CN102807563B - Method for preparing voriconazole and intermediate thereof - Google Patents
Method for preparing voriconazole and intermediate thereof Download PDFInfo
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Abstract
The invention discloses a method for preparing voriconazole and intermediate thereof. The method comprises the following steps of: enabling the compound 4-(1-halogenated ethyl)-5-fluoropyrimidine in the formula (II) to react with 2,4-difluorobenzaldehyde to generate the compound alpha-(5-fluoropyrimidine-4-yl)-2,4-difluoroacetone in the formula (III); then reacting with the compound 1-halogen methyl-1,2,4-triazole in the formula (VI) to generate the compound 1-(1,2,4-triazole-1-yl)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidine-4-yl)-2-butanol in the formula (IV); and finally resolving to obtain the voriconazole, shown as the accompanying drawing, wherein R1 and R2 are respectively halogen. The method for preparing voriconazole is easy in raw material obtaining, moderate in reaction conditions, and short in steps; each reaction is the mature organic reaction; and the method is widely applied in industry, and has certain industrial production conditions.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, be specifically related to a kind of voriconazole and intermediate α-(5-FU-4-base)-2 thereof, 4-difluorobenzene acetone (III) and 1-(1,2,4-triazole-1-base)-2-(2,4-difluorophenyl)-3-(5-5-FU-4-base) preparation method of-2-butanols (IV).
Background technology
Voriconazole (voriconazole) [(2R, 3S)-1-(1,2,4-triazole-1-base)-2-(2,4-difluorophenyl)-3-(5-5-FU-4-base)-2-butanols] be the triazole species broad-spectrum antifungal medicine of new generation that Pfizer develops, be mainly used in the treatment of the whole body deep fungal infection disease caused as aspergillus, cryptococcus and candidiasis etc.Voriconazole is because unique pharmacodynamic profile and good Clinical practice effect are considered to have extremely wide market outlook.The lower formula I of this compound represents:
In EP0440372A1 with the fluoro-4-ethyl-pyrimidine of the chloro-5-of 6-for starting raw material, through and α-(1,2,4-triazole-1-base)-2,4 difluorobenzene ethyl ketone condensation at low temperatures, hydrogenation slough pyrimidine chlorine in ring and finally split and synthesize voriconazole.US6586594B1 is with 4-(1-bromotrifluoromethane) the fluoro-6-chloropyrimide of-5-is starting raw material, through with α-(1,2,4-triazole-1-base)-2,4 difluorobenzene ethyl ketone condensation under zinc powder effect, hydrodechlorination, fractionation and synthesize voriconazole.
Above two patent routes are all so that α-(1,2,4-triazole-1-base)-2,4 difluorobenzene ethyl ketone is for key intermediate, and 4-ethyl-pyrimidine compounds carries out condensation in the α position of ethyl and carbonyl and synthesizes voriconazole.Need in preparation process to use cold condition (-60 DEG C to-70 DEG C), yield is lower, is not suitable for industrial production.
Disclose in patent of invention CN1473825A with the chloro-6-(1-bromotrifluoromethane of 4-under the Lewis acid effect of zinc)-5-FU and α-(1,2,4-triazole-1-base)-2,4 difluorobenzene ethyl ketone condensation reaction hydrodechlorination, fractionation and synthesize voriconazole in tetrahydrofuran (THF) etc. suitably organic solvent.Yield improves a lot, and reaction conditions is gentle, but uses plumbous grade for heavy metal in reaction, there is the problems such as environment protection.
Disclosing a kind of brand-new preparation method in patent of invention CN100999518A, adopt 2-(5-fluoro-4-yl) acetic acid carries out esterification with ethanol, then react with methylating reagent in the basic conditions, the fluoro-4-yl of generation 2-(5-) ethyl propionate.Hydrolysis, fractionation also chlorination obtain the fluoro-4-yl of S-2-(5-) propionyl chloride, then carry out Friedel-Crafts reaction and generate key intermediate S-1-2, the fluoro-4-yl of 4-difluorophenyl-2-(5-) acetone, with 1-methyl isophthalic acid-hydrogen-1,2,4-triazole is obtained by reacting voriconazole under basic conditions.Use super base n-Butyl Lithium in preparation process, preparation condition is harsh, is unfavorable for suitability for industrialized production.
