CN101421227A - Substantially pure o-desmethylvenlafaxine and processes for preparing it - Google Patents
Substantially pure o-desmethylvenlafaxine and processes for preparing it Download PDFInfo
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- CN101421227A CN101421227A CNA2007800133552A CN200780013355A CN101421227A CN 101421227 A CN101421227 A CN 101421227A CN A2007800133552 A CNA2007800133552 A CN A2007800133552A CN 200780013355 A CN200780013355 A CN 200780013355A CN 101421227 A CN101421227 A CN 101421227A
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- 238000000034 method Methods 0.000 title claims abstract description 111
- KYYIDSXMWOZKMP-UHFFFAOYSA-N O-desmethylvenlafaxine Chemical compound C1CCCCC1(O)C(CN(C)C)C1=CC=C(O)C=C1 KYYIDSXMWOZKMP-UHFFFAOYSA-N 0.000 title abstract description 3
- 239000000203 mixture Substances 0.000 claims description 130
- 238000002360 preparation method Methods 0.000 claims description 85
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 56
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 45
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 claims description 42
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 claims description 40
- 229960004688 venlafaxine Drugs 0.000 claims description 39
- 239000012535 impurity Substances 0.000 claims description 38
- 239000003480 eluent Substances 0.000 claims description 34
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 32
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 30
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- 241000629719 Oat dwarf virus Species 0.000 claims description 18
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 16
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 16
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
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- DVVGIUUJYPYENY-UHFFFAOYSA-N 1-methylpyridin-2-one Chemical compound CN1C=CC=CC1=O DVVGIUUJYPYENY-UHFFFAOYSA-N 0.000 claims description 2
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Methods for preparing crystalline forms of O-desmethylvenlafaxine a described.
Description
The cross reference of related application
The application requires the rights and interests of following U.S. Provisional Patent Application: 60/792,801, be filed on April 17th, 2006; 60/796,739, be filed on May 1st, 2006; 60/899,166, be filed on February 1st, 2007; 60/902,418, be filed on February 20th, 2007; 60/872,955, be filed on December 4th, 2006; 60/903,988, be filed on February 27th, 2007.The content of these applications is incorporated this paper by reference into.
Invention field
The present invention relates to pure substantially O-ODV.
Background of invention
Venlafaxine, i.e. (±)-1-[2-(dimethylamino)-1-(4-ethoxyl phenenyl) ethyl] hexalin is first kind in the class antidepressive.The effect of Venlafaxine is the re-uptake that suppresses norepinephrine and serotonin, its alternative tricyclic antidepressants and selectivity reuptake inhibitor.Venlafaxine has chemical formula shown in the following formula I:
Formula I
O-ODV, i.e. 4-[2-(dimethylamino)-1-(1-hydroxy-cyclohexyl) ethyl] phenol, be the major metabolite of Venlafaxine, it has been proved to be able to suppress the re-uptake of norepinephrine and serotonin.Referring to Klamerus, K.J. etc. " Introduction of the Composite Parameter to thePharmacokinetics of Velafaxine and its Active O-Desmethyl Metabolite ", J.Clin.Pharmacol.32:716-724 (1992).The O-ODV has chemical formula shown in the Formula Il:
C
16H
25NO
2
Molecular weight: 263.38
Formula II
The synthetic method of O-ODV comprises that it is described in United States Patent (USP) the 7th, 026 with the step of the phenolic group demethylation of Venlafaxine, 508 and 6,689, in No. 912, and in No. the 2005/0197392nd, the U.S. Patent Publication, by reference it is incorporated herein.
Disclosed synthetic method is according to following scheme implementation in the above reference:
" MBC " nail base benzyl cyanide, " CMBC " finger ring hexyl methyl benzyl cyanide, " DDMV " refers to the dinor-Venlafaxine, " ODV " refers to the O-ODV.
As any synthetic compound, the O-ODV may contain from the xenobiontics in multiple source or impurity.They may be unreacted raw material, byproduct of reaction, side reaction product or degraded product.Impurity in O-ODV or any active pharmaceutical ingredient (API) all is undesirable, under extreme case, even may be to harmful with the patient of the formulation treatment that contains API.
This area is also known, and the impurity among the API may be from the degraded of API self, this with pure API between the shelf lives stability and comprise that the manufacture method of chemosynthesis is relevant.Process contaminants comprises chemical derivative, synthetic by product and the degraded product of impurities in unreacted raw material, the raw material.
Except stability (influencing a factor of API shelf-life), the purity of the API for preparing in the industrialization manufacturing processed obviously is to be used for industrialized prerequisite.The impurity of introducing in the industrialization manufacturing processed must be limited in very little amount, preferably not have impurity basically.For example, require process contaminants to keep below the limit of setting at the ICHQ7A guide of API manufacturers, concrete measure has the quality of regulation raw material; Control process parameters is as temperature, pressure, time and stoichiometric ratio; And in preparation process, comprise purification step, as crystallization, distillation and liquid-liquid extraction.
The product mixtures of chemical reaction seldom is to have enough purity to meet the simplification compound of pharmaceutical standards.In most cases, used auxiliary reagent also can be stayed in the mixture of products in byproduct, byproduct of reaction and the reaction.In some stage of handling API (as the O-ODV), must carry out purity check, generally analyze by means of HPLC, NMR or TLC, whether be fit to subsequent disposal to determine it, finally whether be suitable as medicine.API need not be definitely pure because absolute pure be theoretic ideal state, in fact do not reach.Be intended to guarantee that API is free from foreign meter as far as possible and set purity rubric, thus safe as far as possible for clinical use.As discussed above, in the U.S., food and drug administration's guideline recommendation is limited in the amount of some impurity and is lower than 0.1%.
Usually, byproduct, by product and auxiliary reagent (general designation " impurity ") are to identify with spectrographic technique and/or another kind of physical method, and then with a peak position (as the peak position in the color atlas), perhaps the spot on the TLC plate connects that (Strobel p.953, Strobel, H.A.; Heieman, W.R., ChemicalInstrumentation:A Systematic Approach, the 3rd edition (Wiley ﹠amp; Sons:New York1989)).After this, can for example identify impurity by the relative position of impurity in color atlas, wherein the position in the color atlas normally measure in through several minutes between detector to this special component wash-out in that sample is injected by post.Relative position in the color atlas is called " retention time ".
Therefore, because its medical use, people wish to obtain pure substantially O-ODV.
Summary of the invention
In one embodiment, the invention provides pure substantially O-ODV, its total impurities is less than about 5% HPLC area (area by HPLC), more preferably less than about 3% HPLC area, even more preferably less than about 1% HPLC area.
Preferably, the total impurities of O-ODV is less than about 0.7% HPLC area.More preferably, total impurities is less than about 0.2% HPLC area, and most preferably, the total impurities of O-ODV is less than about 0.07% HPLC area.
In another embodiment, the invention provides the method for the pure substantially O-ODV of preparation, it comprises: under reduced pressure with Venlafaxine, organic solvent be selected from thiophenol, sodium sulphite and C
1~C
8The reagent mix of alkyl sulfide alkoxide forms mixture, heats this mixture to about 30 ℃~about 220 ℃ temperature, reclaims the O-ODV.
In another embodiment, the invention provides the method for the pure substantially O-ODV of preparation, it comprises: with Venlafaxine, organic solvent and C
1~C
8Alkyl sulfide alkoxide or sodium sulphite mix, and form mixture, heat this mixture to about 100 ℃~about 210 ℃ temperature, reclaim the O-ODV.
