CN106588889A - Preparation method of voriconazole - Google Patents
Preparation method of voriconazole Download PDFInfo
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- CN106588889A CN106588889A CN201611059650.9A CN201611059650A CN106588889A CN 106588889 A CN106588889 A CN 106588889A CN 201611059650 A CN201611059650 A CN 201611059650A CN 106588889 A CN106588889 A CN 106588889A
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- 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
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Abstract
The invention discloses a preparation method of voriconazole, which includes the steps of: dissolving a compound B in a solvent, controlling the temperature of the reaction liquid to be -70 - 0 DEG C, stirring the reaction liquid, adding alkali with stirring and controlling the temperature of the reaction liquid to be -70 - 0 DEG C, stirring the reaction liquid, dropwise adding a mixed liquid of A and a solvent, and after the mixed liquid is added completely, controlling the temperature of the reaction liquid to be -70 - 0 DEG C to perform a reaction for 2-48 h to obtain the compound (1). In the process, a required chiral configuration is introduced from the raw material A, so that the method has high stereoselectivity and is free of chiral resolution in the subsequent steps. Qualified product can be produced only through a simple re-crystallization step, so that the method is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of voriconazole, belongs to technical field of medicine synthesis.
Background technology
Voriconazole ((2R, 3S) -2- (2,4 difluorobenzene base) -3- (5-FU -4- bases) -1- (1H-1,2,4- triazoles -
1- yls) -2- butanol) it is a kind of New-type wide-spectrum antifungal agent developed by the beginning of Pfizer (Pfizer) company is in 21 century
Thing, compares similar triazole antifungal agent antimicrobial spectrum wider.In view of voriconazole is widely applied field, its synthesis work
Skill research receives the extensive concern of domestic and international researcher.
At present the method for the synthesis voriconazole of report is all to first pass through the voriconazole intermediate (2R, the 3S that prepare DL
And 2S, 3R), the method for reusing chiral separation obtains desired configuration, mainly has two methods to prepare in DL voriconazole
Mesosome, a kind of coupling reaction (US5567817, US5278175, WO06065726, WO07013096) for being to be based on organic lithium salt,
Its synthetic route is as follows:
Another be based on Reformatsky coupling reaction (US6586594,6946555,7193083), its synthesis
Route is as follows:
Above two synthetic method is all related to the preparation of voriconazole DL intermediate, and follow-up chiral separation,
This causes the yield of final products extremely low, and in addition the discarded of configuration causes atom utilization low, and pollution is increased to environment,
Cause greatly waste.A kind of technique of highly-solid selectively is developed, to reducing the dirt of production cost and reduction to environment
Dye has great importance.
The content of the invention
It is an object of the invention to provide a kind of voriconazole (2R, 3S) -2- (2,4 difluorobenzene base) -3- (5-FU -4-
Base) -1- (1H-1,2,4- triazol-1-yls) -2- butanol (compound 1) preparation method, the method stereo selectivity is high, cost
Cheap, high income.
To achieve these goals, the technical solution used in the present invention is:
A kind of preparation method of voriconazole, compound B is dissolved in aprotic solvent, control reacting liquid temperature-
70~0 DEG C, stirring is subsequently adding alkali, stirs, control reacting liquid temperature at -70~0 DEG C, stirring, Deca compound A and solvent
Mixed liquor, after completion of dropping, warm naturally to room temperature, react 2~48h, obtain the reactant liquor of compound 1, reactant liquor is quenched,
Solvent extraction, vacuum distillation, recrystallization obtains compound 1.Synthetic route is seen below shown in formula:
The carbon on the less epoxy of carbanion attack compound A steric hindrances that compound B is formed under basic conditions, causes out
Ring forms our target product.
X is any one in H, Cl, Br or I in the compound B.
The alkali is the one kind in n-BuLi, tert-butyl lithium or lithium diisopropylamine, compound B and alkali mole
Ratio is 1:(0.8~3.0).
Described aprotic solvent can in ether, tetrahydrofuran, methyltetrahydrofuran or methyl tertiary butyl ether(MTBE) at least
It is a kind of.
