CN106117186A - A kind of voriconazole and the preparation method of intermediate thereof - Google Patents
A kind of voriconazole and the preparation method of intermediate thereof Download PDFInfo
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- CN106117186A CN106117186A CN201610426022.3A CN201610426022A CN106117186A CN 106117186 A CN106117186 A CN 106117186A CN 201610426022 A CN201610426022 A CN 201610426022A CN 106117186 A CN106117186 A CN 106117186A
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- voriconazole
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- 0 *C1=CN(CC(C(C2)c3ncncc3F)(c(c(F)c3)*2cc3F)O)N=CC1 Chemical compound *C1=CN(CC(C(C2)c3ncncc3F)(c(c(F)c3)*2cc3F)O)N=CC1 0.000 description 2
- AYZDRTRWCASUFO-UHFFFAOYSA-N CCc1ncncc1F Chemical compound CCc1ncncc1F AYZDRTRWCASUFO-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
Abstract
The invention provides a kind of preparation method being prepared voriconazole and intermediate thereof by voriconazole isomer.This method is with voriconazole isomer as raw material, under basic reaction conditions, reacts 1~24 hour, then carries out condensation reaction, prepare voriconazole raceme at 25~100 DEG C, obtains voriconazole after voriconazole raceme carries out chiral separation.Use a large amount of discarded voriconazole isomers produced in this method recoverable commercial process, it is to avoid prepare supplementary material and the waste of resource during voriconazole.It is possible not only to production cost is greatly reduced, it is also possible to development cyclic production, plays the purpose economizing on resources and protecting environment.
Description
Technical field
The present invention relates to medicinal chemistry art, be particularly used for treating the second filial generation of acute or chronic deep fungal infection
Triazole antifungal agent voriconazole and a kind of new preparation method of intermediate thereof.
Background technology
Voriconazole is a chiral drug, containing two chiral centres in molecule, has four isomers.Be respectively (2R,
3S/2S, 3R) and (2S, 3S/2R, 3R).Structure activity study (SAR) confirms, wherein (2R, 3S/2S, 3R) enantiomer is antibacterial
Activity is more than 200 times of (2S, 3S/2R, 3R) enantiomer.Further to (2R, 3S/2S, the 3R) a pair with excellent activity
Enantiomer carries out the experimental study split, and result shows, single isomer (2R, 3S), i.e. voriconazole.To aspergillosis (fungus)
More than 200 times that inhibitory activity is (2S, 3R) isomer, and be compared to (2S, 3R), isomer (2R, 3S) has wider
General antimicrobial spectrum.The active component (API) used clinically at present is (2R, the 3S) individual isomer with absolute configuration.
The method preparing voriconazole of document report is summed up main by two approach, and wherein one for first to prepare
(2R, 3S/2S, 3R) raceme, then splits preparation.Article 2 approach is carried out not for using chiral reagent (catalyst or part)
Symmetrical condensation directly preparation.Now above two approach preparing voriconazole are explained in detail.