In another embodiment, the invention provides the method for the pure substantially O-ODV of preparation, it comprises: mix Venlafaxine and thiophenol, form mixture, heat this mixture to about 100 ℃~about 210 ℃ temperature, reclaim the O-ODV.
In a kind of embodiment also, the invention provides C
1~C
8Alkyl sulfide alkoxide and the sodium sulphite purposes in the demethylation of Venlafaxine.
In another embodiment, the invention provides the method for the pure substantially O-ODV of preparation, it comprises: as preparation three ODVs as described in the common co-pending application 60/849216 (by reference it being incorporated herein); Described three ODVs are converted into the O-ODV; Reclaim the O-ODV.
In another embodiment, the present invention relates to test the analytical procedure of the chemical purity of O-ODV.
In another embodiment, the invention provides a kind of pharmaceutical composition, it comprises pure substantially O-ODV and pharmaceutically acceptable vehicle.
In another embodiment, the invention provides a kind of method of useful in preparing drug formulations, it comprises pure substantially O-ODV is mixed with pharmaceutically acceptable carrier.
Detailed Description Of The Invention
Term used herein " pure substantially " is meant that the area measurement according to %HPLC, the purity of O-ODV are about 95% or higher.The purity of pure substantially O-ODV is preferably about 97%HPLC area, and more preferably about 99%HPLC area, even more preferably about 99.3%HPLC area most preferably are about 99.8%HPLC area.
The invention provides O-ODV (ODV), its total impurities is less than about 5%HPLC area, preferably is less than about 3%HPLC area, more preferably less than about 1%HPLC area.Term used herein " %HPLC area " is meant the relative value of the total area at all peaks in the area at one or more peaks in the HPLC color atlas and this HPLC color atlas, represents with its percentage ratio that accounts for the total area.In this article, the purity of O-ODV can further be expressed as " HPLC " purity.So, " HPLC purity " is calculated divided by the total area under the curve in the HPLC color atlas by area under the peak of O-ODV.
Preferably, the total impurities of O-ODV is less than about 0.7%HPLC area.More preferably, total impurities is less than about 0.2% HPLC area, and most preferably, the impurity of O-ODV always contains and is less than about 0.07% HPLC area.
O-ODV or racemic modification that the present invention obtains, or optical purity O-ODV.
Concerning any those skilled in the art, it is evident that, further make the crystallization of thick O-ODV can obtain higher purity.
In another embodiment, the invention provides the method for the pure substantially O-ODV of a kind of preparation, it comprises: with Venlafaxine (VNL), organic solvent be selected from thiophenol, sodium sulphite and C
1~C
8The reagent mix of alkyl sulfide alkoxide (preferably mixing under reduced pressure) forms mixture, preferably with the temperature of this mixture heating up to about 30 ℃~about 220 ℃ (preferred about 30 ℃~about 100 ℃), reclaims pure substantially O-ODV.
Term used herein " decompression " is meant and is lower than about 1 atmospheric pressure, preferably is lower than 0.5 atmospheric pressure, more preferably less than about 0.1 atmospheric pressure.
Described organic solvent can be selected from: C
3~C
7Ketone, C
3~C
7Ester, C
5~C
8Aliphatic hydrocrbon or C
6~C
12Aromatic hydrocarbon, high boiling solvent, C
2~C
8Ether, hydrochloric ether and C
2~C
8Alcohol.More preferably, described solvent is selected from acetone, ethyl acetate, toluene, DMF, NMP, DMA, THF and ethanol.
Term used herein " high boiling solvent " is meant that boiling point is higher than about 100 ℃ solvent.Preferably, described high boiling solvent is selected from: toluene, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), N-methyl-2-pyridone, N-N-methyl-2-2-pyrrolidone N-, 1-Methyl-2-Pyrrolidone (pyrolidinone) are (NMP) and N,N-DIMETHYLACETAMIDE (DMA).More preferably, described high boiling solvent is DMA, DMF or NMP.
When using NMP, the volume ratio of NMP and Venlafaxine is preferably 1~20, and more preferably 2~4.
When using DMA or DMF, the volume ratio of DMA and DMF and Venlafaxine is preferably at least about 1, and more preferably 1~10, most preferably be about 2.5.
When in described method, using thiophenol, preferably in reaction mixture, use catalyzer.More preferably, described catalyzer is an alkali.Most preferably, described catalyzer is an alkali metal base, as salt of wormwood.
Preferably, the pure substantially O-ODV that obtains by above method contains the total impurities that is less than about 0.7%HPLC area.More preferably, contain the total impurities that is less than about 0.2% HPLC area, most preferably, the O-ODV that obtains by above method contains the total impurities that is less than about 0.07% HPLC area.
Can from mixture, reclaim the O-ODV by any method known to those skilled in the art.
Preferably, the O-ODV that obtains like this is a crystallized form, is about 12.1 °, 13.2 °, 15.9 ° and 20.4 ° ± 0.2 ° X-ray powder diffraction reflections of locating by 2 θ and characterizes.
In another embodiment, the invention provides the method for the pure substantially O-ODV of a kind of preparation, it comprises: with Venlafaxine, organic solvent and C
1~C
8Alkyl sulfide alkoxide or sodium sulphite mix, and form mixture, with the temperature of this mixture heating up to about 100 ℃~about 210 ℃ (preferred about 100 ℃~about 190 ℃, more preferably from about 135 ℃~about 190 ℃), reclaim pure substantially O-ODV.
Used organic solvent as mentioned above.
When using NMP, the volume ratio of NMP and Venlafaxine is preferably 1~20, and more preferably 2~4.
When using DMA or DMF, the volume ratio of DMA and DMF and Venlafaxine is preferably at least about 1, and more preferably 1~10, most preferably be about 2.5.
Preferably, the pure substantially O-ODV that obtains by above method contains the total impurities that is less than about 0.7%HPLC area.More preferably, contain the total impurities that is less than about 0.2%HPLC area, most preferably, the O-ODV that obtains by above method contains the total impurities that is less than about 0.07%HPLC area.
Can from mixture, reclaim the O-ODV by any method known to those skilled in the art.
Preferably, the O-ODV that obtains like this is a crystallized form, is about 12.1 °, 13.2 °, 15.9 ° and 20.4 ° ± 0.2 ° X-ray powder diffraction reflections of locating by 2 θ and characterizes.
In another embodiment, the invention provides the method for the pure substantially O-ODV of a kind of preparation, it comprises: mix Venlafaxine and thiophenol, form mixture, with extremely about 100 ℃~about 210 ℃ (preferred about 100 ℃~about 190 ℃ of this mixture heating up, more preferably from about 135 ℃~about 190 ℃) temperature, reclaim pure substantially O-ODV.
Randomly, described method can be carried out in the presence of for non-hydroxyl (non-hydroxilic) solvent or non-ether (nonethereal) solvent, and described solvent can be selected from NMP, DMSO, DMF, DMA, carbowax (carbowax), thermal oil (marlotherm) and silicone oil.Described solvent is preferably NMP.
When using NMP, the volume ratio of NMP and Venlafaxine is preferably 1~20, and more preferably 2~4.
Preferably in the reaction mixture of Venlafaxine and thiophenol, use catalyzer.More preferably, described catalyzer is an alkali.Most preferably, described catalyzer is an alkali metal base, as salt of wormwood.
Preferably, the pure substantially O-ODV that obtains by above method contains the total impurities that is less than about 0.7%HPLC area.More preferably, contain the total impurities that is less than about 0.2%HPLC area, most preferably, the O-ODV that obtains by above method contains the total impurities that is less than about 0.07%HPLC area.