Summary of the invention
The object of the invention is on the basis of existing technology, a kind of novel method preparing voriconazole is provided.
Another object of the present invention is to provide a kind of voriconazole intermediate 1-(1,2,4-triazole-1-base)-2-(2,4-difluorophenyl)-3-(5-5-FU-4-base) synthetic method of-2-butanols.
Object of the present invention can be reached by following measures:
A kind of preparation method of voriconazole: first adopt formula (II) compound 4-(1-halogenated ethyl)-5-FU and 2,4-difluorobenzaldehyde reaction production (III) compound α-(5-FU-4-base)-2,4-difluorobenzene acetone (step a), again with formula (VI) compound 1-monochloromethyl-1,2,4-triazole reaction production (IV) compound 1-(1,2,4-triazole-1-base)-2-(2,4-difluorophenyl)-3-(5-5-FU-4-base)-2-butanols (step b), finally by fractionation, (step c) obtains voriconazole
Wherein, R
1and R
2be respectively halogen.
Step a) preparation formula (III) compound time, a kind of preferred scheme is: formula (II) compound is prepared into organic zinc reagent, then or simultaneously carries out addition reaction with 2,4 difluorobenzene formaldehyde, then carries out oxidizing reaction and obtain,
Described R
1be preferably-Cl ,-Br or-I.
The process of above-mentioned steps a) preparation formula (III) compound, comprises organic zinc reagent processed reaction, addition reaction and oxidizing reaction.
In step a) reaction of draft machine zincon, the catalyzer adopted can be selected from one or more in iodine, copper powder, mercury bichloride, acetylacetic ester mantoquita, zinc bromide, and the solvent adopted can be tetrahydrofuran (THF), and temperature of reaction is 20 ~ 30 DEG C.
Step a) in, addition reaction can be carried out after formula (II) compound is prepared into organic zinc reagent, also directly can carry out in the process preparing organic zinc reagent.In addition reaction, formula (II) compound and the mol ratio both 2,4 difluorobenzene formaldehyde are preferably 1:1.4 ~ 1:1, and addition reaction temperature is-5 ~ 50 DEG C, preferably 0 ~ 10 DEG C, and the addition reaction time is 1 ~ 20h.The solvent of addition reaction can be selected from one or more in ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, benzene,toluene,xylene, Methylal(dimethoxymethane), dimethyl sulfoxide (DMSO), preferably adopts tetrahydrofuran (THF).
Step a) in, the oxygenant in oxidizing reaction is selected from one or more in potassium permanganate, Manganse Dioxide, chromic acid pyridine complex, chromic anhydride pyridine complex, chromium trioxide pyridine or perchloric acid, preferably adopts chromium trioxide pyridine.The solvent of oxidizing reaction can be methylene dichloride, and temperature of reaction is 20 ~ 50 DEG C, preferably 35 ~ 41 DEG C, and the reaction times is 0.5 ~ 24h.
At above-mentioned steps b) preparation formula (IV) compound process in, a kind of preferred scheme is: formula (VI) compound is prepared into organic zinc reagent, then or carry out addition reaction simultaneously with formula (III) compound and obtain,
Described R
2be preferably-Cl ,-Br or-I.
Above-mentioned steps b) process of preparation formula (VI) compound, comprise organic zinc reagent processed reaction and addition reaction.
In step b) draft machine zincon reaction in, the catalyzer adopted can be selected from one or more in iodine, copper powder, mercury bichloride, acetylacetic ester mantoquita, zinc bromide, and the solvent adopted can be tetrahydrofuran (THF), and temperature of reaction is 20 ~ 30 DEG C.
