CN106117186B - A kind of preparation method of voriconazole and its intermediate - Google Patents
A kind of preparation method of voriconazole and its intermediate Download PDFInfo
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- CN106117186B CN106117186B CN201610426022.3A CN201610426022A CN106117186B CN 106117186 B CN106117186 B CN 106117186B CN 201610426022 A CN201610426022 A CN 201610426022A CN 106117186 B CN106117186 B CN 106117186B
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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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- 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
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Abstract
The present invention provides a kind of preparation methods preparing voriconazole and its intermediate by voriconazole isomers.This method is using voriconazole isomers as raw material, under basic reaction conditions, is reacted 1~24 hour at 25~100 DEG C, then carry out condensation reaction, prepares voriconazole raceme, and voriconazole is obtained after carrying out chiral resolution to voriconazole raceme.Using the largely discarded voriconazole isomers generated in this method recoverable commercial process, the waste of supplementary material and resource during preparing voriconazole is avoided.Production cost can not only be greatly reduced, cycle production can also be developed, play economizing on resources and the purpose of environmental protection.
Description
Technical field
The present invention relates to medicinal chemistry arts, and in particular to the second generation for treating acute or chronic deep fungal infection
Triazole antifungal agent voriconazole and its a kind of new preparation method of intermediate.
Background technology
Voriconazole is a chiral drug, is contained in molecule there are two chiral centre, there are four isomers.Respectively (2R,
3S/2S, 3R) and (2S, 3S/2R, 3R).Structure activity study (SAR) confirms, wherein the antibacterial of (2R, 3S/2S, 3R) enantiomer
Activity is 200 times or more of (2S, 3S/2R, 3R) enantiomer.It is further a pair of to (2R, 3S/2S, 3R) with excellent activity
The experimental study that enantiomer is split, the results showed that, single isomers (2R, 3S), i.e. voriconazole.To Aspergillus (fungi)
Inhibitory activity be 200 times or more of (2S, 3R) isomers, and be compared to (2S, 3R), isomers (2R, 3S) has wider
General antimicrobial spectrum.The active constituent (API) clinically used at present is (2R, 3S) individual isomer with absolute configuration.
The method for preparing voriconazole of document report is summed up mainly by two approach, wherein one is first to prepare
Then (2R, 3S/2S, 3R) raceme splits and prepares.Article 2 approach is to be carried out not using chiral reagent (catalyst or ligand)
Symmetrical condensation is directly prepared.Now above two approach for 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 reports is all first to prepare voriconazole raceme (2R, 3S/2S, 3R mixture, respectively account for
50%) two pairs of diastereoisomer physical properties then, are utilized by forming two pairs of diastereoisomers with chiral camphor sulfonic acid
The difference of (solubility), and then achieve the purpose that fractionation.Voriconazole is prepared using such method, reaction condition is simple, is suitble to
In industrialized production, but there is also apparent defect, it is mainly manifested in and prepares voriconazole raceme (2R, 3S/2S, 3R) mistake
Cheng Zhong inevitably generates (2S, 3S/2R, 3R) a pair of of isomers, and (2S, 3S/2R, 3R) is as the non-right of voriconazole
Though reflecting isomers can remove by recrystallizing, it is reduction of the conversion ratio of target product eventually, and then eventually reduce receipts
Rate.On the other hand, in carrying out optical resolution preparation process to voriconazole raceme (2R, 3S/2S, 3R), inevitably
Give up (2S, 3R) isomers again.Total recovery during preparing voriconazole product is caused at least to reduce by 50% again.(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 reports is mainly the pyrimidine ring structure fragment and 2' in voriconazole, bis- fluoro- 2- [1- of 4'-
(1H-1,2,4- triazolyls)] acetophenone introduced during carrying out carbonyl addition or in pyrimidine ring structure fragment it is chiral
Auxiliary reagent, or by the way that transition-metal catalyst in the condensation process, is added, chiral ligand (reagent) carries out asymmetric induction
Reaction prepares voriconazole (2R, 3S) isomers.Voriconazole is prepared using such strategy, advantage is that (2R, 3S) isomers accounts for
Relatively high (generally higher than 50%), but there is also following problems at present, first, preparing voriconazole in asymmetric syntheses
Or in which during mesosome, needs to use expensive and be difficult to transition-metal catalyst (such as bi triphenyl largely obtained
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), currently, such method is still within laboratory, to prepare volt on a small scale vertical
Health azoles sample stage, cannot be satisfied requirement of the industrialized production to cost control.Although being lied prostrate second is that being prepared using asymmetric syntheses
Vertical health azoles, makes the content accounting of (2R, 3S) isomers improve, but due to the selective problems of asymmetric syntheses, increase rate has
It limits, in the voriconazole of preparation, the content of isomer impurities (2S, 3R) still can account for (5%~30%), therefore final
The voriconazole product of acquisition isomer impurities content qualification is such as needed, there is still a need for carry out deconsolidation process for subsequent purification.It needs
It is mentioned that document [11], the method for [14] report only improve (2R, 3S/2S, 3R) isomers pair and (2S, 3S/2R, 3R)
The ratio of isomers pair, because rather than proper asymmetric syntheses, only to the optimization of method for splitting.
