CN106588889B - A kind of preparation method of voriconazole - Google Patents
A kind of preparation method of voriconazole Download PDFInfo
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- CN106588889B CN106588889B CN201611059650.9A CN201611059650A CN106588889B CN 106588889 B CN106588889 B CN 106588889B CN 201611059650 A CN201611059650 A CN 201611059650A CN 106588889 B CN106588889 B CN 106588889B
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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 kind of preparation methods of voriconazole, in a solvent by compound B dissolution, reacting liquid temperature is controlled at -70 ~ 0 DEG C, stirring, is then added alkali, stirs, reacting liquid temperature is controlled at -70 ~ 0 DEG C, the mixed liquor of A and solvent is added dropwise, after being added dropwise in stirring, reacting liquid temperature is controlled at -70 ~ 0 DEG C, 2 ~ 48h is reacted, compound 1 is obtained, process route passes through chiral configuration required for introducing from raw material A, with high three-dimensional reaction selectivity, later period chiral resolution is not needed, simple recrystallization can be obtained by qualified products, be suitble to industrialized production.
Description
Technical field
The present invention relates to a kind of preparation methods of voriconazole, belong to technical field of medicine synthesis.
Background technique
Voriconazole ((2R, 3S) -2- (2,4 difluorobenzene base) -3- (5-FU -4- base) -1- (1H-1,2,4- triazole -
1- yl) -2- butanol) it is a kind of New-type wide-spectrum antifungal developed as at the beginning of Pfizer (Pfizer) company in 21 century
Object, it is wider compared to similar triazole antifungal agent antimicrobial spectrum.It is widely applied field in view of voriconazole, its synthesis work
Skill research receives the extensive concern of domestic and international researcher.
The method for the synthesis voriconazole reported at present is all voriconazole intermediate (2R, the 3S for first passing through preparation mixed
And 2S, 3R), the method for reusing chiral resolution obtains desired configuration, and there are mainly two types of in method preparation mixed voriconazole
Mesosome, one is the coupling reaction (US5567817, US5278175, WO06065726, WO07013096) based on organic lithium salt,
Its synthetic route is as follows:
Another is the coupling reaction (US6586594,6946555,7193083) based on Reformatsky, synthesis
Route is as follows:
Above two synthetic method is all related to the preparation and subsequent chiral resolution of voriconazole mixed intermediate,
This causes the yield of final products extremely low, and in addition the discarded of configuration causes atom utilization low, increases pollution to environment,
Cause great waste.The technique for developing a kind of highly-solid selectively, the dirt to reduction production cost and reduction to environment
Dye has great importance.
Summary of the invention
The object of the present invention is 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, this method stereoselectivity is high, cost
Cheap, high income.
To achieve the goals above, the technical solution adopted by the present invention are as follows:
A kind of preparation method of voriconazole, compound B is dissolved in aprotic solvent, control reacting liquid temperature-
70~0 DEG C, then alkali is added in stirring, stir, and controls reacting liquid temperature at -70~0 DEG C, compound A and solvent is added dropwise in stirring
Mixed liquor, after being added dropwise, warm naturally to room temperature, react 2~48h, obtain the reaction solution of compound 1, reaction solution is quenched,
Solvent extraction is evaporated under reduced pressure, and recrystallization obtains compound 1.Synthetic route is seen below shown in formula:
The carbon on the smaller epoxy of carbanion attack compound A steric hindrance 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 one of n-BuLi, tert-butyl lithium or lithium diisopropylamine, mole of compound B and alkali
Ratio is 1:(0.8~3.0).
The 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, controls reacting liquid temperature at -70 DEG C
Alkali is added, temperature control is within -60 DEG C during dropwise addition, stirring, after being added dropwise, continues -70~-60 DEG C of heat preservation, stirring 1
Hour, reacting liquid temperature is controlled at -70~-60 DEG C, the mixed liquor of compound A and solvent is added dropwise, and after being added dropwise, is heated up naturally
For 24 hours to room temperature reaction, the reaction solution of compound 1 is obtained.
Compound A is 1- (((2R, 3R) -2- (2,4 difluorobenzene base) -3- methyl epoxy ethyl -2- base) methyl) -1H-1,
2,4- triazoles, be it is commercially available Chinese mugwort Fluconazole precursor an isomers, can directly buy, can also be with bibliography 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 obtains.
