S type isomer is removed to discard also cause significant wastage.Not open R.S type non-activity isomer with PalonosetronHydrochloride is converted into the method for active S.S type isomer in the prior art.
CN101157691A (CN200710156229.4) discloses a kind of new production technique of highly purified PalonosetronHydrochloride.Upper silica gel column chromatography behind the PalonosetronHydrochloride dissolving crude product that will be synthetic behind wash-out repeatedly, is collected target components, and target components obtains the PalonosetronHydrochloride finished product through recrystallization.The Instructions Page 1-2 background technology of this patent document has partly been put down in writing three kinds of synthesis techniques of PalonosetronHydrochloride, pass course 1, route 2, the route 3 synthetic crude products that obtain PalonosetronHydrochloride, the application quotes the full text of this patent document as prior art.
Summary of the invention
For the deficiency that prior art exists, the present invention aims to provide a kind of method for transformation of PalonosetronHydrochloride isomer, the PalonosetronHydrochloride R.S type isomer of non-activity is changed into the PalonosetronHydrochloride S.S type isomer of biologic activity.
Technical scheme of the present invention is as follows:
A kind of PalonosetronHydrochloride R.S type isomer transfers the method for S.S type isomer to, may further comprise the steps:
(1) gets the PalonosetronHydrochloride crude product and put into reaction flask through the recovery solid of mother liquor behind the primary purification, add the dissolving of entry or alcohol solution, add palladium carbon or palladium hydroxide catalyzer, open and stir, after with hydrogen the reaction flask Air fully being replaced, be forced into 0.05-1.5MPa, stirring at room reaction 1-50h; Get reaction solution;
(2) fully replace hydrogen in the above-mentioned reaction flask with nitrogen or argon gas after, with Temperature Setting at 0-80 ℃, again with nitrogen or argon pressurization to 0.05-1.5MPa, continue the reaction solution in the whipping step (1), be down to 50% when following until detect the non-activity content of isomer with high performance liquid chromatography (HPLC), be considered as conversion and finish.
In the above-mentioned method for transformation, further comprising the steps of:
(3) reaction flask that transforms the reaction solution finish to above-mentioned steps (2) passes into hydrogen, and fully then nitrogen or the argon gas in the replacement(metathesis)reaction bottle be forced into 0.05-1.5MPa, and stirring reaction 40 ~ 80h in 0-80 ℃ of scope is to reacting completely;
(4) with step (3) gained reaction solution suction filtration, evaporated under reduced pressure filtrate; Solid behind the evaporate to dryness is used the alcoholic solvent agitator treating again, suction filtration, oven dry filter cake;
(5) filter cake that obtains of step (4) dissolves with alcoholic solvent, and heated and stirred is back to solids and all dissolves, and drips the less the second solvent of polarity under reflux state, dropwises stopped heating, suction filtration, oven dry filter cake;
(6) filter cake that obtains of step (5) is with alcohol or alcohol solution dissolving, and heated and stirred is back to solid and all dissolves, suction filtration while hot, and filtrate naturally cools to room temperature, suction filtration, filtration cakes torrefaction gets PalonosetronHydrochloride active isomer S.S type isomer.
Non-activity R.S type content of isomer can transform greater than the active S.S type of active PalonosetronHydrochloride content of isomer in the recovery solid of the described PalonosetronHydrochloride crude product of step of the present invention (1) primary purification mother liquor.Preferably, PalonosetronHydrochloride non-activity R.S type content of isomer further is preferably greater than 90% greater than 80% in the recovery solid of the described PalonosetronHydrochloride crude product of step (1) primary purification mother liquor.
Alcohol has no special requirements with the volume ratio of water in the alcohol solution described in the step (1), as long as can dissolved solids.Alcohol in the preferred alcohols aqueous solution of the present invention: the volume ratio of water (v/v) is 1 ~ 4:1; Described alcohol is selected from ethanol, methyl alcohol, Virahol etc., preferred alcohol.
Preferred according to the present invention, the described palladium carbon of step (1) is 10% palladium carbon (English name: Palladium10%on Carbon, CAS number: 7440-05-3); Described palladium hydroxide is 10% palladium hydroxide; 10% content that all refers to palladium wherein, mass ratio, this routine that belongs to this area represents.As well known to those skilled in the art, palladium carbon and palladium hydroxide be easily spontaneous combustion in air, and for fear of burning, according to the general knowledge of this area, the technician often adds palladium carbon or palladium hydroxide in the reaction after with wet with solvent again.