In step b) in, addition reaction can be carried out after formula (VI) compound is prepared into organic zinc reagent, also directly can carry out in the process preparing organic zinc reagent.In addition reaction, the mol ratio of formula III compound and formula VI compound is 1:1.5 ~ 1:1.1, addition reaction temperature is 0 ~ 30 DEG C, preferably 0 ~ 5 DEG C, reaction times is 2 ~ 10h, addition reaction solvent can be selected from one or more in ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, benzene,toluene,xylene, Methylal(dimethoxymethane), dimethyl sulfoxide (DMSO), preferably adopts tetrahydrofuran (THF).
In step c) split and preparation formula (I) compound time, a kind of preferred scheme is: formula (IV) compound splits via (-)-10-camphorsulfonic acid and obtains voriconazole.One or more in solvent selected from acetone during fractionation, ethanol, methylene dichloride or water.In concrete split process first by formula (IV) compound dissolution in a solvent, dissolve, add (-)-10-camphorsulfonic acid again, stirring is warming up to entirely molten, and cooling leaves standstill, the solid that collecting by filtration is separated out, drying, then the solid obtained is dissolved in two kinds of immiscible solvents, with sodium hydroxide adjust pH to 10 ~ 11, collected organic layer also except desolventizing, can obtain voriconazole.
In a kind of preferred version, voriconazole is prepared by following method:
Adopting 4-(1-halogenated ethyl)-5-FU and 2,4 difluorobenzene formaldehyde reaction generate key intermediate α-(5-FU-4-base)-2,4 difluorobenzene acetone (III).Then react with 1-monochloromethyl-1,2,4-triazole and generate 1-(1,2,4-triazole-1-base)-2-(2,4-difluorophenyl)-3-(5-5-FU-4-base)-2-butanols (IV), then obtain voriconazole through splitting.
The invention also discloses a kind of voriconazole intermediate, i.e. 1-(1,2,4-triazole-1-base)-2-(2,4-difluorophenyl)-3-(5-5-FU-4-base) preparation method of-2-butanols: first adopt formula (II) compound and 2,4 difluorobenzene formaldehyde reaction production (III) compound, then react with formula (VI) compound, synthesis type (IV) compound voriconazole intermediate
Wherein, R
1and R
2be respectively halogen.Each concrete steps in the method and condition described above.
Beneficial effect of the present invention:
The method preparing voriconazole of the present invention, its starting raw material is easy to get, and reaction conditions is gentle, and route is brief, and each step reaction is ripe organic reaction, industrially applies very wide, has certain commercial production conditions.
Embodiment
Following examples further describe the present invention, but these embodiments are only for illustration of the present invention, instead of limitation of the scope of the invention.
The preparation of embodiment 1: α-(5-FU-4-base)-2,4 difluorobenzene acetone (III)
Add zinc powder 6.33g in there-necked flask, THF25g, the lower 25gTHF solution dripping 9g iodine of room temperature under nitrogen protection, drips and finishes, stirring at room temperature 30min.Ice bath stirs and lower drips 4-(1-bromotrifluoromethane) the 25gTHF solution of-5-FU 6.4g, 4.88g 2,4 difluorobenzene formaldehyde and 0.88g iodine, control rate of addition, makes temperature of reaction remain on 0 ° of C ~ 5 ° C.Drip and finish, be slowly warming up to stirring at room temperature reaction 5h, ice bath slowly adds the saturated sodium sulfite solution of 50mL under stirring, and stirs 30min.Filter, filtrate decompression is distilled to dry, adds 20mL methylene dichloride in residue, divides and gets organic layer, use the saturated NaHCO of 50ml respectively
3the saturated NaCl solution washing of solution, 2 × 50ml, anhydrous magnesium sulfate drying.Filter, add chromium trioxide pyridine 6.3g, be slowly warming up to back flow reaction 3h under filtrate stirring at room temperature, cooling, filter, filtrate uses hydrochloric acid 100ml, the water 3 × 150ml of 10% to wash respectively, anhydrous magnesium sulfate drying.Reclaim under reduced pressure methylene dichloride, residue is dissolved in 50ml ethanol, slowly adds 100ml water under gained solution stirring, solid is separated out, and collecting by filtration separates out solid, recrystallization in the ethanol of 50%, obtain faint yellow solid compound 5.11g, mp:68 ° of C ~ 72 ° C, yield: 60.6%.