(1) Split Method: document [1] _ WO2012114273A1, [2] _ CN102516233A, [3] _ CN102190628A,
[4]_WO2009084029A2,[5]_CN1814597A,[6]_CN1488630A,[7]_CN1473825A,[8]_Organic
Process Research&Development(2001),5(1),28-36,[9]_WO9706160A1,[10]_
The method of WO2008075205A2 report is all first to prepare voriconazole raceme (2R, 3S/2S, 3R mixture, respectively accounts for
50%), then by being formed two to diastereomer with chiral camphor sulfonic acid, two are utilized to diastereomer physical property
The difference of (dissolubility), and then reach the purpose split.Using this kind of way to prepare voriconazole, reaction condition is simple, is suitable for
In industrialized production, but there is also obvious defect, be mainly manifested in and prepare voriconazole raceme (2R, 3S/2S, 3R) mistake
Cheng Zhong, inevitably generates (2S, 3S/2R, 3R) a pair isomer, (2S, 3S/2R, 3R) non-right as voriconazole
Though reflecting isomer to be removed by recrystallization, but eventually it is reduction of the conversion ratio of target product, and then eventually reduces receipts
Rate.On the other hand, voriconazole raceme (2R, 3S/2S, 3R) is being carried out in optical resolution preparation process, inevitably
Give up (2S, 3R) isomer again.During causing preparing voriconazole product, total recovery the most at least reduces by 50%.(2) no
Symmetrical synthetic method: document [11] _ CN1919846A, [12] _ CN104987325A, [13] _ WO2015041148A1, [14] _
CN103788073A,[15]_Journal of Organic Chemistry(2013),78(22),11396-11403,[16]_
The method of WO2014060900A1 report is mainly at pyrimidine ring structure fragment and 2', the 4'-bis-fluoro-2-[1-of voriconazole
(1H-1,2,4-triazolyls)] 1-Phenylethanone. is during carrying out carbonyl addition, or introduce chirality at pyrimidine ring structure fragment
Auxiliary reagent, or by the condensation process, add transition-metal catalyst, chiral ligand (reagent) carries out asymmetric induction
Voriconazole (2R, 3S) isomer is prepared in reaction.Using this kind of strategy to prepare voriconazole, advantage is that (2R, 3S) isomer accounts for
Relatively high (generally higher than 50%), but currently also there is following problem, one is to prepare voriconazole in asymmetric synthesis
Or during its intermediate, need to use to transition-metal catalyst that is expensive and that be difficult to obtain in a large number (such as bi triphenyl
Phosphorus palladium chloride (II), CuF (PPh3) 2) and chiral ligand ((S)-1-((SP)-2-[2-(diphenylphosphine) phenyl] ferrocene
Base) ethyl two [3,5-bis-(trifluoromethyl) phenyl] phosphine), at present, this kind of method is still within test chamber preparation volt on a small scale and stands
Health azoles sample stage, it is impossible to meet the industrialized production requirement to cost control.Although two is to use asymmetric synthesis preparation volt
Vertical health azoles, makes the content accounting of (2R, 3S) isomer improve, but due to the selective problems of asymmetric synthesis, increase rate has
Limit, in the middle of the voriconazole of preparation, the content of isomer impurities (2S, 3R) still can account for (5%~30%), the most finally
The voriconazole product qualified if desired for obtaining isomer impurities content, subsequent purification need nonetheless remain for carrying out deconsolidation process.Need
Being mentioned that document [11], the method that [14] are reported simply improves (2R, 3S/2S, 3R) isomer pair and (2S, 3S/2R, 3R)
The ratio of isomer pair, because of rather than proper asymmetric synthesis, the simply optimization to method for splitting.
To sum up, make formula I in aforementioned manners, due to theoretical and produce greatly the restriction to cost control, though can
So that partial parameters is optimized, but in commercial process, supplementary material utilization rate still cannot be greatly improved, and then obtain
Yield is higher, the voriconazole crude drug that production cost is lower, for this kind of new technical scheme, to provide more excellent work
Skill condition, improves supplementary material utilization rate, reduces the wasting of resources and protection environment, reduces production cost to greatest extent so that it is more
Be conducive to large-scale industrial production.
Summary of the invention
It is an object of the invention to provide and a kind of prepared voriconazole and the preparation side of intermediate thereof by voriconazole isomer
Method, it is high that the method has supplementary material utilization rate, and reaction condition is gentle, and raw material is low with reagent toxicity, and isolated and purified process is simple, non-
It is very suitable for heavy industrialization cyclic production.