Preferred according to the present invention, the consumption of the described palladium carbon of step (1) or palladium hydroxide is 0.01-0.5 times of solid material, and preferred 0.05-0.1 doubly.
Preferred according to the present invention, the described reaction times of step (1) is 5-40h; Further preferred 10-24h.
Preferred according to the present invention, fully being replaced into described in step (1), (2), (3) replaced 6 ~ 8 times.
Preferred according to the present invention, Temperature Setting is 40-70 ℃ in the step (2), more preferably 55-65 ℃.
Preferred according to the present invention, the described temperature of reaction of step (3) is 10-45 ℃, more preferably 20-30 ℃.
Preferred according to the present invention, the volume mass of the solid after the consumption of the described alcoholic solvent of step (4) and the evaporate to dryness filtrate is than being 1-10:1, Unit/mL/g, and further preferred alcohols solvent and the volume mass of solid are than being 2-5:1, Unit/mL/g; Described alcoholic solvent is selected from ethanol, methyl alcohol, Virahol etc., preferred alcohol.
Preferred according to the present invention, the alcoholic solvent described in the step (5) is selected from methyl alcohol, ethanol or Virahol etc., particular methanol; The volume mass of this alcoholic solvent and filter cake is than 4-10:1, Unit/mL/g;
Preferred according to the present invention, the second solvent that the polarity described in the step (5) is less is ethyl acetate, toluene, acetone, normal hexane etc., ethyl acetate; The second solvent load that described polarity is less be the alcoholic solvent amount the 4-10 volume doubly.
Preferred according to the present invention, the described alcohol of step (6) is selected from methyl alcohol, ethanol or Virahol, preferred alcohol; Alcohol in the described alcohol solution: the volume ratio of water (v/v) is 40 ~ 60:1, preferred 50:1.
The preparation of the raw material PalonosetronHydrochloride crude product described in the present invention is by prior art, for example can adopt J.Med.Chem.1993,36, the disclosed method of 2645-2657, the primary purification of PalonosetronHydrochloride crude product can adopt disclosed method in the prior art, for example can adopt the US7737280 embodiment 10 disclosed process for purification first time (Fisrt Crystallization) to carry out, and also can adopt J.Med.Chem.1993, the disclosed method of 36,2645-2657.
Because above-mentioned conversion process is a balanced reaction process, so drop to 50% when following when the non-activity content of isomer, this reaction has just reached balance, just can be considered as conversion and finish.Proceed step (3) and can remove impurity, and then carry out aftertreatment.For remaining isomer is continued to transform, after step (4) agitator treating step was finished, suction filtration gained filtrate can add in next batch the conversion reaction, proceeds to transform, so circulation, thus realize the industrial applications that the PalonosetronHydrochloride isomer transforms.
Behind the recovery dissolution of solid of the present invention after with PalonosetronHydrochloride crude product primary purification through pressurized with hydrogen displacement, nitrogen pressurized displacement, again remove impurity, carry out recrystallization and obtain the high purity hydrochloric acid Palonosetron.R.S type non-activity isomer is turned waste into wealth in the present invention, changes into PalonosetronHydrochloride S.S type active isomer, has greatly avoided waste.The yield of conversion process gained PalonosetronHydrochloride active isomer of the present invention is about 25%, and purity is more than 99.9%.But technique iterative cycles of the present invention is very suitable for industrial applications.
Those skilled in the art can learn apparently that by reading this method this conversion process also is applicable to PalonosetronHydrochloride S.S type isomer and transforms to R.S type isomer, and the mutual conversion between S.R and the R.R type isomer.
Embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples, but this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1
PalonosetronHydrochloride crude product 1000g pulls an oar with dehydrated alcohol, fully washs 2 times, and the each consumption of dehydrated alcohol is 2000mL, filters, and the solid that leaches is the PalonosetronHydrochloride product; Merging filtrate, evaporated under reduced pressure obtain solid 500g, are the recovery solid of mother liquor behind the PalonosetronHydrochloride crude product primary purification.