The preparation of embodiment 2: α-(5-FU-4-base)-2,4 difluorobenzene acetone (III)
Add zinc powder 3.2Kg in reactor, THF13Kg, the lower 13KgTHF solution dripping 5Kg iodine of room temperature under nitrogen protection, drips and finishes, stirring at room temperature 30min.Ice bath stirs and lower drips 4-(1-bromotrifluoromethane) the 12KgTHF solution of-5-FU 3.3Kg, 2.44Kg 2,4 difluorobenzene formaldehyde and 0.44Kg iodine, control rate of addition, makes temperature of reaction remain on 0 ° of C ~ 10 ° C.Drip and finish, be slowly warming up to stirring at room temperature reaction 5.5h, ice bath slowly adds the saturated sodium sulfite solution of 25L under stirring, and stirs 30min.Filter, filtrate decompression reclaims THF, adds 2L methylene dichloride in residue, divides and gets organic layer, use the saturated NaHCO of 25L respectively
3the saturated NaCl solution washing of solution, 2 × 25L, anhydrous magnesium sulfate drying.Filter, add chromium trioxide pyridine 3.16Kg, be slowly warming up to back flow reaction 4h under filtrate stirring at room temperature, cooling, filter, filtrate uses hydrochloric acid 40L, the water 3 × 50L of 10% to wash respectively, anhydrous magnesium sulfate drying.Reclaim under reduced pressure methylene dichloride, residue is dissolved in 25L ethanol, slowly adds 50L water under gained solution stirring, solid is separated out, and collecting by filtration separates out solid, recrystallization in the ethanol of 50%, obtain faint yellow solid compound 5.55kg, mp:68 ° of C ~ 71 ° C, yield: 65.2%
The preparation of embodiment 3:1-brooethyl-1,2,4-triazole (VI ')
Add 7.5LTHF in reactor, 630g NaH, ice bath slowly adds 1,2,4-triazole 1050g under stirring in batches, and ice bath stirs 1h.Drip the 500mLTHF solution of methyl iodide 3300g, control rate of addition, make temperature of reaction remain on 5 ° of C ~ 10 ° C.Drip and finish, be slowly warming up to stirring at room temperature reaction 3h.Add 3300g NBS in reaction solution, 4g Diisopropyl azodicarboxylate, under stirring, be warming up to back flow reaction 20h.Cooling, decompression and solvent recovery, adds 8L methylene dichloride in residue, use the saturated Na of 3 × 3L respectively
2cO
3the saturated NaCl solution washing of solution, 3 × 3L, anhydrous magnesium sulfate drying.Filter, filtrate decompression recycling design, to dry, obtains brown oil compound (VI ') 1686g, yield: 68.1%.This product need not be refined and directly can be participated in the next step.
Embodiment 4:1-(1,2,4-triazole-1-base)-2-(2,4-difluorophenyl)-3-(5-5-FU-4-base) preparation of-2-butanols (IV)
Zinc powder 12.7g is added, THF100g, the lower THF(170g dripping 50g iodine of room temperature under nitrogen protection in there-necked flask) solution, drips and finishes, stirring at room temperature 30min.Ice bath stirs the lower 200gTHF solution dripping 34.4g compound III, 25.1g1-brooethyl-1,2,4-triazole (VI '), 5g iodine, controls rate of addition, makes temperature of reaction remain on 0 ° of C ~ 5 ° C.Drip and finish, be slowly warming up to stirring at room temperature reaction 5h, ice bath slowly adds 1L saturated sodium thiosulfate solution under stirring, and stirs 30min.Filter, filtrate decompression reclaims THF, adds 1L methylene dichloride in residue, divides and gets organic layer, use the saturated NaHCO of 1L respectively
3the saturated NaCl solution washing of solution, 2 × 1L, anhydrous magnesium sulfate drying.Filter, decompression and solvent recovery, residue 250ml 95% ethyl alcohol recrystallization, obtain off-white color solid 32.7g, fusing point: 126 ° of C ~ 129 ° C, yield: 69.1%.