Can from mixture, reclaim the O-ODV by any method known to those skilled in the art.
Preferably, the O-ODV that obtains like this is a crystallized form, is about 12.1 °, 13.2 °, 15.9 ° and 20.4 ° ± 0.2 ° X-ray powder diffraction reflections of locating by 2 θ and characterizes.
After the pure substantially O-ODV method of above-mentioned all preparations, can make the O-ODV of gained in the mixture of organic solvent and water, form slurries, to reduce salt impurity.Have mensuration purity by forming pure substantially O-ODV that slurries (slurrying) obtain, more preferably have 99% mensuration purity at least about 95%.Preferably, organic solvent/water mixture can be alcohol/water mixture or water/acetonitrile mixture; More preferably, described alcohol/water mixture is C
1~C
4Alcohol/water mixture; Most preferably, described alcohol/water mixture is an iso-propanol/water mixture.
Term used herein " mensuration purity " is meant the purity of measuring by a kind of known method, area percent and the area percent of the standard substance quality of calculating O-ODV of described method by comparative sample.
Randomly, make the O-ODV in water/IPA mixture, form slurries.The volume ratio of water/IPA mixture is preferably 15:25 to 80:20, more preferably 80:20.
Described slurries are at about 20 ℃ to about 70 ℃ (preferred about 20 ℃ to about 40 ℃, room temperature more preferably from about) kept under the temperature about 5 minutes to about 5 hours (preferably about 30 minutes to about 4 hours, more preferably from about 1 hour to about 3 hours, most preferably from about 2 hours), to obtain to measure the pure substantially O-ODV that purity is about 95% (preferred about 99%).Can be by any method known to those skilled in the art from from slurries, reclaiming described pure substantially O-ODV.Recovery preferably includes the O-ODV is precipitated from the aqueous solution or the suspension among water/IPA, wherein with pH regulator to 7.5~13.5, preferably is adjusted to 7.5~10, more preferably is adjusted to be about 8 pH.Regulate pH and comprise adding acid, described acid is preferably selected from HCl and organic acid, and described acid is citric acid or succsinic acid more preferably, and described acid most preferably is succsinic acid.
In another embodiment, the invention provides C
1~C
8Alkyl sulfide alkoxide and the sodium sulphite purposes in the demethylation of Venlafaxine.In another embodiment, the invention provides the method for the pure substantially O-ODV of preparation, it comprises: as preparation three ODVs (TDMV) as described in the common co-pending application 60/849216 (by reference it being incorporated herein); Described three ODVs are converted into the O-ODV; From reaction mixture, reclaim pure substantially O-ODV.
The method for preparing three ODVs comprises: dinor-Venlafaxine, high boiling solvent and thiolate are mixed, form mixture; With the temperature of this mixture heating up to about 100 ℃ to about 220 ℃ (preferred about 140 ℃ to 210 ℃, more preferably from about 155 ℃ to 210 ℃); And optional three ODVs that from mixture, reclaim.
The total impurities of three ODVs that obtain by above method preferably is less than the 5%HPLC area.
Described high boiling solvent preferably as mentioned before.
Described thiolate is preferably high molecular thiolate or aromatic hydrocarbons thiolate.Described thiolate is lauryl mercaptan sodium or thiophenol more preferably.Described lauryl mercaptan sodium can obtain by any method known to the skilled (for example sodium methylate, methyl alcohol and lauryl mercaptan being mixed).
When using thiophenol, preferably in reaction mixture, use catalyzer.More preferably, described catalyzer is an alkali.Most preferably, described catalyzer is an alkali metal base, and for example described catalyzer is a salt of wormwood.
Preferably with described mixture heating up to about 155 ℃ to about 210 ℃ temperature.
Can from this mixture, reclaim three ODVs by any method known to those skilled in the art.
Three ODVs also can carry out described in common co-pending application 60/849216 (by reference it being incorporated herein) to the conversion of O-ODV.This method comprises: the solution of three ODVs and formaldehyde source is mixed with sodium borohydride or sodium triacetoxy borohydride, obtain slurries, randomly reclaim the O-ODV from these slurries.
Randomly, described three ODV raw materials be with organic solvent (as C
1-4Alcohol) solution that forms.
Randomly, described method is implemented under acidic conditions.Described acid source is preferably organic acid, for example formic acid or acetate.
Preferably, with before sodium borohydride or sodium triacetoxy borohydride mix, described solution is cooled to be lower than the temperature of about 10 ℃ (more preferably less than about 5 ℃).
Can further from reaction mixture, reclaim pure substantially O-ODV by any method known to those skilled in the art.Reclaim pure substantially O-ODV preferably include will contain the thick O-ODV reaction mixture of step of converting (for example from) the pH regulator of suspension to about 7.5~13.5, obtain pure substantially O-ODV.The pH that adjusting contains the suspension of thick O-ODV can cause or make that pure substantially O-ODV precipitates from this suspension.This suspension that contains thick O-ODV can be the suspension that three ODVs are converted into the reaction mixture formation of O-ODV, or at water/C
1~C
4Suspension in the alcohol mixture.Available any appropriate organic or mineral acid are regulated PH, preferably with citric acid or amber acid for adjusting pH.When reclaiming pure substantially O-ODV, preferably with pH regulator to about 7.5~10, more preferably be adjusted to pH and be about 8.Reclaim pure substantially O-ODV and can further comprise the pure substantially O-ODV that filters gained.Randomly, in the suspension of having regulated pH, add anti-solvent, wherein anti-solvent be can be miscible with water solvent.Described anti-solvent is preferably C
1~C
4Alcohol, more preferably Virahol (IPA).
Preferably, the pure substantially O-ODV that obtains by above method contains the total impurities that is less than about 0.7%HPLC area.More preferably, contain the total impurities that is less than about 0.2% HPLC area, most preferably, the O-ODV that obtains by above method contains the total impurities that is less than about 0.07% HPLC area.
Can from these slurries, reclaim the O-ODV by any method known to those skilled in the art.
In other embodiments, the present invention relates to be used to test the analytical procedure of the chemical purity of O-ODV, it comprises and mixes O-ODV sample and acetonitrile: the mixture of buffer reagent (about 3:7) obtains solution; With this injection of solution to C-18 post (for example parts number is the Zorbax SB C-18 post (4.6*250 millimeter) of 28105-020 or similar post), used acetonitrile then at about 55 minutes: the mixture (being designated as eluent A) and the acetonitrile of buffer reagent (about 3:7): buffer reagent: trifluoroacetic acid: the mixture of triethylamine (being designated as eluent B) is measured the chemical purity of associated sample as eluent elution samples from post with the UV detector.Eluent B is preferably by adding about 1.6 parts of trifluoroacetic acids and about 2.9 parts of triethylamines in the mixture of about 700 parts of acetonitriles and about 300 parts of buffer reagents, the pH regulator of the mixture of gained is prepared to about 3.0, eluent B more preferably passes through to mix 700 milliliters of acetonitriles, about 300 milliliters of buffer reagents, about 1.6 milliliters of trifluoroacetic acids and 2.9 milliliters of triethylamines, and pH regulator is prepared to about 3.0.
Preferably, described buffer reagent contains 0.4% trifluoroacetic acid of having an appointment, about 0.7% triethylamine and about 98.9% water, and pH is about 3.0.
Preferably, used eluent can be the mixture of eluent A and eluent B, and their ratio time to time change is the gradient elution agent.In the time of 0 minute, this eluent contains 100% eluent A and 0% eluent B.In the time of about 21 minutes, this eluent preferably contains have an appointment 100% eluent A and about 0% eluent B.In the time of about 55 minutes, this eluent contains have an appointment 45% eluent A and about 55% eluent B.