Embodiment 2
(1) recovery solid (can prepare by the embodiment 1) 500.0g that gets mother liquor behind the PalonosetronHydrochloride crude product primary purification adds in the 5L single port bottle, puts into magneton, adds 1000mL aqueous ethanolic solution (ethanol/water volume ratio=2:1); Take by weighing 50.0g10% palladium carbon (catalyzer), be transferred in the above-mentioned single port bottle after with the aqueous ethanolic solution of 700mL equal volume ratio that it is wetting, fix reaction unit, open induction stirring, behind hydrogen exchange 6-8 time, be forced into 0.05-0.20MPa, stirring at room reaction 15-24h;
(2) with behind the hydrogen in the above-mentioned reaction flask of nitrogen replacement 6-8 time, open heating, after temperature is increased to 30-40 ℃, again nitrogen is forced into 0.50-0.80MPa, the reaction solution that keeps this temperature whipping step (1) to obtain, be down to 50% when following until detect the non-activity content of isomer with HPLC, be considered as conversion and finish;
(3) transform the reaction solution of finishing in the step (2), behind the nitrogen in the abundant replacement(metathesis)reaction bottle of hydrogen 6-8 time, be forced into 0.05-0.20MPa, at 50 ℃ of stirring reaction 40-50h;
(4) with behind step (3) the gained reaction solution suction filtration removal catalyzer, evaporated under reduced pressure filtrate; Solid transfer behind the evaporate to dryness adds dehydrated alcohol (dehydrated alcohol: solid volume mass ratio 3:1, mL/g) agitator treating to 3L single port bottle, suction filtration, oven dry filter cake;
(5) filter cake that obtains of step (4) moves in the 10L three-necked bottle, (anhydrous methanol compares 6:1 with the volume mass of filter cake with the anhydrous methanol dissolving, Unit/mL/g), heated and stirred is back to solids and all dissolves, and drips the ethyl acetate of 8 volumes times anhydrous methanol amount under reflux state, after complete, stopped heating stirs, and naturally is cooled to 40 ~ 50 ℃, suction filtration, the oven dry filter cake;
(6) filter cake that obtains of step (5) moves in the 10L three-necked bottle, be the aqueous ethanolic solution dissolving of 50:1 with volume ratio (v/v), heated and stirred is back to solid and all dissolves, suction filtration while hot, after filtrate naturally cools to room temperature, suction filtration, filter cake vacuum-drying gets PalonosetronHydrochloride active isomer 128.0g.Yield is 25.6%, and purity is 99.9%.
Embodiment 3
(1) gets that the recovery solid 500.0g of mother liquor adds in the 5L single port bottle behind the PalonosetronHydrochloride crude product primary purification that embodiment 1 obtains, put into magneton, add 1000mL methanol aqueous solution (methanol/water volume ratio=4:1); Take by weighing 25.0g10% palladium carbon (catalyzer), be transferred in the above-mentioned single port bottle after with the methanol aqueous solution of 500mL equal volume ratio that it is wetting, fix reaction unit, open induction stirring, behind hydrogen exchange 6-8 time, be forced into 0.40-0.60MPa, stirring at room 10-15h;
(2) with behind the hydrogen in nitrogen replacement step (1) reaction flask 6-8 time, open heating, after temperature is increased to 20-30 ℃, again nitrogen is forced into 1.0-1.5MPa, the reaction solution that keeps this temperature whipping step (1) to obtain, be down to 50% when following until detect the non-activity content of isomer with HPLC, be considered as conversion and finish;
(3) transform in the step (2) reaction solution finished with the nitrogen in the abundant replacement(metathesis)reaction bottle of hydrogen 6-8 time after, be forced into 0.10-0.20MPa, at 60 ℃ of stirring reaction 50-60h;
(4) with behind step (3) the gained reaction solution suction filtration removal catalyzer, evaporated under reduced pressure filtrate; Solid transfer behind the evaporate to dryness adds dehydrated alcohol (dehydrated alcohol: solid volume mass ratio 2:1, mL/g) agitator treating to 3L single port bottle, suction filtration, oven dry filter cake;
(5) filter cake that obtains of step (4) moves in the 10L three-necked bottle, (anhydrous methanol: the filter cake volume mass compares 7:1 with the anhydrous methanol dissolving, mL/g), heated and stirred is back to solid and all dissolves, and drips the ethyl acetate of 6 volumes times anhydrous methanol amount under reflux state, after complete, stopped heating stirs, and naturally is cooled to 35 ~ 45 ℃, suction filtration, the oven dry filter cake;
(6) filter cake that obtains of step (5) moves in the 10L three-necked bottle, be the aqueous ethanolic solution dissolving of 40:1 with volume ratio (v/v), heated and stirred is back to solid and all dissolves, suction filtration while hot, after filtrate naturally cools to room temperature, suction filtration, filter cake vacuum-drying gets PalonosetronHydrochloride active isomer 120.5g.Yield is 24.1%, and purity is 99.9%.