The present invention provides the preparation method of a kind of voriconazole intermediate, it is characterised in that comprise the following steps: vertical with volt
Health azoles isomer is raw material, under the conditions of alkalescence, after reacted and post processing compound ii and compound III;
Described voriconazole isomer refers to that two chiral centres in voriconazole molecule have 2S, 3S or 2R, 3R
Or the molecule of 2S, 3R configuration or its pharmaceutically acceptable salt or the mixture of above-mentioned substance;
Described alkalescence condition refers to the mixed liquor of alkaline aqueous solution or alkaline aqueous solution and organic solvent;
Wherein, described organic solvent is selected from hydrocarbon, halogenated hydrocarbons, ester or ether;Hydrocarbon or halogenated hydrocarbons are selected from toluene, 1,2-bis-chloroethene
Alkane, dichloromethane, chloroform;Preferably 1,2-dichloroethanes or dichloromethane;Ester is selected from Ethyl formate, methyl acetate, acetic acid
Ethyl ester, butyl acetate or propyl acetate;Ether is selected from ether, diisopropyl ether or methyl tertiary butyl ether(MTBE);
Wherein, the described alkali for preparing alkaline aqueous solution is selected from alkali metal or alkaline earth metal cation and OH-, CO3 2-,
HCO3 -, H-,-OCH3,-OC2H5,-OC4H9;Preferably NaOH, KOH, Na2CO3, K2CO3, NaH, NaOCH3, KOCH3, Ca (OH)2Deng;
Wherein, the concentration of described alkaline aqueous solution is 0.01~12mol/L;Preferably, concentration is 0.5~10mol/L;Relatively
Preferably, concentration is 1~8mol/L;More preferably, concentration is 2~6mol/L;More preferably, concentration is 2.5~5mol/L;?
Preferably, concentration is 3mol/L;
Wherein, described voriconazole isomer is 1:0.5~20.0 with the molar ratio of alkali;More preferably, ratio is
1:1.0~15.0;More preferably, ratio is 1:1.2~10.0;More preferably, ratio is 1:1.2~7.0;Most preferably, than
Example is 1:4.5;
Wherein, the temperature that described voriconazole isomer and alkaline aqueous solution carry out reacting is 25~100 DEG C;Preferably,
Reaction temperature is 30~80 DEG C;More preferably, reaction temperature is 40~70 DEG C;It is furthermore preferred that reaction temperature is 50~60 DEG C;
Wherein, the time that described voriconazole isomer and alkaline aqueous solution carry out reacting is 1~24 hour;Preferably,
Response time is 2~12 hours;Preferably, the response time is 4~6 hours;
Described post-reaction treatment step includes extracting, concentrates, distills;Preferably, described post processing includes first extracting
Isolate the extract of inclusion compound II and compound III, then extract is concentrated, it is thus achieved that residue solid, to described
Residue solid carries out recrystallization or does not carry out recrystallization and can obtain compound III;Collect simultaneously and concentrate the concentrated solution obtained, then
Concentrated solution is distilled, it is thus achieved that compound ii;
It addition, present invention also offers the preparation method of a kind of voriconazole, it is characterised in that comprise the following steps: with
Voriconazole isomer is raw material, in the basic conditions, after reacted and post processing compound ii and compound III, by chemical combination
Thing II and compound III carry out condensation reaction, prepare voriconazole racemic modification, voriconazole racemic modification is carried out light
Learn and split, after refining, obtain voriconazole, i.e. compounds I;
Described condensation reaction refers to carry out Reformatsky reaction with compound III after compound ii bromo, or
Person carries out condensation reaction in the presence of diisopropylamino lithium or hexamethl disilamine base lithium etc.;
The described common methods that method is this area that voriconazole racemic modification is carried out chiral separation;Preferably,
Described resolution reagent is acid resolution reagent;It is further preferred that described resolution reagent is: described chemical resolution method
Resolution reagent is acid resolution reagent;Preferably, described resolution reagent is: (+)-tartaric acid, (+)-dextrocamphoric acid., L-(+)-sweet
Propylhomoserin or L-Camphora-10-sulfonic acid;It is furthermore preferred that described resolution reagent is L-Camphora-10-sulfonic acid.