In another embodiment, the invention provides a kind of pharmaceutical composition, it comprises pure substantially O-ODV and pharmaceutically acceptable vehicle.
In another embodiment, the invention provides the method for useful in preparing drug formulations, it comprises pure substantially O-ODV is mixed with pharmaceutically acceptable carrier.
Pharmaceutical composition can be made per os, parenteral, rectum, transdermal, through cheek or intranasal administered agents.Be fit to oral form and comprise tablet, compression or coated pill, sugar-pill, packed medicine (sachet), hard capsule or gelatine capsule, sublingual tablet, syrup and suspensoid.The form that is fit to parenteral administration comprises water-based or non-aqueous solution or emulsion, and the form of suitable rectal administration comprises the suppository that contains wetting ability or hydrophobic carrier.For topical application, the invention provides suitable transdermal delivery known in the art, for the intranasal transmission, provide suitable aerosol transfer system known in the art.
Except activeconstituents, pharmaceutical composition of the present invention can contain one or more vehicle or assistant agent.Scientific formulation man is based on experience and consider the standard program of this area and reference works is determined selection to vehicle and consumption thereof at an easy rate.
Thinner increases the volume of solid composite medicament, can make the easier processing of patient and paramedic contain the pharmaceutical dosage form of described composition.The thinner that is used for solids composition comprises that for example Microcrystalline Cellulose (for example
), fine cellulose, lactose, starch, pre-gelatinized starch, lime carbonate, calcium sulfate, sugar, dextrate, dextrin, glucose, calcium phosphate dibasic dihydrate, calcium phosphate, kaolin, magnesiumcarbonate, magnesium oxide, maltodextrin, N.F,USP MANNITOL, polymethacrylate (for example
), Repone K, cellulose powder, sodium-chlor, Sorbitol Powder and talcum.
The solid composite medicament that is compressed into the formulation such as tablet can comprise vehicle, and its function comprises that to help activeconstituents and other vehicle bonding after compression.The tackiness agent that is used for solid composite medicament (for example comprises gum arabic, alginic acid, carbomer (for example Ka Baibo (carbopol)), Xylo-Mucine, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, Natvosol, hydroxypropylcellulose
), Vltra tears (for example
), Liquid Glucose, magnesium aluminum silicate, maltodextrin, methylcellulose gum, polymethacrylate, polyvidone (for example
), pre-gelatinized starch, sodium alginate and starch.
In the compression solid pharmaceutical composition, add disintegrating agent and can improve the dissolution rate of said composition in patient's stomach.Disintegrating agent (for example comprises alginic acid, calcium carboxymethylcellulose, Xylo-Mucine
), colloid silica, croscarmellose sodium, polyvinylpolypyrrolidone (for example
), guar gum, magnesium aluminum silicate, methylcellulose gum, Microcrystalline Cellulose, Polacrilin potassium, cellulose powder, pre-gelatinized starch, sodium alginate, Explotab (for example
) and starch.
Can add the accuracy of glidant to improve the mobile of non-compacted solid composition and to improve dosed administration.The vehicle that can play the glidant effect comprises colloid silica, Magnesium Trisilicate, cellulose powder, starch, talcum and calcium phosphate.
When by the formulation of compressing powder preparation of compositions such as tablet, said composition is exerted pressure with formpiston and former (punchand die).Some vehicle and activeconstituents have the tendency that adheres on formpiston and the female mold surfaces, and this can make product have depression and other surface irregularity.Can in said composition, add lubricant, adhere to, make product be easy to the demoulding to reduce.Lubricant comprises Magnesium Stearate, calcium stearate, glyceryl monostearate, palmitinic acid stearin, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyoxyethylene glycol, Sodium Benzoate, Sodium Lauryl Sulphate BP/USP, stearyl fumarate, stearic acid, talcum and Zinic stearas.
Seasonings and odorant make formulation more agreeable to the taste to the patient.The seasonings that is usually used in medicament production and the odorant that can be included in the present composition comprise voitol, vanillin food grade,1000.000000ine mesh, vanirone, menthol, citric acid, fumaric acid, veltol plus and tartrate.
The also available any pharmaceutically acceptable tinting material dyeing of solid and liquid composition is with the outward appearance of improving them and/or make things convenient for the patient to discern product and unitary dose.
In composition of liquid medicine of the present invention, activeconstituents and any other solid excipient are suspended in the liquid vehicle, described carrier for example is water, vegetables oil, alcohol, polyoxyethylene glycol, propylene glycol or glycerine.
Composition of liquid medicine can comprise emulsifying agent, spreads all in composition so that be insoluble to activeconstituents or other vehicle homodisperse of liquid vehicle.The emulsifying agent that can be used in the liquid composition of the present invention comprises for example gelatin, yolk, casein, cholesterol, gum arabic, tragacanth gum, carrageenin, pectin, methylcellulose gum, carbomer, the pure and mild hexadecanol of cetearyl alcohol.
Composition of liquid medicine of the present invention also can comprise tackifier, with mouthfeel and/or the covering stomach inwall that improves product.This tackifier comprise gum arabic, alginic acid, wilkinite, carbomer, calcium carboxymethylcellulose or Xylo-Mucine, cetostearyl alcohol, methylcellulose gum, ethyl cellulose, gelatin, guar gum, Natvosol, hydroxypropylcellulose, Vltra tears, maltodextrin, polyvinyl alcohol, polyvidone, Texacar PC, alginic acid propylene glycol ester, sodium alginate, Explotab, starch tragacanth gum and xanthan gum.
Can add sweeting agent to improve taste, described sweeting agent for example is Sorbitol Powder, asccharin, soluble saccharin, sucrose, aspartame, fructose, N.F,USP MANNITOL and Nulomoline.
Adding sanitas of absorption level safely and sequestrant (as alcohol, Sodium Benzoate, butylated hydroxytoluene, fourth hydroxyanisol and ethylenediamine tetraacetic acid (EDTA)) are to improve stability in storage.
According to the present invention, liquid composition also can comprise buffer reagent, as gluconic acid, lactic acid, citric acid or acetate, Sunmorl N 60S, Sodium.alpha.-hydroxypropionate, Trisodium Citrate or sodium acetate.
Scientific formulation man is based on experience and consider the standard program of this area and reference works is determined selection to vehicle and consumption thereof at an easy rate.
Solids composition of the present invention comprises powder, particle, aggregate and compressed compositions.Dosage comprises suitable per os, through the dosage of cheek, rectum, parenteral (comprising subcutaneous, intramuscular and intravenously), suction and ocular administration.Be subjected to sanatory character and severity though the optimum method of application under any given situation depends on, most preferred route of administration of the present invention is oral.Described dosage can provide with unit dose shape easily, can be by the known any method preparation of pharmaceutical field.
Formulation comprises solid dosage such as tablet, powder, capsule, suppository, packed medicine, lozenge and lozenge, and liquid sugar sirup, suspensoid and elixir.
Formulation of the present invention can be the capsule that comprises described composition (being preferably powdery of the present invention or granular solids composition) in hard coat or bladder.Described shell can be made by gelatin, randomly comprises softening agent (as glycerine and Sorbitol Powder) and opalizer or tinting material.
Activeconstituents and vehicle can be formulated in composition and the formulation with methods known in the art.