The utility model has the advantages that
Preparation method synthesis condition provided by the invention is simple, and process route passes through chiral required for introducing from raw material A
Configuration has high three-dimensional reaction selectivity, does not need later period chiral resolution, and simple recrystallization can be obtained by qualified products, fit
Close industrialized production.
Specific embodiment
Compound A title: 1- (((2R, 3R) -2- (2,4 difluorobenzene base) -3- methyl epoxy ethyl -2- base) methyl) -
1H-1,2,4- triazoles, the compound are mainly an isomers of commercially available Chinese mugwort Fluconazole precursor, which can directly purchase
It buys, is bibliography Jaan Pesti, * Chien-Kuang Chen etc., The Process in following embodiment
Development of Ravuconazole:An Efficient Multikilogram Scale Preparation of
An Antifungal Agent.Organic Process Research&Development 2009,13,716-728, synthesis
It obtains.
1 voriconazole of embodiment (2R, 3S) -2- (2,4 difluorobenzene base) -3- (5-FU -4- base) -1- (1H-1,2,
4- triazol-1-yl) -2- butanol (compound 1) preparation
Prepare dry, clean 1000mL glass four-hole bottle, prepare suitable mechanical agitator, condenser pipe and thermometer,
Charging before pay attention to check air-tightness, N2 protection under into reaction flask be added the bromo- 5-FU of 35.4g4- (0.2mol, 1eq.) and
200mL tetrahydrofuran starts stirring, and reacting liquid temperature is down to -70 DEG C, then slowly be added dropwise 80ml (0.2mol,
1.0eq.) the normal-butyl solution of 2.5N, temperature control is within -60 DEG C during dropwise addition, after being added dropwise, continues heat preservation -70
~-60 DEG C are stirred 1 hour.Stir 1h after, control reaction Nei Wen -70~-60 DEG C, be added dropwise containing 60.3g (0.24mol,
After being added dropwise, it is (anti-after being added dropwise for 24 hours to be to slowly warm up to room temperature reaction for the 1.2eq.) tetrahydrofuran solution of compound A
Answering temperature is to warm naturally to react at room temperature, 20-30 degree), 100mL water quenching reaction is then added dropwise, reaction solution reduced pressure removes
The extraction of 200ml ethyl acetate, the ethyl acetate phase separated 200mL water washing organic phase, separation is added after removing most of solvent
Organic phase after vacuum distillation removes partial solvent, is added 300ml normal heptane and is 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 obtains is not in enantiomter either diastereo-isomerism
Body, stereoselectivity are high.
2 voriconazole of embodiment (2R, 3S) -2- (2,4 difluorobenzene base) -3- (5-FU -4- base) -1- (1H-1,2,
4- triazol-1-yl) -2- butanol (compound 1) preparation
Prepare dry, clean 1000mL glass four-hole bottle, prepare suitable mechanical agitator, condenser pipe and thermometer,
Charging before pay attention to check air-tightness, N2 protection under into reaction flask be added the chloro- 5-FU of 26.5g4- (0.2mol, 1eq.) and
200mL tetrahydrofuran starts stirring, and reacting liquid temperature is down to -70 DEG C, then slowly be added dropwise 80ml (0.2mol,
1.0eq.) the normal-butyl solution of 2.5N, temperature control is within -60 DEG C during dropwise addition, after being added dropwise, continues heat preservation -70
~-60 DEG C are stirred 1 hour.Stir 1h after, control reaction Nei Wen -70~-60 DEG C, be added dropwise containing 60.3g (0.24mol,
1.2eq.) the tetrahydrofuran solution of compound A after being added dropwise, warms naturally to (20-30 DEG C) of room temperature reaction for 24 hours, then drips
The extraction of 200ml ethyl acetate is added after adding 100mL water quenching reaction, reaction solution that the most of solvent of removing is concentrated under reduced pressure, separates
Ethyl acetate phase 200mL water washing organic phase separates organic phase, and after vacuum distillation removes partial solvent, 300ml positive heptan is added
Alkane is recrystallized to give white solid powder compound 1 14.46g (yield: 20.7%).