Embodiment 5:1-(1,2,4-triazole-1-base)-2-(2,4-difluorophenyl)-3-(5-5-FU-4-base) preparation of-2-butanols (IV)
Add zinc powder 0.64Kg in reactor, THF5Kg, the lower 8KgTHF solution dripping 2.5Kg iodine of room temperature under nitrogen protection, drips and finishes, stirring at room temperature 30min.Ice bath stirs the lower 10KgTHF solution dripping 1.72Kg compound III, 1.25Kg 1-brooethyl-1,2,4-triazole (VI ') and 0.25Kg iodine, controls rate of addition, makes temperature of reaction remain on 0 ° of C ~ 5 ° C.Drip and finish, be slowly warming up to stirring at room temperature reaction 6h, ice bath slowly adds 30L saturated sodium thiosulfate solution under stirring, and stirs 30min.Filter, filtrate decompression reclaims THF, adds 30L methylene dichloride in residue, divides and gets organic layer, use the saturated NaHCO of 30L respectively
3the saturated NaCl solution washing of solution, 2 × 30L, anhydrous magnesium sulfate drying.Filter, decompression and solvent recovery, residue 12L 95% ethyl alcohol recrystallization, change to obtain off-white color solid 1.07Kg, fusing point: 126 ° of C ~ 129 ° C, yield: 68.05%
Embodiment 6:(2R, 3S)-1-(1,2,4-triazole-1-base)-2-(2,4-difluorophenyl)-3-(5-5-FU-4-base) preparation of-2-butanols (I)
Add 0.6Kg compound (IV) in reactor, acetone 9.8Kg dissolves 30min. under stirring, and adds 0.42Kg (-)-10-camphorsulfonic acid, 3Kg ethanol, stirring is warming up to entirely molten, cooling, hold over night, collecting by filtration separates out solid, 50 ° of C forced air dryings, gained colorless solid is added in flask, adds 5Kg methylene dichloride, 5Kg water, stir lower dissolving, NaOH solution with 10% adjusts pH to 10 ~ 11, leave standstill to divide and get organic layer, 3 × 5Kg water washing, anhydrous magnesium sulfate drying.Filter, filtrate decompression recycling design, to dry, obtain crude Compound 280g, is added in there-necked flask, add Virahol 2000ml, be warming up to entirely molten, add a small amount of gac, return stirring 10min under stirring.Filtered while hot, filtrate naturally cools to room temperature, puts into refrigerator cold-storage.Filter, 50 ° of C dry fine work 260g, yield 43.3%, m.p.:128 ° of C-130 ° of C, [α]
d=-62 ° (C=1, methyl alcohol).
Claims (7)
1. the preparation method of a voriconazole, it is characterized in that first adopting formula (II) compound 4-(1-halogenated ethyl)-5-FU and 2,4-difluorobenzaldehyde reaction production (III) compound α-(5-FU-4-base)-2,4-difluorobenzene acetone, again with formula (VI) compound 1-monochloromethyl-1,2,4-triazole reacts production (IV) compound 1-(1 at 0 ~ 30 DEG C, 2,4-triazole-1-base)-2-(2,4-difluorophenyl)-3-(5-FU-4-base)-2-butanols, obtain voriconazole finally by fractionation
When preparation formula (III) compound, formula (II) compound is prepared into organic zinc reagent, then or simultaneously with 2,4-difluorobenzaldehyde carries out addition reaction at-5 ~ 50 DEG C, carry out oxidizing reaction again to obtain, the oxygenant in oxidizing reaction is chromium trioxide pyridine, and oxidation solvent is methylene dichloride, oxidizing reaction temperature is 20 ~ 50 DEG C
Wherein, R
1for-Cl ,-Br or-I;
When preparation formula (IV) compound, formula (VI) compound is prepared into organic zinc reagent, then or simultaneously with formula (III) compound carries out addition reaction obtained,
Described R
2for-Cl ,-Br or-I; Make in the reaction of organic zinc reagent at formula (VI) compound, the catalyzer adopted is selected from one or more in iodine, copper powder, mercury bichloride, acetylacetic ester mantoquita, zinc bromide, and the solvent adopted is tetrahydrofuran (THF).