The composition that is used for compressing tablet or filled capsules can prepare by wet granulation.In wet granulation, some or all powdered activated compositions of blend and vehicle further mix in the presence of liquid (being generally water) then, make powder gather into particle.Particle is sieved and/or mills, and required particle diameter is sieved and/or be milled into to drying then.Can perhaps before compressing tablet, add other vehicle, as glidant and/or lubricant to the particle compressing tablet then.
Tableted compositions can be by conventional dry mix preparation.For example, the blend composition compressed to slugs or the sheet of activeconstituents and vehicle can be made compressing grains then.Compressing grains can be pressed into tablet then.
As a kind of alternative method of non-slurry pelletizing, can adopt direct compact technique that blend composition directly is pressed into compressed dosage forms.Directly compacting produces more uniform tablet without granulation.The vehicle that is particularly suitable for direct compression comprises Microcrystalline Cellulose, spray-dired lactose, calcium phosphate dibasic dihydrate and colloid silica.The appropriate use of these and other vehicle in direct compression known by the preparation experience with direct compression and the those skilled in the art of technology.
Capsule of the present invention is filled can comprise described any blend and particle when compressing tablet is mentioned in the front, but they do not carry out last compressing tablet step.
In another embodiment, the invention provides treatment patient's method, it comprises its above pure substantially O-ODV of patient's administering therapeutic significant quantity of needs.Preferably, described method treatment patient, described patient suffers from the illness of the reuptake inhibitor treatment of available norepinephrine or serotonin.This type of patient may suffer dysthymia disorders.
Invention has been described with reference to specific preferred implementation, to those skilled in the art, considers that other embodiment of this specification sheets will be conspicuous.Further limit the present invention below in conjunction with following examples, these embodiment describe the synthetic of compounds three ODVs in detail and to the further conversion of O-ODV.To one skilled in the art obviously can be and do not break away from the scope of the invention to starting material and the multiple change of process implementing.
Embodiment
In model is X ' TRA, is furnished with and implements the XRD diffraction experiment on the Scintag x-ray powder diffraction instrument of solid-state detector.Use 1.5418
Copper radiation.Specimen holder is that background is zero circular standard aluminum specimen holder substantially.The sweep parameter scope is: 2 θ: 2~40 °; Scan pattern: continuous sweep; Step-length: 0.05 °; Scanning speed: 5 °/minute.
Be used to measure the HPLC method of chemical purity:
The post parts number is the Zorbax SB C-18 (4.6*250 millimeter) of 28105-202
Or equivalent chromatographic column
Buffer reagent 0.4% trifluoroacetic acid, 0.7% triethylamine, 98.9% water (being adjusted to pH=3.0)
Eluent A:30% acetonitrile, 70% buffer reagent
Eluent B: be prepared as follows: in the mixture of 700 milliliters of acetonitriles and 300 milliliters of buffer reagents, add 1.6 milliliters of trifluoroacetic acids and 2.9 milliliters of triethylamines (being adjusted to pH=3.0)
Stand-by time: 55 minutes
The eluent gradient: the time (minute) eluent A (%) eluent B (%)
0 100 0
21 100 0
55 45 55
Starting time: 10 minutes
Flow: 1.0 ml/min
Detector: 230 nanometers
Volume injected: 10 microlitres
Thinner: eluent A
Column temperature: 25 ℃
Embodiment 1: preparation O-ODV in NMP
In being housed, 500 milliliters of three-necked flasks of agitator, condenser and thermometer add Venlafaxine (50 grams, 180 mmoles), thiophenol (20 milliliters, 195 mmoles), K
2CO
3(1 gram, 6 mmoles) and NMP (90 milliliters).With mixture heating up to 190 ℃.Remove heating bath 190 ℃ of maintenances after 5 hours.(being less than 1.5%VNL).Add IPA (300 milliliters) at 80 ℃.Solution is cooled to 0~5 ℃ to spend the night.The filtration under diminished pressure solid, and with IPA and water washing.At 50 ℃ this solid vacuum-drying is spent the night then, obtain pure ODV alkali (base).The purity of gained ODV is 97%, and measuring purity is 93.5%.
Embodiment 2: preparation O-ODV in NMP
Under room temperature and flow of nitrogen gas, in single neck flask that magnetic stirring apparatus, Dean and Stark apparatus (dean stark), condenser and thermometer are housed, add VNL (5 grams, 18.2 mmoles), hydration Na
2S (1.58 grams, 12 mmoles are measured purity〉60%) and NMP (12 milliliters).In 1 hour, reaction mixture is heated to 150 ℃, and under this temperature, kept 7.5 hours.With the reaction mixture cool to room temperature, under this temperature, stir and spend the night then.Add hydration Na subsequently
2S (0.71 gram, 5.4 mmoles are measured purity〉60%).In 1 hour,, and under this temperature, kept 5 hours this mixture heating up to 165 ℃.After this reaction solution is cooled to 40 ℃, slowly adds IPA (30 milliliters) and 10% aqueous citric acid solution (20 milliliters) by dropping funnel, until observing slight precipitation (pH10).At room temperature suspension was stirred weekend (overweekend), the filtration under diminished pressure solid is with IPA (20 milliliters) washing.Make solid in vacuum oven in 50 ℃ of dried overnight, obtain dry ODV (measure purity 55.2%, HPLC purity 99.11%).Embodiment 3: preparation O-ODV under pressurized conditions
In 250 milliliters of autoclaves, add 5 gram VNL (0.0182 mole), 3.81 gram sulfur alcohol sodium (0.0458 mole, 2.5 equivalents) and NMP (10 milliliters).Stirred reaction mixture 4 hours under the pressure of 30 ℃~220 ℃ and 1~20 crust.Then with this mixture cool to room temperature.Add IPA (10 milliliters) and water (10 milliliters) at ambient temperature.In this mixture, add 10% aqueous citric acid solution, make pH reach about 12.Begin to be settled out solid, at room temperature stirred 2.5 hours.Filtration under diminished pressure solid then, and use solvent wash.In vacuum oven,, obtain pure ODV in 50 ℃ of dry wet filter cakes.
Embodiment 4: preparation O-ODV in DMA
In being housed, 100 milliliters of three-necked flasks of mechanical stirrer, thermometer and condenser add 5 gram VNL (0.0182 mole), 3.81 gram sulfur alcohol sodium (0.0458 mole, 2.5 equivalents) and N,N-DIMETHYLACETAMIDEs (10 milliliters).With mixture heating up to 135 ℃, kept 4 hours, then cool to room temperature.Add IPA (10 milliliters) and water (10 milliliters) at ambient temperature.Reaction mixture is clarifying.In this mixture (pH13), add 10% aqueous citric acid solution, make pH reach 12.4.Begin to be settled out solid, at room temperature stirred 2.5 hours.Filtration under diminished pressure solid then, and wash with IPA.In vacuum oven,, obtain thick ODV (measuring purity 78%, HPLC purity 99.84%) in 50 ℃ of dry wet filter cakes.
Embodiment 5: preparation O-ODV in DMA
In being housed, 100 milliliters of three-necked flasks of mechanical stirrer, thermometer and condenser add 10 gram VNL (0.0364 mole), 7.62 gram sulfur alcohol sodium (0.091 mole, 2.5 equivalents) and N,N-DIMETHYLACETAMIDEs (20 milliliters).With mixture heating up to 110 ℃, kept 9 hours, then cool to room temperature.Under this temperature, add IPA (25 milliliters) and water (15 milliliters).Reaction mixture is clarifying.In this mixture (pH12.43), add 32%HCl, make pH reach 10.Begin to be settled out solid, stirred at ambient temperature 2.5 hours.Cross filter solid then, wash with IPA.In vacuum oven,, obtain thick ODV (measuring purity 77.9%, HPLC purity 94.98%) in 50 ℃ of dry wet filter cakes.