The molar ratio of the compound B and compound A is 1:(1-5).
In the preparation method, preferably compound B is dissolved in aprotic solvent, control reacting liquid temperature is at -70 DEG C
Alkali is added, within -60 DEG C, stirring after completion of dropping, continues to be incubated -70~-60 DEG C, stirring 1 temperature control during Deca
Hour, control reacting liquid temperature at -70~-60 DEG C, the mixed liquor of Deca compound A and solvent, after completion of dropping, intensification naturally
To room temperature reaction 24h, the reactant liquor of compound 1 is obtained.
Compound A is 1- (((2R, 3R) -2- (2,4 difluorobenzene base) -3- methyl epoxy ethyl -2- bases) methyl) -1H-1,
2,4- triazoles, are an isomers of commercially available Chinese mugwort fluconazole precursor, can directly be bought, it is also possible to list of references Jaan
Pesti, * Chien-Kuang Chen etc., The Process Development of Ravuconazole:An
Efficient Multikilogram Scale Preparation of an Antifungal Agent, Organic
Process Research&Development 2009,13,716-728, synthesis is obtained.
Beneficial effect:
The preparation method synthesis condition that the present invention is provided is simple, chirality of the process route required for by introducing from raw material A
Configuration, with high solid reaction selectivity, it is not necessary to which later stage chiral separation, simple recrystallization can be obtained by qualified products, fit
Close industrialized production.
Specific embodiment
Compound A titles:1- (((2R, 3R) -2- (2,4 difluorobenzene base) -3- methyl epoxy ethyl -2- bases) methyl) -
1H-1,2,4- triazoles, compound is mainly an isomer of commercially available Chinese mugwort fluconazole precursor, and the intermediate can be purchased directly
Buy, be list of references Jaan Pesti in following examples, * Chien-Kuang Chen etc., The Process
Development of Ravuconazole:An Efficient Multikilogram Scale Preparation of
An Antifungal Agent.Organic Process Research&Development 2009,13,716-728, synthesis
Obtain.
Voriconazole (2R, 3S) -2- (2,4 difluorobenzene base) -3- (5-FU -4- the bases) -1- of embodiment 1 (1H-1,2,
4- triazol-1-yls) -2- butanol (compound 1) preparation
Prepare dry, clean 1000mL glass four-hole bottles, prepare suitable mechanical agitator, condensing tube and thermometer,
Note checking air-tightness before charging, add in reaction bulb under N2 protections the bromo- 5-FUs (0.2mol, 1eq.) of 35.4g4- and
200mL tetrahydrofurans, start stirring, and reacting liquid temperature is down to into -70 DEG C, then slowly Deca 80ml (0.2mol,
1.0eq.) the normal-butyl solution of 2.5N, temperature control after completion of dropping, continues to be incubated -70 within -60 DEG C during Deca
~-60 DEG C are stirred 1 hour.Stirring 1h after, control reaction interior temperature -70~-60 DEG C, Deca contain 60.3g (0.24mol,
1.2eq.) the tetrahydrofuran solution of compound A, after completion of dropping, is to slowly warm up to room temperature reaction 24h (anti-after completion of dropping
Temperature is answered to be to warm naturally to room temperature reaction, 20-30 degree), then Deca 100mL water quenching is gone out reaction, and reactant liquor concentrating under reduced pressure is removed
Go after most of solvent to add the extraction of 200ml ethyl acetate, the ethyl acetate phase for separating 200mL water washing organic faciess to separate
Organic faciess, vacuum distillation is removed after partial solvent, adds 300ml normal heptane to be recrystallized to give white solid powder compound 1
18.37g (yield:26.3%).1H NMR (CDCl3,400MHz) δ:9.02 (s, 1H), 8.72 (s, 1H), 8.10 (s, 1H),
7.65-7.58 (m, 1H), 7.20 (s, 1H), 6.93-6.77 (m, 2H), 6.00, (br s, 1H), 4.78 (m, 1H), 4.33 (d,
1H), 4.20 (m, 1H), 1.10 (d, 3H).The product that the reaction is obtained is not in enantiomer or diastereo-isomerism
Body, stereo selectivity is high.