Embodiment 4
(1) gets the solid 250.0g that embodiment 1 obtains and add in the 3L single port bottle, put into magneton, add 600mL aqueous ethanolic solution (ethanol/water volume ratio=3:1); Take by weighing 12.0g10% palladium hydroxide (catalyzer), be transferred in the above-mentioned single port bottle after with the aqueous ethanolic solution of 300mL equal volume ratio that it is wetting, fix reaction unit, open induction stirring, behind hydrogen exchange 6-8 time, be forced into 0.20-0.40MPa, stirring at room 40-50h;
(2) reaction solution in the step (1) with the hydrogen in nitrogen replacement reaction flask 6-8 time after, open heating, after temperature is increased to 25-35 ℃, again nitrogen is forced into 0.5-1.0MPa, keep this temperature to stir, be down to 50% when following until detect the non-activity content of isomer with HPLC, be considered as transforming complete;
(3) transform in the step (2) completely reaction solution with the nitrogen in the abundant replacement(metathesis)reaction bottle of hydrogen 6-8 time after, be forced into 0.5-0.8MPa, at 40 ℃ of stirring reaction 60-70h;
(4) with behind step (3) the gained reaction solution suction filtration removal catalyzer, evaporated under reduced pressure filtrate; Solid transfer behind the evaporate to dryness adds anhydrous methanol (anhydrous methanol: solid volume mass ratio 2:1, mL/g) agitator treating to 3L single port bottle, suction filtration, oven dry filter cake;
(5) filter cake that obtains of step (4) moves in the 5L three-necked bottle, (anhydrous methanol: the filter cake volume mass compares 8:1 with the anhydrous methanol dissolving, mL/g), heated and stirred is back to solid and all dissolves, and drips the acetone of 5 times of anhydrous methanol amounts under reflux state, after complete, stopped heating stirs, and naturally is cooled to 30 ~ 35 ℃, suction filtration, the oven dry filter cake;
(6) filter cake that obtains of step (5) moves in the 5L three-necked bottle, be the isopropanol water solution dissolving of 40:1 with volume ratio (v/v), heated and stirred is back to solid and all dissolves, suction filtration while hot, after filtrate naturally cools to room temperature, suction filtration, filter cake vacuum-drying gets PalonosetronHydrochloride active isomer 61.3g.Yield is 24.5%, and purity is 99.9%.
Embodiment 5
(1) gets the solid 250.0g that embodiment 1 obtains and add in the 3L single port bottle, put into magneton, add 500mL isopropanol water solution (isopropanol/water volume ratio=1:1); Take by weighing 12.0g10% palladium carbon (catalyzer), be transferred in the above-mentioned single port bottle after with the isopropanol water solution of 300mL equal volume ratio that it is wetting, fix reaction unit, open induction stirring, behind hydrogen exchange 6-8 time, be forced into 0.6-1.0MPa, stirring at room 1-15h;
(2) reaction solution in the step (1) with the hydrogen in nitrogen replacement reaction flask 6-8 time after, open heating, after temperature is increased to 60-80 ℃, again nitrogen is forced into 0.05-0.20MPa, keep this temperature to stir, be down to 50% when following until detect the non-activity content of isomer with HPLC, be considered as conversion and finish;
(3) transform in the step (2) reaction solution finished with the nitrogen in the abundant replacement(metathesis)reaction bottle of hydrogen 6-8 time after, be forced into 0.6-1.0MPa, at 20 ℃ of stirring reaction 70-80h;
(4) with behind step (3) the gained reaction solution suction filtration removal catalyzer, evaporated under reduced pressure filtrate; Solid transfer behind the evaporate to dryness adds dehydrated alcohol (dehydrated alcohol: solid volume mass ratio 3:1, mL/g) agitator treating to 3L single port bottle, suction filtration, oven dry filter cake;
(5) filter cake that obtains of step (4) moves in the 5L three-necked bottle, (anhydrous methanol: the filter cake volume mass compares 6:1 with the anhydrous methanol dissolving, mL/g), heated and stirred is back to solid and all dissolves, and drips the toluene of 8 times of anhydrous methanol amounts under reflux state, after complete, stopped heating stirs, and naturally is cooled to 40 ~ 45 ℃, suction filtration, the oven dry filter cake;
(6) filter cake that obtains of step (5) moves in the 5L three-necked bottle, be the aqueous ethanolic solution dissolving of 50:1 with volume ratio (v/v), heated and stirred is back to solid and all dissolves, suction filtration while hot, after filtrate naturally cools to room temperature, suction filtration, filter cake vacuum-drying gets PalonosetronHydrochloride active isomer 65.4g.Yield is 26.2, and purity is 99.9%.