Beneficial effects of the present invention
Compared with prior art, the technological merit that the present invention embodies is embodied in the following aspects:
(1) technical scheme that the present invention provides is with voriconazole isomer as initiation material, uses and simply reacts bar
Part can prepare compound ii and compound III, it is not necessary to uses preparative hplc or chromatographic column to separate, compared to prior art
Prepare the scheme of compound ii and compound III have synthetic route step short (only need a step can obtain simultaneously compound ii with
Compound III), yield is high, low cost, it is easier to the advantage that large-scale industrial produces.
(2) present invention provide technical scheme use initiation material voriconazole isomer, be prior art preparation or
The solid waste produced during splitting voriconazole raceme or impurity, be the clearer production technology scheme of a kind of " turning waste into wealth ",
Prior art can be greatly improved and prepare voriconazole supplementary material utilization rate, economize on resources and protect environment, not only can reduce
Cost, can also make production capable of circulationization of voriconazole.
(3) present invention provides the compound ii for preparing of technical scheme and compound III, be subsequently used for carrying out volt vertical
The preparation of health azoles is prepared voriconazole inevitably need to make without being used palladium carbon to carry out dechlorination hydrogenolysis, relatively prior art
Carry out dechlorination hydrogenolysis with palladium carbon and saved again a step chemical reaction, not only simplify subsequent operation, reduce further system simultaneously
The cost of standby voriconazole.
Accompanying drawing explanation
Fig. 1 is the chemical structural formula of compounds I voriconazole;
Fig. 2 is with voriconazole isomer as raw material, prepares voriconazole intermediate compound ii, the reaction scheme of III
Figure;
Fig. 3 is with voriconazole isomer as raw material, prepares the reaction scheme figure of compounds I voriconazole;
The reaction scheme figure of Fig. 4 embodiment 2;
Fig. 5 is LC-MS (LC-MS) collection of illustrative plates of compound ii;
Fig. 6 is LC-MS (LC-MS) collection of illustrative plates of compound III;
Fig. 7 is compounds I voriconazole1HNMR collection of illustrative plates.
Detailed description of the invention
Embodiment 1:
The preparation method of a kind of voriconazole intermediate, it is characterised in that comprise the following steps: with voriconazole isomer
(2S, 3R) is raw material, takes raw material 157.5g, reacts in NaOH aqueous solution, and the concentration of NaOH is 2mol/L, reaction temperature
Being 50 DEG C, the response time is 5 hours, after reaction terminates, is cooled down by reaction mixture, first uses ethyl acetate going out of extract and separate
Compound II and the mixture of compound III, then concentrate and obtain compound III, the most again the concentrated solution collected is carried out normal pressure steaming
Evaporate, to obtain compound ii.Accompanying drawing 5 and 6 is shown in by the LC-MS collection of illustrative plates of compound ii and compound III.
Embodiment 2:
The preparation method of a kind of voriconazole, it is characterised in that comprise the following steps: with voriconazole isomer (2S,
3R) being raw material, take raw material 157.5g, react in NaOH aqueous solution, the concentration of NaOH is 1mol/L, and reaction temperature is 50
DEG C, the response time is 7 hours, reaction terminate after, by reaction mixture cool down, through ethyl acetate extract, obtain compound ii with
The mixture of compound III, then concentrates and obtains compound III, the most again the concentrated solution collected is carried out air-distillation, and obtain
Compound ii.Compound ii is used NBS bromo (referring to corresponding document), it is thus achieved that 4-(1-bromoethyl)-5-FU.Add again
Enter reaction reagent, carry out Reformatsky reaction condensation reaction with compound III, prepare voriconazole racemic modification, so
Rear addition chiral reagent (L)-Camphora-10-sulfonic acid carries out optical resolution to above-mentioned racemic modification, resolved product is crystallized, free
Obtaining voriconazole, i.e. compounds I, reaction scheme figure is shown in accompanying drawing 4.Voriconazole1Accompanying drawing 7 is shown in by HNMR collection of illustrative plates.