Voriconazole (2R, 3S) -2- (2,4 difluorobenzene base) -3- (5-FU -4- the bases) -1- of embodiment 2 (1H-1,2,
4- triazol-1-yls) -2- butanol (compound 1) preparation
Prepare dry, clean 1000mL glass four-hole bottles, prepare suitable mechanical agitator, condensing tube and thermometer,
Note checking air-tightness before charging, add in reaction bulb under N2 protections the chloro- 5-FUs (0.2mol, 1eq.) of 26.5g4- and
200mL tetrahydrofurans, start stirring, and reacting liquid temperature is down to into -70 DEG C, then slowly Deca 80ml (0.2mol,
1.0eq.) the normal-butyl solution of 2.5N, temperature control after completion of dropping, continues to be incubated -70 within -60 DEG C during Deca
~-60 DEG C are stirred 1 hour.Stirring 1h after, control reaction interior temperature -70~-60 DEG C, Deca contain 60.3g (0.24mol,
1.2eq.) the tetrahydrofuran solution of compound A, after completion of dropping, warms naturally to (20-30 DEG C) reaction 24h of room temperature, then drips
Plus 100mL water quenchings are gone out reaction, reactant liquor concentrating under reduced pressure removes and the extraction of 200ml ethyl acetate is added after most of solvent, separates
Ethyl acetate phase 200mL water washing organic faciess, separate organic faciess, and vacuum distillation is removed after partial solvent, add 300ml positive heptan
Alkane is recrystallized to give the 14.46g (yields of white solid powder compound 1:20.7%).
Voriconazole (2R, 3S) -2- (2,4 difluorobenzene base) -3- (5-FU -4- the bases) -1- of embodiment 3 (1H-1,2,
4- triazol-1-yls) -2- butanol (compound 1) preparation
Prepare dry, clean 1000mL glass four-hole bottles, prepare suitable mechanical agitator, condensing tube and thermometer,
Note checking air-tightness before charging, add in reaction bulb under N2 protections the bromo- 5-FUs (0.2mol, 1eq.) of 35.4g4- and
200mL tetrahydrofurans, start stirring, and reacting liquid temperature is down to into -70 DEG C, then slowly Deca 138.5ml (0.18mol,
0.9eq.) the t-butyl solution of 1.3N, temperature control after completion of dropping, continues to be incubated -70 within -60 DEG C during Deca
~-60 DEG C are stirred 1 hour.Stirring 1h after, control reaction interior temperature -70~-60 DEG C, Deca contain 60.3g (0.24mol,
1.2eq.) the tetrahydrofuran solution of compound A, after completion of dropping, is to slowly warm up to room temperature reaction 24h, then Deca 100mL water
Reaction is quenched, reactant liquor concentrating under reduced pressure removes and the extraction of 200ml ethyl acetate, the ethyl acetate phase for separating are added after most of solvent
With 200mL water washing organic faciess, organic faciess are separated, vacuum distillation is removed after partial solvent, add 300ml normal heptane recrystallization to obtain
To the 12.92g (yields of white solid powder compound 1:18.5%).
Voriconazole (2R, 3S) -2- (2,4 difluorobenzene base) -3- (5-FU -4- the bases) -1- of embodiment 4 (1H-1,2,
4- triazol-1-yls) -2- butanol (compound 1) preparation
Prepare dry, clean 1000mL glass four-hole bottles, prepare suitable mechanical agitator, condensing tube and thermometer,
Note checking air-tightness before charging, add in reaction bulb under N2 protections the chloro- 5-FUs (0.2mol, 1eq.) of 26.5g4- and
200mL tetrahydrofurans, start stirring, and reacting liquid temperature is down to into -70 DEG C, then slowly Deca 138.5ml (0.18mol,
0.9eq.) the t-butyl solution of 1.3N, temperature control after completion of dropping, continues to be incubated -70 within -60 DEG C during Deca
~-60 DEG C are stirred 1 hour.Stirring 1h after, control reaction interior temperature -70~-60 DEG C, Deca contain 60.3g (0.24mol,
1.2eq.) the tetrahydrofuran solution of compound A, after completion of dropping, is to slowly warm up to room temperature reaction 24h, then Deca 100mL water
Reaction is quenched, reactant liquor concentrating under reduced pressure removes and the extraction of 200ml ethyl acetate, the ethyl acetate phase for separating are added after most of solvent
With 200mL water washing organic faciess, organic faciess are separated, vacuum distillation is removed after partial solvent, add 300ml normal heptane recrystallization to obtain
To the 17.46g (yields of white solid powder compound 1:25.0%).