Embodiment 6
(1) gets the solid 500.0g that embodiment 1 obtains and add in the 5L single port bottle, put into magneton, add the 1200mL purified water; Take by weighing 25.0g10% palladium carbon (catalyzer), be transferred in the above-mentioned single port bottle after with the 500mL purification of aqueous solutions that it is wetting, fix reaction unit, open induction stirring, behind hydrogen exchange 6-8 time, be forced into 0.08-0.20MPa, stirring at room 30-40h;
(2) reaction solution in the step (1) with the hydrogen in nitrogen replacement reaction flask 6-8 time after, open heating, after temperature is increased to 20-30 ℃, again nitrogen is forced into 0.6-1.0MPa, keep this temperature to stir, be down to 50% when following until detect the non-activity content of isomer with HPLC, be considered as conversion and finish;
(3) transform in the step (2) reaction solution finished with the nitrogen in the abundant replacement(metathesis)reaction bottle of hydrogen 6-8 time after, be forced into 0.10-0.15MPa, at 10 ℃ of stirring reaction 50-60h;
(4) with behind step (3) the gained reaction solution suction filtration removal catalyzer, evaporated under reduced pressure filtrate; Solid transfer behind the evaporate to dryness adds dehydrated alcohol (dehydrated alcohol: solid volume mass ratio 2:1, mL/g) agitator treating to 3L single port bottle, suction filtration, oven dry filter cake;
(5) filter cake that obtains of step (4) moves in the 10L three-necked bottle, (anhydrous methanol: the filter cake volume mass compares 6:1 with the anhydrous methanol dissolving, mL/g), heated and stirred is back to solid and all dissolves, and drips the ethyl acetate of 7 times of anhydrous methanol amounts under reflux state, after complete, stopped heating stirs, and naturally is cooled to 55 ~ 65 ℃, suction filtration, the oven dry filter cake;
(6) filter cake that obtains of step (5) moves in the 10L three-necked bottle, and with the anhydrous methanol dissolving, heated and stirred is back to solid and all dissolves, suction filtration while hot, after filtrate naturally cools to room temperature, suction filtration, filter cake vacuum-drying gets PalonosetronHydrochloride active isomer 130.5g.Yield is 26.1%, and purity is 99.9%.
Claims (10)
1. a PalonosetronHydrochloride R.S type isomer transfers the method for S.S type isomer to, may further comprise the steps:
(1) gets the PalonosetronHydrochloride crude product through the recovery solid of mother liquor behind the primary purification, put into reaction flask, add the dissolving of entry or alcohol solution, add palladium carbon or palladium hydroxide catalyzer, open and stir, after with hydrogen the reaction flask Air fully being replaced, be forced into 0.05-1.5MPa, stirring at room reaction 1-50h; Get reaction solution;
(2) fully replace hydrogen in the above-mentioned reaction flask with nitrogen or argon gas after, with Temperature Setting at 0-80 ℃, again with nitrogen or argon pressurization to 0.05-1.5MPa, continue the reaction solution in the whipping step (1), be down to 50% when following until detect the non-activity content of isomer with high performance liquid chromatography (HPLC), be considered as conversion and finish.