Embodiment 6: preparation O-ODV in DMF
In being housed, 100 milliliters of three-necked flasks of mechanical stirrer, thermometer and condenser add 5 gram VNL (0.0364 mole), 3.81 gram sulfur alcohol sodium (0.0454 mole, 2.5 equivalents) and dimethyl formamides (10 milliliters).With mixture heating up to 135 ℃, kept 3 hours 20 minutes.Then with this solution cool to room temperature.
Under this temperature, add ethyl acetate (10 milliliters), produce some throw outs.With mixture reheat to 70 ℃, slowly be cooled to envrionment temperature then.Under this temperature, stir the mixture and spend the night.In this mixture, add IPA, salt solution and 10% aqueous citric acid solution then, make pH reach 9~10.At room temperature stirred suspension is 5 minutes, filtration under diminished pressure.Wet cake washs with IPA, and in vacuum oven in 50 ℃ of dried overnight, obtain thick ODV (measure purity 76.3%, HPLC purity 99.29%).
Embodiment 7: by the slurry preparation O-ODV among water/IPA
At ambient temperature, in 5 ml waters: IPA (80:20) mixture, stirred 1 gram ODV (GS 1652) 2 hours.Stirred these slurries at ambient temperature 2 hours, the filtration under diminished pressure solid is used 2 ml waters: IPA (80:20) washing.In vacuum oven, spend the night, obtain the pure ODV of exsiccant (measuring purity 98.7%, HPLC purity 99.93%) in 50 ℃ of drying solids.
Embodiment 8: by the slurries in the water (slurry) preparation O-ODV
At room temperature, in 100 ml flasks that magnetic stirring apparatus is housed, add wet ODV (5.65 gram) and the water (40 milliliters) for preparing previously.Stirred suspension is 2.5 hours at ambient temperature.Filtration under diminished pressure suspension then, water (10 milliliters) washing.In vacuum oven, spend the night, obtain white pure solid ODV (measuring purity 95%, HPLC purity 99%) in 50 ℃ of drying solids.
Embodiment 9: preparation O-ODV in NMP
Under room temperature and flow of nitrogen gas, in the three-necked flask that magnetic stirring apparatus, condenser and thermometer are housed, add VNL (12 grams, 43.26 mmoles), hydration Na
2S (6.2 grams, 47.69 mmoles are measured purity〉60%) and NMP (24 milliliters).In 1 hour, reaction mixture is heated to 175 ℃, under this temperature, kept 3 hours.Reaction mixture is cooled to 90 ℃ then.Add entry (36 milliliters) and succsinic acid (5 grams, 42.34 mmoles), observe slight precipitation (pH8.0).In this solution, add diethyl carbonate (24 milliliters), 60 ℃ of stirred suspensions 0.5 hour.Then with the reaction mixture cool to room temperature, filtration under diminished pressure solids, water (2x20 milliliter) washing.In vacuum oven, spend the night, obtain the pure ODV alkali of 9.26 gram (productive rate=79.43%) exsiccant (measuring purity 97.7%, HPLC purity 99.34%) in 50 ℃ of drying solids.Embodiment 10: preparation O-ODV in NMP
Under room temperature and flow of nitrogen gas, in the three-necked flask that magnetic stirring apparatus, condenser and thermometer are housed, add VNL (12 grams, 43.26 mmoles), hydration Na
2S (6.2 grams, 47.69 mmoles are measured purity〉60%) and NMP (24 milliliters).In 1 hour, reaction mixture is heated to 175 ℃, under this temperature, kept 3 hours.Reaction mixture is cooled to 90 ℃ then.Add entry (36 milliliters) and succsinic acid (6 grams, 50.8 mmoles), observe slight precipitation (pH8.0).Add acetonitrile (24 milliliters), 60 ℃ of stirred suspensions 0.5 hour.Then with the reaction mixture cool to room temperature, filtration under diminished pressure solid, water (2x20 milliliter) washing.In vacuum oven, spend the night, obtain the pure ODV alkali of exsiccant (measuring purity 95.8%, HPLC purity 99.47%) in 50 ℃ of drying solids.
Embodiment 11: preparation O-ODV in NMP
Under room temperature and flow of nitrogen gas, in the three-necked flask that magnetic stirring apparatus, condenser and thermometer are housed, add VNL (12 grams, 43.26 mmoles), hydration Na
2S (6.2 grams, 47.69 mmoles are measured purity〉60%) and NMP (24 milliliters).In 1.5 hours, reaction mixture is heated to 175 ℃, under this temperature, kept 4 hours.Then with the reaction mixture cool to room temperature.Add entry (60 milliliters) and succsinic acid (5 grams, 42.34 mmoles), observe appearance precipitation (pH8.0).Suspension is heated to 95 ℃, stirred 1 hour at 95 ℃.Then with the reaction mixture cool to room temperature, filtration under diminished pressure solid, water (20 milliliters of 2 x) washing.In vacuum oven, spend the night, obtain 11.34 gram ODV alkali (productive rate=95.38%, analytical value 95.8%, HPLC purity 98.07%) in 50 ℃ of drying solids.
The preparation of 12: three ODVs of embodiment
In being furnished with 250 ml flasks of magnetic stirring apparatus, condenser and nitrogen inlet, add DDMVxHCl (10 grams, 40 mmoles), K
2CO
3(6 grams, 44 mmoles), thiophenol (8 milliliters, 60 mmoles) and NMP (40 milliliters) heat in sand-bath.Keep 210 ℃ sand-bath temperature 5.5 hours.HPLC analytical proof DDMV all is consumed.Obtain TDMV, purity is 95%.
Embodiment 13: the preparation of pure substantially O-ODV
TDMV (0.2 gram, 0.85 mmole) is dissolved in the methyl alcohol.Add formalin solution (0.4 milliliter, 5 mmoles), cooling gained solution in ice bath.In cold soln, add NaBH
4(65 milligrams, 1.7 mmoles).After 15 minutes, use the HPLC analytic sample, after measured, contain 85% ODV in the reaction mixture.
In mixture, add IPA and 10% citric acid then, reach 9~10 to pH.Stirred suspension is 5 minutes under the room temperature, filtration under diminished pressure.Wet cake washs with IPA, and dried overnight in 50 ℃ of vacuum ovens obtains pure ODV.
The embodiment 4 of comparative example: WO 03/048104
To be dissolved in NaOMe in the methyl alcohol (3 milliliters) (1.3 grams, 24 mmoles) and Dodecyl Mercaptan (5.83 milliliters=4.92 grams, 24 mmoles) mixes, place 90 ℃ with reduced pressure under Rotary Evaporators.In this resistates, add Venlafaxine (5.12 grams, 18 mmoles) and PEG 400 (3.7 grams, 0.75 volume).Then at 200 ℃ of heated mixt.(T
Inner=190 ℃).After 3 hours, add IPA (18 milliliters), use the HCl aqueous solution pH regulator to 9.5.The filtration under diminished pressure solid is with IPA and water washing.Wet ODV is carried out drying under reduced pressure, obtain ODV.The purity of gained ODV is 73.5%, and analytical value is 74.2%.