To sum up, using above method preparation of compounds of formula I, the limitation due to theoretical and big production to cost control, though it can
To be optimized to partial parameters, but in commercial process, supplementary material utilization rate still can not be greatly improved, and then obtain
Yield is higher, the lower voriconazole bulk pharmaceutical chemicals of production cost, thus a kind of urgently new technical solution, to provide more preferably work
Skill condition improves supplementary material utilization rate, reduces the wasting of resources and environmental protection, reduces production cost to greatest extent, make it more
Be conducive to large-scale industrial production.
Invention content
The object of the present invention is to provide a kind of preparation sides preparing voriconazole and its intermediate by voriconazole isomers
Method, this method have supplementary material utilization rate high, and reaction condition is mild, and raw material is low with reagent toxicity, and it is simple to isolate and purify process, non-
It is very suitable for heavy industrialization cycle production.
The present invention provides a kind of preparation method of voriconazole intermediate, which is characterized in that includes the following steps:It is vertical to lie prostrate
Health azoles isomers is raw material, and under alkaline condition, compound ii and compound III are obtained after reacted and post-processing;
The voriconazole isomers, which refers to two chiral centres in voriconazole molecule, has 2S, 3S or 2R, 3R
Or the molecule of 2S, 3R configuration or the mixture of its pharmaceutically acceptable salt or above-mentioned substance;
The alkaline condition refers to the mixed liquor of alkaline aqueous solution or alkaline aqueous solution and organic solvent;
Wherein, the organic solvent is selected from hydrocarbon, halogenated hydrocarbons, ester or ether;Hydrocarbon or halogenated hydrocarbons are selected from toluene, bis- chloroethenes of 1,2-
Alkane, dichloromethane, chloroform;It is preferred that 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, isopropyl ether or methyl tertiary butyl ether(MTBE);
Wherein, the alkali for preparing alkaline aqueous solution is selected from alkali or alkaline earth metal cation and OH-, CO3 2-,
HCO3 -, H-,-OCH3,-OC2H5,-OC4H9;It is preferred that NaOH, KOH, Na2CO3, K2CO3, NaH, NaOCH3, KOCH3, Ca (OH)2Deng;
Wherein, a concentration of 0.01~12mol/L of the alkaline aqueous solution;Preferably, a concentration of 0.5~10mol/L;Compared with
Preferably, a concentration of 1~8mol/L;More preferably, a concentration of 2~6mol/L;More preferably, a concentration of 2.5~5mol/L;Most
Preferably, a concentration of 3mol/L;
Wherein, the molar ratio of the voriconazole isomers and alkali is 1:0.5~20.0;More preferably, ratio is
1:1.0~15.0;More preferably, ratio 1:1.2~10.0;More preferably, ratio 1:1.2~7.0;Most preferably, than
Example is 1:4.5;
Wherein, the temperature that the voriconazole isomers is reacted with alkaline aqueous solution 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 the voriconazole isomers is reacted with alkaline aqueous solution is 1~24 hour;Preferably,
Reaction time is 2~12 hours;Preferably, the reaction time is 4~6 hours;
The post-reaction treatment step includes extraction, concentration, distillation;Preferably, the post-processing includes first extracting
The extract liquor for including compound ii and compound III is isolated, then extract liquor is concentrated, residue solid is obtained, to described
Residue solid carries out recrystallization or can be obtained compound III without recrystallization;It is collected simultaneously the concentrate that concentration obtains, then
Concentrate is distilled, compound ii is obtained;
In addition, the present invention also provides a kind of preparation methods of voriconazole, which is characterized in that include the following steps:With
Voriconazole isomers is raw material, under alkaline condition, compound ii and compound III is obtained after reacted and post-processing, by chemical combination
Object II carries out condensation reaction with compound III, prepares voriconazole racemic modification, and light is carried out to voriconazole racemic modification
It learns and splits, voriconazole, i.e. chemical compounds I are obtained after refined;
The condensation reaction refer to will after compound ii bromo with compound III carry out Reformatsky reaction, or
Person carries out condensation reaction in the presence ofs diisopropylamino lithium or hexamethl disilamine base lithium etc.;
The method for carrying out chiral resolution to voriconazole racemic modification is the common methods of this field;Preferably,
The resolution reagent is acid resolution reagent;It is further preferred that the resolution reagent is:The chemical resolution method
Resolution reagent is acid resolution reagent;Preferably, the resolution reagent is:(+)-tartaric acid, (+)-camphoric acid, L- (+)-sweet
Propylhomoserin or L- camphor -10- sulfonic acid;It is furthermore preferred that the resolution reagent is L- camphor -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 solution provided by the invention is using voriconazole isomers as starting material, using simple reaction item
Part can prepare compound ii and compound III, without using preparing chromatography or chromatography post separation, compared to the prior art
The scheme of prepare compound II and compound III have synthetic route step it is short (only need a step can obtain simultaneously compound ii with
Compound III), high income is at low cost, it is easier to the advantage of scale industrial production.