2. method for transformation according to claim 1 characterized by further comprising following steps:
(3) reaction flask that transforms the reaction solution finish to above-mentioned steps (2) passes into hydrogen, and fully then nitrogen or the argon gas in the replacement(metathesis)reaction bottle be forced into 0.05-1.5MPa, and stirring reaction 40 ~ 80h in 0-80 ℃ of scope is to reacting completely;
(4) with step (3) gained reaction solution suction filtration, evaporated under reduced pressure filtrate; Solid behind the evaporate to dryness is used the alcoholic solvent agitator treating again, suction filtration, oven dry filter cake;
(5) filter cake that obtains of step (4) dissolves with alcoholic solvent, and heated and stirred is back to solids and all dissolves, and drips the less the second solvent of polarity under reflux state, dropwises stopped heating, suction filtration, oven dry filter cake;
(6) filter cake that obtains of step (5) is with alcohol or alcohol solution dissolving, and heated and stirred is back to solid and all dissolves, suction filtration while hot, and filtrate naturally cools to room temperature, suction filtration, filtration cakes torrefaction gets PalonosetronHydrochloride active isomer S.S type isomer.
3. method for transformation according to claim 1 is characterized in that the content of non-activity R.S type isomer in the recovery solid of the described PalonosetronHydrochloride crude product of step (1) primary purification mother liquor is greater than the content of active isomer; Preferred non-activity R.S type content of isomer is greater than 80%; The content of further preferred non-activity R.S type isomer is greater than 90%.
4. method for transformation according to claim 1, it is characterized in that alcohol in the alcohol solution described in the step (1): the volume ratio of water is 1 ~ 4:1; Described alcohol is selected from ethanol, methyl alcohol or Virahol; Preferred alcohol wherein.
5. method for transformation according to claim 1, the consumption that it is characterized in that the described palladium carbon of step (1) or palladium hydroxide be solid material 0.01-0.5 doubly; Wherein preferred 0.05-0.1 doubly; The described reaction times is 5-40h; Further preferred 10-24h.
6. method for transformation according to claim 1 is characterized in that fully being replaced into displacement 6 ~ 8 times described in step (1), (2), (3).
7. method for transformation according to claim 1 is characterized in that Temperature Setting is 40-70 ℃ in the step (2), more preferably 55-65 ℃; The described temperature of reaction of step (3) is 10-45 ℃, more preferably 20-30 ℃.
8. the volume mass of the solid behind the method for transformation according to claim 1, the consumption that it is characterized in that the described alcoholic solvent of step (4) and evaporate to dryness filtrate is than being 1-10:1, Unit/mL/g; Further the preferred alcohols solvent is 2-5:1, Unit/mL/g with the volume mass ratio of solid; Described alcoholic solvent is selected from ethanol, methyl alcohol or Virahol, preferred alcohol.
9. method for transformation according to claim 1 is characterized in that the alcoholic solvent described in the step (5) is selected from methyl alcohol, ethanol or Virahol etc., particular methanol; The volume mass of this alcoholic solvent and filter cake is than 4-10:1, Unit/mL/g;
The second solvent that polarity described in the step (5) is less is ethyl acetate, toluene, acetone or normal hexane, ethyl acetate; The second solvent load that described polarity is less be the alcoholic solvent amount the 4-10 volume doubly.
10. method for transformation according to claim 1 is characterized in that the described alcohol of step (6) is selected from methyl alcohol, ethanol or Virahol, preferred alcohol; Alcohol in the described alcohol solution: the volume ratio of water (v/v) is 40 ~ 60:1, wherein preferred 50:1.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009010987A1 (en) * | 2007-07-19 | 2009-01-22 | Natco Pharma Limited | An improved process for the preparation of pure palonosetron hydrochloride |
| WO2009136405A1 (en) * | 2008-05-05 | 2009-11-12 | Natco Pharma Limited | High purity palonosetron base and its solid state characteristics |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009010987A1 (en) * | 2007-07-19 | 2009-01-22 | Natco Pharma Limited | An improved process for the preparation of pure palonosetron hydrochloride |
| WO2009136405A1 (en) * | 2008-05-05 | 2009-11-12 | Natco Pharma Limited | High purity palonosetron base and its solid state characteristics |
Non-Patent Citations (1)
| Title |
|---|
| BRUCE, A.等: "Hydrogenation of a Chiral 1H-Benz[de]isoquinolin-1-one and an Equilibration Using Palladium Catalyst", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》, vol. 1, no. 2, 1 February 1997 (1997-02-01), pages 117 - 120 * |
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