3 voriconazole of embodiment (2R, 3S) -2- (2,4 difluorobenzene base) -3- (5-FU -4- base) -1- (1H-1,2,
4- triazol-1-yl) -2- butanol (compound 1) preparation
Prepare dry, clean 1000mL glass four-hole bottle, prepare suitable mechanical agitator, condenser pipe and thermometer,
Charging before pay attention to check air-tightness, N2 protection under into reaction flask be added the bromo- 5-FU of 35.4g4- (0.2mol, 1eq.) and
200mL tetrahydrofuran starts stirring, and reacting liquid temperature is down to -70 DEG C, then slowly be added dropwise 138.5ml (0.18mol,
0.9eq.) the t-butyl solution of 1.3N, temperature control is within -60 DEG C during dropwise addition, after being added dropwise, continues heat preservation -70
~-60 DEG C are stirred 1 hour.Stir 1h after, control reaction Nei Wen -70~-60 DEG C, be added dropwise containing 60.3g (0.24mol,
1.2eq.) the tetrahydrofuran solution of compound A after being added dropwise, is to slowly warm up to room temperature reaction for 24 hours, 100mL water is then added dropwise
The extraction of 200ml ethyl acetate, the ethyl acetate phase separated is added after the most of solvent of removing is concentrated under reduced pressure in quenching reaction, reaction solution
With 200mL water washing organic phase, organic phase is separated, after vacuum distillation removes partial solvent, 300ml normal heptane is added and recrystallizes
To white solid powder compound 1 12.92g (yield: 18.5%).
4 voriconazole of embodiment (2R, 3S) -2- (2,4 difluorobenzene base) -3- (5-FU -4- base) -1- (1H-1,2,
4- triazol-1-yl) -2- butanol (compound 1) preparation
Prepare dry, clean 1000mL glass four-hole bottle, prepare suitable mechanical agitator, condenser pipe and thermometer,
Charging before pay attention to check air-tightness, N2 protection under into reaction flask be added the chloro- 5-FU of 26.5g4- (0.2mol, 1eq.) and
200mL tetrahydrofuran starts stirring, and reacting liquid temperature is down to -70 DEG C, then slowly be added dropwise 138.5ml (0.18mol,
0.9eq.) the t-butyl solution of 1.3N, temperature control is within -60 DEG C during dropwise addition, after being added dropwise, continues heat preservation -70
~-60 DEG C are stirred 1 hour.Stir 1h after, control reaction Nei Wen -70~-60 DEG C, be added dropwise containing 60.3g (0.24mol,
1.2eq.) the tetrahydrofuran solution of compound A after being added dropwise, is to slowly warm up to room temperature reaction for 24 hours, 100mL water is then added dropwise
The extraction of 200ml ethyl acetate, the ethyl acetate phase separated is added after the most of solvent of removing is concentrated under reduced pressure in quenching reaction, reaction solution
With 200mL water washing organic phase, organic phase is separated, after vacuum distillation removes partial solvent, 300ml normal heptane is added and recrystallizes
To white solid powder compound 1 17.46g (yield: 25.0%).
Claims (5)
1. a kind of preparation method of voriconazole, which is characterized in that synthetic route is shown below:
Compound B is dissolved in aprotic solvent, controls reacting liquid temperature at -70 ~ 0 DEG C, then alkali is added in stirring, it stirs,
Reacting liquid temperature is controlled at -70 ~ 0 DEG C, the mixed liquor of compound A and solvent is added dropwise in stirring, after being added dropwise, controls reaction solution
Temperature reacts 2 ~ 48h, obtains the reaction solution of compound 1 at -70 ~ 30 DEG C, and reaction solution is quenched, solvent extraction, is evaporated under reduced pressure, weight
Crystallization, obtains compound 1；X is any one in Cl, Br or I in the compound B.
2. a kind of preparation method of voriconazole according to claim 1, which is characterized in that the alkali be n-BuLi,
At least one of tert-butyl lithium or lithium diisopropylamine.
3. a kind of preparation method of voriconazole according to claim 1, which is characterized in that the compound B and alkali
Molar ratio is 1:(0.8 ~ 3.0).
4. a kind of preparation method of voriconazole according to claim 1, which is characterized in that the aprotic solvent is
At least one of ether, tetrahydrofuran, methyltetrahydrofuran or methyl tertiary butyl ether(MTBE).
5. a kind of preparation method of voriconazole according to claim 1, which is characterized in that the compound B and chemical combination
The molar ratio of object A is 1:(1-5).
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| 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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| 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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| 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》.2014,第57卷第3687—3706页. |
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