(2) the starting material voriconazole isomers that technical solution provided by the invention uses, be prior art preparation or
The solid waste generated during voriconazole raceme or impurity are split, is the clearer production technology scheme of a kind of " turning waste into wealth ",
Prior art preparation voriconazole supplementary material utilization rate can be greatly improved, is economized on resources and environmental protection, can not only be reduced
Cost can also make production recyclableization of voriconazole.
(3) compound ii and compound III that technical solution provided by the invention prepares are subsequently used for lie prostrate vertical
The preparation of health azoles carries out dechlorination hydrogenolysis without using palladium carbon, and preparing voriconazole compared with prior art inevitably needs to make
Dechlorination hydrogenolysis is carried out with palladium carbon and has saved step chemical reaction again, not only simplifies subsequent operation, while further reduced system
The cost of standby voriconazole.
Description of the drawings
Fig. 1 is the chemical structural formula of chemical compounds I voriconazole;
Fig. 2 be using voriconazole isomers as raw material, prepare voriconazole intermediate compound ii, III reaction route
Figure;
Fig. 3 is to prepare the reaction route figure of chemical compounds I voriconazole using voriconazole isomers as raw material;
The reaction route figure of Fig. 4 embodiments 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 chemical compounds I voriconazole1HNMR collection of illustrative plates.
Specific implementation mode
Embodiment 1:
A kind of preparation method of voriconazole intermediate, which is characterized in that include the following steps:With voriconazole isomers
(2S, 3R) is raw material, takes raw material 157.5g, is reacted in NaOH aqueous solutions, a concentration of 2mol/L of NaOH, reaction temperature
It it is 50 DEG C, the reaction time is 5 hours, after reaction, reaction mixture is cooled down, first using ethyl acetate going out of extraction and separation
The mixture of object II and compound III is closed, then concentration obtains compound III, then carries out normal pressure steaming to the concentrate of collection again
It evaporates, to obtain compound ii.Compound ii and the LC-MS collection of illustrative plates of compound III are shown in attached Figures 5 and 6.
Embodiment 2:
A kind of preparation method of voriconazole, which is characterized in that include the following steps:With voriconazole isomers (2S,
It is 3R) raw material, takes raw material 157.5g, reacted in NaOH aqueous solutions, a concentration of 1mol/L of NaOH, reaction temperature 50
DEG C, the reaction time be 7 hours, after reaction, reaction mixture is cooled down, is extracted by ethyl acetate, obtain compound ii with
The mixture of compound III, then concentration obtains compound III, then carries out air-distillation to the concentrate of collection again, and obtains
Compound ii.Compound ii is used into NBS bromos (can refer to corresponding document), obtains 4- (1- bromoethyls) -5-FU.Again plus
Enter reaction reagent, carries out Reformatsky reaction condensation reaction with compound III, prepare voriconazole racemic modification, so
Chiral reagent (L)-camphor -10- sulfonic acid is added afterwards, optical resolution is carried out to above-mentioned racemic modification, resolved product is crystallized, is dissociated
Voriconazole is obtained, i.e. chemical compounds I, reaction route figure is shown in attached drawing 4.Voriconazole1HNMR collection of illustrative plates is shown in attached drawing 7.