2. method according to claim 1, it is characterized in that formula (II) compound and 2, when 4-difluorobenzaldehyde carries out addition reaction, the mol ratio of the two is 1:1.4 ~ 1:1, reaction times is 1 ~ 20h, and reaction solvent is selected from one or more in ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, benzene,toluene,xylene, Methylal(dimethoxymethane), dimethyl sulfoxide (DMSO).
3. method according to claim 1, is characterized in that the reaction times of described oxidizing reaction is 0.5 ~ 24h.
4. method according to claim 1, it is characterized in that making in the reaction of organic zinc reagent at formula (II) compound, the catalyzer adopted is selected from one or more in iodine, copper powder, mercury bichloride, acetylacetic ester mantoquita, zinc bromide, and the solvent adopted is tetrahydrofuran (THF).
5. method according to claim 1, it is characterized in that in the addition reaction of formula (VI) compound and formula (III) compound, the mol ratio of formula III compound and formula VI compound is 1:1.5 ~ 1:1.1, the reaction times of formula III compound and formula VI compound is 2 ~ 10h, and reaction solvent is selected from one or more in ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, benzene,toluene,xylene, Methylal(dimethoxymethane), dimethyl sulfoxide (DMSO).
6. method according to claim 1, it is characterized in that formula (IV) compound splits via (-)-10-camphorsulfonic acid and obtains voriconazole, one or more in solvent selected from acetone during fractionation, ethanol, methylene dichloride or water.
7. the preparation method of a voriconazole intermediate, it is characterized in that first adopting formula (II) compound 4-(1-halogenated ethyl)-5-FU and 2,4-difluorobenzaldehyde reaction production (III) compound α-(5-FU-4-base)-2,4-difluorobenzene acetone, again with formula (VI) compound 1-monochloromethyl-1,2,4-triazole reacts at 0 ~ 30 DEG C, synthesis type (IV) compound 1-(1,2,4-triazole-1-base)-2-(2,4 difluorobenzene base)-3-(5-FU-4-base)-2-butanols, i.e. voriconazole intermediate
When preparation formula (III) compound, formula (II) compound is prepared into organic zinc reagent, then or simultaneously with 2,4-difluorobenzaldehyde carries out addition reaction at-5 ~ 50 DEG C, carry out oxidizing reaction again to obtain, the oxygenant in oxidizing reaction is chromium trioxide pyridine, and oxidation solvent is methylene dichloride, oxidizing reaction temperature is 20 ~ 50 DEG C
Wherein, R
1for-Cl ,-Br or-I;
When preparation formula (IV) compound, formula (VI) compound is prepared into organic zinc reagent, then or simultaneously with formula (III) compound carries out addition reaction obtained,
Described R
2for-Cl ,-Br or-I; Make in the reaction of organic zinc reagent at formula (VI) compound, the catalyzer adopted is selected from one or more in iodine, copper powder, mercury bichloride, acetylacetic ester mantoquita, zinc bromide, and the solvent adopted is tetrahydrofuran (THF).
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| CN1473825A (en) * | 2002-08-07 | 2004-02-11 | 张文祥 | Process for preparing voriconazole |
| CN100999518A (en) * | 2006-12-31 | 2007-07-18 | 中国医学科学院医药生物技术研究所 | Voriconazole derivate and preparation process thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1473825A (en) * | 2002-08-07 | 2004-02-11 | 张文祥 | Process for preparing voriconazole |
| CN100999518A (en) * | 2006-12-31 | 2007-07-18 | 中国医学科学院医药生物技术研究所 | Voriconazole derivate and preparation process thereof |
Non-Patent Citations (1)
| Title |
|---|
| Development and Validation of a Stability-Indicating HPLC Method for Determination of Voriconazole and Its Related Substances;Ping Gu et al.;《Journal of Chromatographic Science》;20090831;第47卷;594-598 * |
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