Claims (6)
1. a kind of preparation method of voriconazole, it is characterised in that synthetic route is shown below:
Compound B is dissolved in aprotic solvent, at -70~0 DEG C, stirring is subsequently adding alkali to control reacting liquid temperature, stirs
Mix, control reacting liquid temperature is stirred at -70~0 DEG C, the mixed liquor of Deca compound A and solvent, after completion of dropping, control is anti-
Liquid temp is answered at -70~30 DEG C, 2~48h is reacted, the reactant liquor of compound 1 is obtained, reactant liquor is quenched, solvent extraction, decompression is steamed
Evaporate, recrystallization, obtain compound 1.
2. the preparation method of a kind of voriconazole according to claim 1, it is characterised in that in the compound B X be H,
Any one in Cl, Br or I.
3. the preparation method of a kind of voriconazole according to claim 1, it is characterised in that the alkali be n-BuLi,
At least one in tert-butyl lithium or lithium diisopropylamine.
4. the preparation method of a kind of voriconazole according to claim 1, it is characterised in that the compound B and alkali
Molar ratio is 1:(0.8~3.0).
5. the preparation method of a kind of voriconazole according to claim 1, it is characterised in that described aprotic solvent is
At least one in ether, tetrahydrofuran, methyltetrahydrofuran or methyl tertiary butyl ether(MTBE).
6. the preparation method of a kind of voriconazole according to claim 1, it is characterised in that the compound B and chemical combination
The molar ratio of thing A is 1:(1-5).
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108276387A (en) * | 2018-01-24 | 2018-07-13 | 成都倍特药业有限公司 | A kind of purification process of voriconazole |
CN108997222A (en) * | 2018-07-23 | 2018-12-14 | 山东省农药科学研究院 | A kind of synthetic method of the chloro- 5-FU of fluoxastrobin intermediate 4,6- bis- |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US20030064986A1 (en) * | 2000-03-07 | 2003-04-03 | Javier Bartroli Orpi | Method for preparing pyrimidone derivatives with antifungal activity |
CN101573344A (en) * | 2006-12-29 | 2009-11-04 | 大熊制药株式会社 | Antifungal triazole derivatives, method for the preparation thereof and pharmaceutical composition containing same |
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2016
- 2016-11-25 CN CN201611059650.9A patent/CN106588889B/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030064986A1 (en) * | 2000-03-07 | 2003-04-03 | Javier Bartroli Orpi | Method for preparing pyrimidone derivatives with antifungal activity |
CN101573344A (en) * | 2006-12-29 | 2009-11-04 | 大熊制药株式会社 | Antifungal triazole derivatives, method for the preparation thereof and pharmaceutical composition containing same |
Non-Patent Citations (1)
Title |
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XUFENG CAO ET AL.: "Design,Synthesis,and Structure−Activity Relationship Studies of Novel Fused Heterocycles-Linked Triazoles with Good Activity and Water Solubility", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108276387A (en) * | 2018-01-24 | 2018-07-13 | 成都倍特药业有限公司 | A kind of purification process of voriconazole |
CN108276387B (en) * | 2018-01-24 | 2020-12-18 | 成都倍特药业股份有限公司 | Purification method of voriconazole |
CN108997222A (en) * | 2018-07-23 | 2018-12-14 | 山东省农药科学研究院 | A kind of synthetic method of the chloro- 5-FU of fluoxastrobin intermediate 4,6- bis- |
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