Embodiment 3:
A kind of preparation method of voriconazole intermediate, which is characterized in that include the following steps:With voriconazole isomers
(2R, 3R/2S, 3S/2S, 3R) mixture is raw material, takes raw material 174.5g, is reacted in NaOH aqueous solutions, NaOH's is dense
Degree is 5mol/L, and reaction temperature is 45 DEG C, and the reaction time is 3 hours, after reaction, reaction mixture is cooled down, by two
Chloromethanes extracts, and obtains compound ii and the mixture of compound III, and then concentration obtains compound III, then again to the dense of collection
Contracting liquid fraction carries out air-distillation, and obtains compound ii.Compound ii and the mass spectrogram of compound III are shown in attached Figures 5 and 6.
Embodiment 4:
A kind of preparation method of voriconazole, which is characterized in that include the following steps:With voriconazole isomers (2S,
3R) camsilate is raw material, takes raw material 77.6g, is reacted in NaOH/ ethyl acetate aqueous solutions, NaOH's is a concentration of
1mol/L, reaction temperature are 60 DEG C, and the reaction time is 4 hours, after reaction, reaction mixture is cooled down, through peracetic acid second
Ester extracts, and obtains compound ii and the mixture of compound III, and then concentration obtains compound III, then again to the concentrate of collection
Fraction carries out air-distillation, and obtains compound ii.Compound ii is used into NBS bromos (can refer to corresponding document), obtains 4-
(1- bromoethyls) -5-FU.Reaction reagent is added, Reformatsky reaction condensation reaction, system are carried out with compound III
It is standby to obtain voriconazole racemic modification, chiral reagent (L)-camphor -10- sulfonic acid is then added, optics is carried out to above-mentioned racemic modification
It splits, resolved product is crystallized, dissociate and obtain voriconazole, i.e. chemical compounds I.Voriconazole1HNMR collection of illustrative plates is shown in attached drawing 7.
Claims (33)
1. a kind of preparation method of voriconazole intermediate, which is characterized in that include the following steps:It is with voriconazole isomers
Raw material obtains compound ii and compound III after reacted and post-processing under alkaline condition;
The voriconazole isomers, which refers to two chiral centres in voriconazole molecule, has 2S, 3S or 2R, 3R or 2S,
The mixture of the molecule of 3R configurations or its pharmaceutically acceptable salt or above-mentioned substance.
2. preparation method according to claim 1, which is characterized in that the voriconazole isomers and alkali feed intake mole
Than being 1:0.5~20.0.
3. preparation method according to claim 2, which is characterized in that the voriconazole isomers and alkali feed intake mole
Ratio is 1:1.0~15.0.
4. preparation method according to claim 3, which is characterized in that the voriconazole isomers and alkali feed intake mole
Ratio is 1:1.2~10.0.
5. preparation method according to claim 4, which is characterized in that the voriconazole isomers and alkali feed intake mole
Ratio is 1:1.2~7.0.
6. preparation method according to claim 5, which is characterized in that the voriconazole isomers and alkali feed intake mole
Ratio is 1:4.5.
7. preparation method according to claim 1 or 2, which is characterized in that the alkaline condition refer to alkaline aqueous solution or
The mixed liquor of alkaline aqueous solution and organic solvent.
8. preparation method according to claim 7, which is characterized in that the 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 of formation.
9. preparation method according to claim 8, which is characterized in that the alkali for preparing alkaline aqueous solution is selected from
NaOH, KOH, Na2CO3, K2CO3, NaH, NaOCH3, KOCH3Or Ca (OH)2In any one.
10. preparation method according to claim 7, which is characterized in that a concentration of the 0.01 of the alkaline aqueous solution~
12mol/L。
11. preparation method according to claim 10, which is characterized in that a concentration of the 0.5 of the alkaline aqueous solution~
10mol/L。
12. preparation method according to claim 11, which is characterized in that a concentration of 1~8mol/ of the alkaline aqueous solution
L。
13. preparation method according to claim 12, which is characterized in that a concentration of 2~6mol/ of the alkaline aqueous solution
L。
14. preparation method according to claim 13, which is characterized in that a concentration of the 2.5 of the alkaline aqueous solution~
5mol/L。
15. preparation method according to claim 14, which is characterized in that a concentration of 3mol/L of the alkaline aqueous solution.
16. preparation method according to claim 7, which is characterized in that the organic solvent be selected from hydrocarbon, halogenated hydrocarbons, ester or
Any one in ether.