The embodiment 2 of comparative example: WO 03/048104
In being housed, 100 ml flasks of magnetic stirring apparatus add Venlafaxine (2.8 grams, 10.1 mmoles), benzenethiol sodium salt (3.45 grams, 26 mmoles) and PEG 400 (12.5 grams, 4.5 volumes).In sand-bath with this mixture heating up to 160 ℃.We observe dissolving fully at 90 ℃.Remove sand-bath 160 ℃ of maintenances after 5 hours, add entry (30 milliliters).Use 85% H
3PO
4With pH regulator to 3.5.Remove organic by-products with 25 milliliters of hexane extraction mixtures, with the pH re-adjustment to 9.5 of ammoniacal liquor with water.From then on be settled out solid in the reaction mixture.Cross filter solid, in water (40 milliliters), form slurries once more, filtration under diminished pressure.The solid of drying under reduced pressure gained obtains ODV.The purity of gained ODV is 95.6%, and analytical value is 78.5%.
Claims (74)
1. pure substantially O-ODV.
2. pure substantially O-ODV according to claim 1, wherein total impurities is less than about 5% HPLC area.
3. pure substantially O-ODV according to claim 2, wherein total impurities is less than about 3% HPLC area.
4. pure substantially O-ODV according to claim 3, wherein total impurities is less than about 1% HPLC area.
5. pure substantially O-ODV according to claim 4, wherein total impurities is less than about 0.7% HPLC area.
6. pure substantially O-ODV according to claim 5, wherein total impurities is less than about 0.2% HPLC area.
7. pure substantially O-ODV according to claim 6, wherein total impurities is less than about 0.07% HPLC area.
8. prepare the method for pure substantially O-ODV, it comprises:
A), form mixture with Venlafaxine, organic solvent be selected from the reagent mix of thiophenol, sodium sulphite and C1-C8 alkyl sulfide alkoxide;
B) heat this mixture; And
C) reclaim pure substantially O-ODV.
9. the method for the O-ODV that preparation according to claim 8 is pure substantially, wherein said organic solvent is selected from C
3~C
7Ketone, C
3~C
7Ester, C
5~C
8Aliphatic hydrocrbon or C
6~C
12Aromatic hydrocarbon, high boiling solvent, C
2~C
8Ether, hydrochloric ether and C
2~C
8Alcohol.
10. the method for the O-ODV that preparation according to claim 9 is pure substantially, wherein said high boiling solvent are selected from toluene, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), N-methyl-2-pyridone, N-N-methyl-2-2-pyrrolidone N-, 1-Methyl-2-Pyrrolidone (NMP) and N,N-DIMETHYLACETAMIDE (DMA).
11. the method for the O-ODV that preparation according to claim 10 is pure substantially, wherein said high boiling solvent are DMA, DMF or NMP.
12. the method for the O-ODV that preparation according to claim 9 is pure substantially, wherein said organic solvent is selected from acetone, ethyl acetate, toluene, DMF, NMP, DMA, THF and ethanol.
13. the method for the O-ODV that preparation according to claim 12 is pure substantially, wherein said organic solvent is NMP, and the volume ratio of Venlafaxine and NMP is 1:1 to 1:20 in the mixture.
14. the method for the O-ODV that preparation according to claim 12 is pure substantially, wherein said organic solvent are DMF or DMA, Venlafaxine is 1:1 to 1:10 with the volume of organic solvent ratio.
15. the method for the pure substantially O-ODV of each described preparation wherein when described reagent is thiophenol, adds catalyzer according to Claim 8~14 in the mixture of step a).
16. the method for the O-ODV that preparation according to claim 15 is pure substantially, wherein said catalyzer is an alkali.
17. the method for the O-ODV that preparation according to claim 16 is pure substantially, wherein said alkali is alkaline carbonate.
18. the method for the O-ODV that preparation according to claim 17 is pure substantially, wherein said alkaline carbonate is a salt of wormwood.
19. the method for the pure substantially O-ODV of each described preparation according to Claim 8~18, wherein in step b) with described mixture heating up to about 100 ℃ to about 210 ℃ temperature, keep about 1 hour to about 12 hours time period.
20. the method for the O-ODV that preparation according to claim 19 is pure substantially, wherein with described mixture heating up to about 110 ℃ to about 190 ℃ temperature.
21. according to the method for the pure substantially O-ODV of each described preparation in the claim 19~20, the wherein said time period is about 3 hours to about 10 hours.
22. the method for the pure substantially O-ODV of each described preparation according to Claim 8~21, wherein under reduced pressure with Venlafaxine, organic solvent and reagent mix, and in step b), mixture is heated to about 220 ℃ temperature in about 30 ℃.
23. the method for the O-ODV that preparation according to claim 22 is pure substantially, wherein said pressure is less than 1 normal atmosphere.
24. the method for the pure substantially O-ODV of each described preparation wherein reclaims the O-ODV and comprises crystallization according to Claim 8~23.
25. the method for the O-ODV that preparation according to claim 24 is pure substantially, wherein gained crystallization O-ODV characterizes with x-ray diffractogram of powder, is about 12.1 °, 13.2 °, 15.9 ° and 20.4 ° ± 0.2 ° at 2 θ and locates to have the peak reflection.
26. the method for the pure substantially O-ODV of each described preparation according to Claim 8~23, it further comprises before the pure substantially O-ODV of recovery, makes mixture form slurries in the solvent that is selected from water, water/alcohol mixture and water/acetonitrile mixture.
27. the method for the O-ODV that preparation according to claim 26 is pure substantially, the volume ratio of wherein said water/IPA mixture is 15:25 to 80:20.
28. the method for the O-ODV that preparation according to claim 27 is pure substantially, the volume ratio of wherein said water/IPA mixture is 80:20.
29. according to the method for the pure substantially O-ODV of each described preparation in the claim 26~28, wherein said formation slurries carried out about 5 minutes to about 5 hours to about 70 ℃ temperature at about 20 ℃.
30. the method for the O-ODV that preparation according to claim 28 is pure substantially, wherein said formation slurries were carried out under about room temperature about 2 hours.
31. method according to the pure substantially O-ODV of each described preparation in the claim 26~30, wherein reclaim the O-ODV and comprise adjusting pH to 7.5~13.5, the O-ODV is precipitated from the aqueous solution or the suspension among water/IPA.
32. the method for the O-ODV that preparation according to claim 31 is pure substantially is wherein with pH regulator to 7.5~10.
33. the method for the O-ODV that preparation according to claim 32 is pure substantially is wherein with pH regulator to 8.
34., wherein regulate pH and comprise adding acid according to the method for the pure substantially O-ODV of each described preparation in the claim 31~33.
35. the method for the O-ODV that preparation according to claim 34 is pure substantially, wherein said acid is selected from mineral acid and organic acid.
36. the method for the O-ODV that preparation according to claim 35 is pure substantially, wherein said organic acid is a succsinic acid.
37. pure substantially O-ODV by each described method preparation in the claim 26~36.
38. according to the described pure substantially O-ODV of claim 37, it is measured purity and is at least about 95%.
39. according to the described pure substantially O-ODV of claim 38, it is measured purity and is at least about 99%.
40. prepare the method for pure substantially O-ODV, it comprises:
A) mix Venlafaxine and thiophenol, form mixture;
B) heat this mixture to about 100 ℃~about 210 ℃ temperature; And
C) reclaim pure substantially O-ODV.
41. the method according to the pure substantially O-ODV of the described preparation of claim 40 wherein adds catalyzer in the mixture of step a).
42. according to the method for the pure substantially O-ODV of the described preparation of claim 41, wherein said catalyzer is an alkali.
43. according to the method for the pure substantially O-ODV of the described preparation of claim 42, wherein said alkali is alkaline carbonate.
44. according to the method for the pure substantially O-ODV of each described preparation in the claim 40~43, wherein the mixture in the step a) further comprises solvent, it is non-hydroxyl solvent or non-ether solvents.