Embodiment 3:
The preparation method of a kind of voriconazole intermediate, it is characterised in that comprise the following steps: with voriconazole isomer
(2R, 3R/2S, 3S/2S, 3R) mixture is raw material, takes raw material 174.5g, reacts in NaOH aqueous solution, and NaOH's is dense
Degree is 5mol/L, and reaction temperature is 45 DEG C, and the response time is 3 hours, after reaction terminates, is cooled down by reaction mixture, through two
Chloromethanes extracts, and obtains the mixture of compound ii and compound III, then concentrates and obtain compound III, dense to collect the most again
Contracting liquid fraction carries out air-distillation, and obtains compound ii.The mass spectrum of compound ii and compound III is shown in accompanying drawing 5 and 6.
Embodiment 4:
The preparation method of a kind of voriconazole, it is characterised in that comprise the following steps: with voriconazole isomer (2S,
3R) camsilate is raw material, takes raw material 77.6g, reacts in NaOH/ ethyl acetate aqueous solution, and the concentration of NaOH is
1mol/L, reaction temperature is 60 DEG C, and the response time is 4 hours, after reaction terminates, is cooled down by reaction mixture, through peracetic acid second
Ester extracts, and obtains the mixture of compound ii and compound III, then concentrates and obtain compound III, the most again to the concentrated solution collected
Fraction carries out air-distillation, and obtains compound ii.Compound ii is used NBS bromo (referring to corresponding document), it is thus achieved that 4-
(1-bromoethyl)-5-FU.Add reaction reagent, carry out Reformatsky reaction condensation reaction with compound III, system
Standby acquisition voriconazole racemic modification, is subsequently adding chiral reagent (L)-Camphora-10-sulfonic acid and above-mentioned racemic modification is carried out optics
Split, resolved product is crystallized, free acquisition voriconazole, i.e. compounds I.Voriconazole1Accompanying drawing 7 is shown in by HNMR collection of illustrative plates.
Claims (17)
1. the preparation method of a voriconazole intermediate, it is characterised in that comprise the following steps: be with voriconazole isomer
Raw material, in the basic conditions, after reacted and post processing compound ii and compound III;
Preparation method the most according to claim 1, it is characterised in that described voriconazole isomer refers to voriconazole
Two chiral centres in molecule have 2S, 3S or 2R, the molecule of 3R or 2S, 3R configuration or its pharmaceutically acceptable salt or on
State the mixture of material.
Preparation method the most according to claim 1, it is characterised in that described alkalescence condition refers to alkaline aqueous solution or alkalescence
Aqueous solution and the mixed liquor of organic solvent.
Preparation method the most according to claim 3, it is characterised in that the described alkali for preparing alkaline aqueous solution is selected from alkali
Metal or alkaline earth metal cation and OH-, CO3 2-, HCO3 -, H-,-OCH3,-OC2H5,-OC4H9The alkali formed;Preferably NaOH,
KOH, Na2CO3, K2CO3, NaH, NaOCH3, KOCH3Or Ca (OH)2。
Preparation method the most according to claim 3, it is characterised in that the concentration of described alkaline aqueous solution be 0.01~
12mol/L;Preferably, concentration is 0.5~10mol/L;More preferably, concentration is 1~8mol/L;More preferably, concentration be 2~
6mol/L;More preferably, concentration is 2.5~5mol/L;Most preferably, concentration is 3mol/L.
Preparation method the most according to claim 3, it is characterised in that described organic solvent selected from hydrocarbon, halogenated hydrocarbons, ester or
Ether.
Preparation method the most according to claim 6, it is characterised in that hydrocarbon or halogenated hydrocarbons selected from toluene, 1,2-dichloroethanes,
Dichloromethane or chloroform;Preferably 1,2-dichloroethanes or dichloromethane.
Preparation method the most according to claim 6, it is characterised in that ester is selected from Ethyl formate, methyl acetate, acetic acid second
Ester, butyl acetate or propyl acetate.
Preparation method the most according to claim 6, it is characterised in that ether is selected from ether, diisopropyl ether or methyl tertiary butyl ether(MTBE).