17. preparation method according to claim 16, which is characterized in that wherein hydrocarbon or halogenated hydrocarbons are selected from toluene, 1,2- bis-
Any one in chloroethanes, dichloromethane or chloroform.
18. preparation method according to claim 16, which is characterized in that ester is selected from Ethyl formate, methyl acetate, acetic acid second
Any one in ester, butyl acetate or propyl acetate.
19. preparation method according to claim 16, which is characterized in that ether is selected from ether, isopropyl ether or methyl tertbutyl
Any one in ether.
20. preparation method according to claim 7, which is characterized in that the voriconazole isomers and alkaline aqueous solution
The temperature reacted is 25~100 DEG C.
21. preparation method according to claim 20, which is characterized in that the voriconazole isomers and alkaline aqueous solution
The temperature reacted is 30~80 DEG C.
22. preparation method according to claim 21, which is characterized in that the voriconazole isomers and alkaline aqueous solution
The temperature reacted is 40~70 DEG C.
23. preparation method according to claim 22, which is characterized in that the voriconazole isomers and alkaline aqueous solution
The temperature reacted is 50~60 DEG C.
24. preparation method according to claim 7, which is characterized in that the voriconazole isomers and alkaline aqueous solution
The time reacted is 1~24 hour.
25. preparation method according to claim 24, which is characterized in that the voriconazole isomers and alkaline aqueous solution
The time reacted is 2~12 hours.
26. preparation method according to claim 25, which is characterized in that the voriconazole isomers and alkaline aqueous solution
The time reacted is 4~6 hours.
27. preparation method according to claim 1 or 2, which is characterized in that the post-reaction treatment step includes extraction
It takes, concentrate and distills.
28. preparation method according to claim 27, which is characterized in that the post-reaction treatment step includes first extracting
The extract liquor for including compound ii and compound III is isolated, then extract liquor is concentrated, residue solid is obtained, to described
Residue carries out recrystallization or can be obtained compound III without recrystallization;It is collected simultaneously the concentrate that concentration obtains, then to dense
Contracting liquid is distilled, and compound ii is obtained.
29. a kind of preparation method of voriconazole, which is characterized in that include the following steps:Using voriconazole isomers as raw material,
Under alkaline condition, compound ii and compound III are obtained after reacted and post-processing, compound ii and compound III are contracted
Reaction is closed, voriconazole racemic modification is prepared, chiral resolution is carried out to voriconazole racemic modification, it is vertical to obtain volt after refining
Health azoles, i.e. chemical compounds I;
Wherein, the voriconazole isomers, which refers to two chiral centres in voriconazole molecule, has 2S, 3S or 2R, 3R
Or the molecule of 2S, 3R configuration or the mixture of its pharmaceutically acceptable salt or above-mentioned substance.
30. preparation method according to claim 29, which is characterized in that the condensation reaction refers to by compound ii bromine
Dai Houyu compound IIIs carry out Reformatsky reaction, or in the presence such as diisopropylamino lithium or hexamethl disilamine base lithium
Lower carry out condensation reaction.
31. preparation method according to claim 30, which is characterized in that described to carry out hand to voriconazole racemic modification
Property split method be chemical resolution method.
32. preparation method according to claim 31, which is characterized in that the resolution reagent of the chemical resolution method is acid
Property resolution reagent.
33. preparation method according to claim 32, which is characterized in that the resolution reagent is:(+)-tartaric acid,
(+)-camphoric acid, L- (+)-glycine or L- camphor -10- sulfonic acid.
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CN1053787A (en) * | 1990-02-02 | 1991-08-14 | 美国辉瑞有限公司 | Triazole antifungal agent |
CN1814597A (en) * | 2005-12-09 | 2006-08-09 | 北京丰德医药科技有限公司 | New method for preparing voriconazole |
WO2014108474A1 (en) * | 2013-01-11 | 2014-07-17 | Xellia Pharmaceuticals Aps | Voriconazole inclusion complexes |
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2016
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CN1053787A (en) * | 1990-02-02 | 1991-08-14 | 美国辉瑞有限公司 | Triazole antifungal agent |
CN1814597A (en) * | 2005-12-09 | 2006-08-09 | 北京丰德医药科技有限公司 | New method for preparing voriconazole |
WO2014108474A1 (en) * | 2013-01-11 | 2014-07-17 | Xellia Pharmaceuticals Aps | Voriconazole inclusion complexes |
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Title |
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Process Development of Voriconazole: A Novel Broad-Spectrum Triazole;Mike Butters et al.;《Organic Process Research & Development》;20001121;第5卷;28-36 * |
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