HRP20000680A2 - Process for the preparation of fluconazole - Google Patents
Process for the preparation of fluconazole Download PDFInfo
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- HRP20000680A2 HRP20000680A2 HR20000680A HRP20000680A HRP20000680A2 HR P20000680 A2 HRP20000680 A2 HR P20000680A2 HR 20000680 A HR20000680 A HR 20000680A HR P20000680 A HRP20000680 A HR P20000680A HR P20000680 A2 HRP20000680 A2 HR P20000680A2
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- Prior art keywords
- triazole
- fluconazole
- mol
- preparation
- difluorophenacyl
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- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 title claims description 42
- 229960004884 fluconazole Drugs 0.000 title claims description 17
- 238000002360 preparation method Methods 0.000 title claims description 17
- 238000000034 method Methods 0.000 title claims description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 36
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- XCHRPVARHBCFMJ-UHFFFAOYSA-N 1-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-yl)ethanone Chemical compound FC1=CC(F)=CC=C1C(=O)CN1N=CN=C1 XCHRPVARHBCFMJ-UHFFFAOYSA-N 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 13
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 10
- BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 claims description 9
- 239000011698 potassium fluoride Substances 0.000 claims description 7
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 5
- 235000003270 potassium fluoride Nutrition 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 4
- 150000003852 triazoles Chemical class 0.000 claims description 3
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- 229910001515 alkali metal fluoride Inorganic materials 0.000 claims description 2
- 229910052792 caesium Inorganic materials 0.000 claims description 2
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 claims description 2
- 229960000800 cetrimonium bromide Drugs 0.000 claims description 2
- 238000011065 in-situ storage Methods 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000004094 surface-active agent Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 239000003054 catalyst Substances 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 150000001450 anions Chemical group 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 150000004820 halides Chemical class 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims 1
- 229910052701 rubidium Inorganic materials 0.000 claims 1
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- -1 4-(2',4'-difluorophenacyl)-4H-1,2,4-triazole Chemical compound 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- UENGBOCGGKLVJJ-UHFFFAOYSA-N 2-chloro-1-(2,4-difluorophenyl)ethanone Chemical compound FC1=CC=C(C(=O)CCl)C(F)=C1 UENGBOCGGKLVJJ-UHFFFAOYSA-N 0.000 description 9
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 229910052681 coesite Inorganic materials 0.000 description 8
- 229910052906 cristobalite Inorganic materials 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000000377 silicon dioxide Substances 0.000 description 8
- 235000012239 silicon dioxide Nutrition 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 229910052682 stishovite Inorganic materials 0.000 description 8
- 229910052905 tridymite Inorganic materials 0.000 description 8
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000011877 solvent mixture Substances 0.000 description 6
- FMCUPJKTGNBGEC-UHFFFAOYSA-N 1,2,4-triazol-4-amine Chemical compound NN1C=NN=C1 FMCUPJKTGNBGEC-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 150000002222 fluorine compounds Chemical class 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- 102100027522 Baculoviral IAP repeat-containing protein 7 Human genes 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 230000001408 fungistatic effect Effects 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 235000012907 honey Nutrition 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 229940042055 systemic antimycotics triazole derivative Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
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- Compositions Of Macromolecular Compounds (AREA)
Description
Područje tehnike na koji se izum odnosi Technical field to which the invention relates
Int. klas. C 07 F Int. spike. C 07 F
Izum se odnosi na postupak priprave 2-(2,4-difluorfenil)-1,3-bis(1H-1,2,4-triazol-1-il)propan-2-ola (1), flukonazola. Spoj 1 je prvi predstavnik sintetičkih fungicida (derivata triazola) koji se koriste u liječenju mikoza. Osnovni mehanizam njegovog fungistatskog djelovanja je sprečavanje fungalnog citokroma P-450 koji demetilira steroide na položaju a-C-14. α-Demetiliranje uzrokuje slabljenje biosinteze fungalnih steroida i nagomilavanja 14 α-metilsteroida, što usporava rast mikroorganizama [E. Livin i sur., Nucl. Med. Biol. 19(1) (1992) 191.]. The invention relates to the preparation process of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol (1), fluconazole. Compound 1 is the first representative of synthetic fungicides (triazole derivatives) used in the treatment of mycoses. The basic mechanism of its fungistatic action is the prevention of fungal cytochrome P-450, which demethylates steroids at the a-C-14 position. α-Demethylation causes a weakening of the biosynthesis of fungal steroids and the accumulation of 14 α-methylsteroids, which slows down the growth of microorganisms [E. Livin et al., Nucl. Honey. Biol. 19(1) (1992) 191].