45. according to the method for the pure substantially O-ODV of the described preparation of claim 44, wherein said solvent is selected from NMP, DMSO, DMF, DMA, carbowax, thermal oil and silicone oil.
46. according to the method for the pure substantially O-ODV of the described preparation of claim 45, wherein said solvent is NMP.
47., wherein reclaim pure substantially O-ODV and comprise crystallization according to the method for the pure substantially O-ODV of each described preparation in the claim 40~46.
48. method according to the pure substantially O-ODV of the described preparation of claim 47, wherein gained crystallization O-ODV characterizes with x-ray diffractogram of powder, is about 12.1 °, 13.2 °, 15.9 ° and 20.4 ° ± 0.2 ° at 2 θ and locates to have the peak reflection.
49. method according to the pure substantially O-ODV of each described preparation in the claim 40~48, it further comprises before the recovery O-ODV, makes it to form slurries in the solvent mixture that is selected from water, water/alcohol mixture and water/acetonitrile mixture.
50. according to the method for the pure substantially O-ODV of the described preparation of claim 49, wherein said solvent mixture is that volume ratio is water/IPA mixture of 80:20.
51. according to the method for the pure substantially O-ODV of the described preparation of claim 50, wherein said formation slurries carried out about 5 minutes to about 5 hours to about 70 ℃ temperature at about 20 ℃.
52. according to the method for the pure substantially O-ODV of the described preparation of claim 51, wherein said formation slurries carried out under about room temperature about 2 hours.
53. method according to the pure substantially O-ODV of each described preparation in the claim 49~52, wherein reclaiming pure substantially O-ODV comprises: by regulating pH to 7.5~13.5, the O-ODV is precipitated from the aqueous solution or the suspension among water/IPA.
54. according to the method for the pure substantially O-ODV of the described preparation of claim 53, wherein with pH regulator to 8.
55. pure substantially O-ODV by each described method preparation in the claim 40~54.
56. according to the described pure substantially O-ODV of claim 55, it is measured purity and is at least about 99%.
57., comprise making Venlafaxine and C with the method for Venlafaxine demethylation
1~C
8Alkyl sulfide alkoxide and sodium sulphite reaction.
58. prepare the method for pure substantially O-ODV, it comprises:
A) Venlafaxine, high boiling solvent and thiolate are mixed, form mixture;
B) with extremely about 100 ℃~about 220 ℃ of this mixture heating up, form three ODVs;
C) three ODVs are converted into the O-ODV; And
D) reclaim pure substantially O-ODV.
59. according to the method for the pure substantially O-ODV of the described preparation of claim 58, wherein said thiolate is lauryl mercaptan sodium or thiophenol.
60. method according to the pure substantially O-ODV of the described preparation of claim 59, wherein saidly three ODVs are converted into the O-ODV comprise: the solution of three ODVs and formaldehyde source is mixed with sodium borohydride or sodium triacetoxy borohydride, obtain slurries; And recovery O-ODV.
61. method according to the pure substantially O-ODV of the described preparation of claim 60, wherein with before sodium borohydride or sodium triacetoxy borohydride mix, the solution of described three ODVs and formaldehyde source is cooled to be lower than about 10 ℃ temperature.
62. method according to the pure substantially O-ODV of each described preparation in the claim 58~61, wherein reclaiming pure substantially O-ODV comprises: the pH regulator of the suspension of the thick O-ODV that obtains in the step c) to about 7.5~13.5, and is further filtered this suspension.
63. according to the method for the pure substantially O-ODV of the described preparation of claim 62, wherein with pH regulator to about 7.5~10.
64. according to the method for the pure substantially O-ODV of the described preparation of claim 63, wherein with pH regulator to about 8.
65., wherein use acid for adjusting pH according to the method for the pure substantially O-ODV of each described preparation in the claim 62~64.
66. according to the method for the pure substantially O-ODV of the described preparation of claim 65, wherein said acid is organic acid.
67. according to the method for the pure substantially O-ODV of the described preparation of claim 66, wherein said acid is citric acid or succsinic acid.
68. according to the method for the pure substantially O-ODV of each described preparation in the claim 62~67, it further comprises the anti-solvent that adding can be miscible with water in the suspension of having regulated pH.
69. according to the method for the pure substantially O-ODV of the described preparation of claim 68, wherein said anti-solvent is Virahol (IPA).
70. be used to test the analytical procedure of the chemical purity of O-ODV, it comprises:
1) with O-ODV sample and the acetonitrile of ratio for about 3:7: buffer mixture (eluent A) is mixed, and obtains solution;
2) with injection of solution to the C-18 post;
3) in the time of about 55 minutes, use eluent A and eluent B (about 700 parts of acetonitriles: about 300 parts of buffer reagents: about 1.6 parts of trifluoroacetic acids: the mixture of about 2.9 parts of triethylamines, with pH regulator to about 3.0) mixture as eluent elution samples from post; And
4) chemical purity of usefulness UV detector working sample.
71. according to the described analytical procedure of claim 70, wherein said buffer reagent contains 0.4% trifluoroacetic acid of having an appointment, about 0.7% triethylamine and about 98.9% water, and pH is about 3.0.
72. according to each described analytical procedure in claim 70 and 71, wherein said eluent is the gradient elution agent, it contained 100% eluent A and 0% eluent B in the time of 0 minute; In the time of about 21 minutes, contain have an appointment 100% eluent A and about 0% eluent B; In the time of about 55 minutes, contain have an appointment 45% eluent A and about 55% eluent B.
73. pharmaceutical composition, it comprises pure substantially O-ODV and pharmaceutically acceptable vehicle.
74. the method for useful in preparing drug formulations, it comprises pure substantially O-ODV and pharmaceutically acceptable carrier is mixed.
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CN106995376A (en) * | 2017-04-21 | 2017-08-01 | 上海华源医药科技发展有限公司 | A kind of industrialized producing technology of desmethylvenlafaxine |
CN109232189A (en) * | 2018-09-25 | 2019-01-18 | 杭州盛弗泰新材料科技有限公司 | A kind of preparation method of high-purity 1- hydroxyl pyrene |
CN114478271A (en) * | 2021-12-13 | 2022-05-13 | 植恩生物技术股份有限公司 | Preparation method of desvenlafaxine succinate |
CN114478271B (en) * | 2021-12-13 | 2024-05-31 | 植恩生物技术股份有限公司 | Preparation method of desmethylvenlafaxine succinate |
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CN105348119B (en) * | 2015-11-04 | 2017-09-15 | 江苏豪森药业集团有限公司 | Crystalline Venlafaxine metabolin and preparation method thereof |
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CN106995376A (en) * | 2017-04-21 | 2017-08-01 | 上海华源医药科技发展有限公司 | A kind of industrialized producing technology of desmethylvenlafaxine |
CN109232189A (en) * | 2018-09-25 | 2019-01-18 | 杭州盛弗泰新材料科技有限公司 | A kind of preparation method of high-purity 1- hydroxyl pyrene |
CN109232189B (en) * | 2018-09-25 | 2021-10-08 | 杭州盛弗泰新材料科技有限公司 | Preparation method of high-purity 1-hydroxypyrene |
CN114478271A (en) * | 2021-12-13 | 2022-05-13 | 植恩生物技术股份有限公司 | Preparation method of desvenlafaxine succinate |
CN114478271B (en) * | 2021-12-13 | 2024-05-31 | 植恩生物技术股份有限公司 | Preparation method of desmethylvenlafaxine succinate |
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