Preparation method the most according to claim 1, it is characterised in that described voriconazole isomer rubs with feeding intake of alkali
That ratio is 1:0.5~20.0;More preferably, ratio is 1:1.0~15.0;More preferably, ratio is 1:1.2~10.0;More excellent
Choosing, ratio is 1:1.2~7.0;Most preferably, ratio is 1:4.5.
11. preparation methoies according to claim 3, it is characterised in that described voriconazole isomer and alkaline aqueous solution
The temperature carrying out reacting is 25~100 DEG C;Preferably, reaction temperature is 30~80 DEG C;More preferably, reaction temperature is 40~70
℃;It is furthermore preferred that reaction temperature is 50~60 DEG C.
12. preparation methoies according to claim 3, it is characterised in that described voriconazole isomer and alkaline aqueous solution
The time carrying out reacting is 1~24 hour;Preferably, the response time is 2~12 hours;It is furthermore preferred that the response time is 4~6
Hour.
13. preparation methoies according to claim 1, it is characterised in that described post-reaction treatment step include extraction, dense
Contracting, distillation;Preferably, described post processing includes that first extract and separate goes out the extract of inclusion compound II and compound III, so
Afterwards extract is concentrated, it is thus achieved that residue solid, described residue is carried out recrystallization or do not carry out recrystallization can acquisition
Compound III;Collect simultaneously and concentrate the concentrated solution obtained, then concentrated solution is distilled, it is thus achieved that compound ii.
The preparation method of 14. 1 kinds of voriconazoles, it is characterised in that comprise the following steps: with voriconazole isomer as raw material,
In the basic conditions, after reacted and post processing compound ii and compound III, compound ii is contracted with compound III
Close reaction, prepare voriconazole racemic modification, voriconazole racemic modification is carried out chiral separation, obtain volt after refining vertical
Health azoles, i.e. compounds I;
15. preparation methoies according to claim 14, it is characterised in that described condensation reaction refers to compound ii bromine
Dai Houyu compound III carries out Reformatsky reaction, or exists at diisopropylamino lithium or hexamethl disilamine base lithium etc.
Under carry out condensation reaction.
16. preparation methoies according to claim 14, it is characterised in that described carries out hands to voriconazole racemic modification
Property split method be chemical resolution method.
17. preparation methoies according to claim 16, it is characterised in that the resolution reagent of described chemical resolution method is acid
Property resolution reagent;Preferably, described resolution reagent is: (+)-tartaric acid, (+)-dextrocamphoric acid., L-(+)-glycine or L-Camphor tree
Brain-10-sulfonic acid;It is furthermore preferred that described resolution reagent is L-Camphora-10-sulfonic acid.
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Cited By (3)
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CN107827876A (en) * | 2017-10-27 | 2018-03-23 | 江苏理工学院 | A kind of preparation method of voriconazole raceme |
WO2020169025A1 (en) * | 2019-02-19 | 2020-08-27 | 浙江华海立诚药业有限公司 | Method for preparing voriconazole and intermediate thereof |
WO2021127965A1 (en) * | 2019-12-24 | 2021-07-01 | 刘杰 | Method for recycling voriconazole enantiomer |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107827876A (en) * | 2017-10-27 | 2018-03-23 | 江苏理工学院 | A kind of preparation method of voriconazole raceme |
WO2020169025A1 (en) * | 2019-02-19 | 2020-08-27 | 浙江华海立诚药业有限公司 | Method for preparing voriconazole and intermediate thereof |
CN113614075A (en) * | 2019-02-19 | 2021-11-05 | 浙江华海药业股份有限公司 | Preparation method of voriconazole and intermediate thereof |
WO2021127965A1 (en) * | 2019-12-24 | 2021-07-01 | 刘杰 | Method for recycling voriconazole enantiomer |
CN114829354A (en) * | 2019-12-24 | 2022-07-29 | 刘杰 | Recovery method of voriconazole enantiomer |
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