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Pregledom patentne literature utvrđeno je da postoje tri patenta za pripravu flukonazola (1). Prema [K. Richardson, GB 2 099 818 A (1982)] flukonazol (1) se dobiva kroz četiri stupnja sinteze. U drugom stupnju sinteze, priprava ketona (7) provedena je sa 1/-M,2,4-triazolom (8), sa iskorištenjem od 40%. Upotrebom triazola (8) alkiliranje je moguće i na N-4 triazolskog prstena, te može nastati i 4-(2',4'-difluorfenacil)-4H-1,2,4-triazol (10) sa istom vjerojatnošću nastajanja kao i spoj 7, što je uzrok ovako niskom iskorištenju. Slijedeći nedostatak ove sinteze je priprava odgovarajućeg epoksida (11) u trećem stupnju, koji je nestabilan [A. Narayanan i sur., J. Heterocycl. Chem. 30 (1993) 1405.], što isto tako dovodi do niskog iskorištenja uslijed znatnog usmoljavanja. U istom patentu naveden je j postupak direktne sinteze flukonazola (1), kao i u patentu [K. Richardson, EP 0 096 569 A2 (1983)]. Nedostaci ovog postupka su rad na niskoj temperaturi i nisko iskorištenje. Patent [F. Montserrat i sur., ES 549,020 (1985)] uključuje pripravu Grignardovog reagensa iz halometiltriazola i njegovu adiciju na metilni ester 1,3-difluorfeniloctene kiseline. Nedostaci ovog postupka su rad uz isključenje vlage i nisko iskorištenje. A review of the patent literature revealed that there are three patents for the preparation of fluconazole (1). According to [K. Richardson, GB 2 099 818 A (1982)] fluconazole (1) is obtained through four stages of synthesis. In the second stage of the synthesis, the preparation of ketone (7) was carried out with 1/-M,2,4-triazole (8), with a yield of 40%. By using triazole (8), alkylation is also possible at N-4 of the triazole ring, and 4-(2',4'-difluorophenacyl)-4H-1,2,4-triazole (10) can be formed with the same probability of formation as compound 7, which is the reason for such a low utilization. Another disadvantage of this synthesis is the preparation of the corresponding epoxide (11) in the third step, which is unstable [A. Narayanan et al., J. Heterocycl. Chem. 30 (1993) 1405.], which also leads to low utilization due to significant resinification. The procedure for the direct synthesis of fluconazole (1) is specified in the same patent, as well as in the patent [K. Richardson, EP 0 096 569 A2 (1983)]. The disadvantages of this process are low temperature operation and low efficiency. Patent [F. Montserrat et al., ES 549,020 (1985)] involves the preparation of a Grignard reagent from halomethyltriazole and its addition to 1,3-difluorophenylacetic acid methyl ester. Disadvantages of this procedure are operation with the exclusion of moisture and low utilization.
Prema [A. Narayanan i sur., J. Heterocycl. Chem. 30 (1993) 1405.], flukonazol (1) je pripravljen direktnom metodom iz odgovarajućeg ketona 7. Nedostaci ove metode su nisko iskorištenje i dugotrajno zagrijavanje reakcijske smjese. According to [A. Narayanan et al., J. Heterocycl. Chem. 30 (1993) 1405.], fluconazole (1) was prepared by a direct method from the corresponding ketone 7. The disadvantages of this method are low yield and long-term heating of the reaction mixture.
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Rezultat našeg izuma je efikasna metoda priprave flukonazola (1) direktnom sintezom iz 1-(2',4'-difluorfenacil)-1H-1,2,4-triazola (7), 1H-1,2,4-triazola (8) sa trimetil-sulfoksonijevim jodidom (9), katalizirana fluoridima alkalijskih metala. The result of our invention is an efficient method of preparing fluconazole (1) by direct synthesis from 1-(2',4'-difluorophenacyl)-1H-1,2,4-triazole (7), 1H-1,2,4-triazole (8) ) with trimethyl-sulfoxonium iodide (9), catalyzed by alkali metal fluorides.
Pronašli smo da fluoridi alkalijskih metala (CsF, RbF, KF, NaF, LiF), pokazuju jako izraženo katalitičko djelovanje, što znatno skraćuje vrijeme reakcije i povećava iskorištenje. lako su fluoridi općenito jake baze, njihova bazičnost ovisi o upotrebljenom otapalu. Kako je kao otapalo u našem izumu upotrebljen t-butil alkohol koji smanjuje bazičnost fluorida, za povećanje bazičnosti upotrebljen je kalijev hidroksid. Potrebno je istaknuti da smo upotrebom kvaternih amonijevih surfaktanata (cetrimonijev bromid, tetrabutilamonijev hidrogensulfat, benzil-trietilamonijev klorid i sl.) postigli povećano iskorištenje i značajno skraćenje vremena reakcije. Katalitički utjecaj fluorida raste u nizu od litija prema ceziju. Navedeni postupak sinteze prikazan je na shemi 1. We found that fluorides of alkali metals (CsF, RbF, KF, NaF, LiF) show a strong catalytic effect, which significantly shortens the reaction time and increases the yield. easy fluorides are generally strong bases, their basicity depends on the solvent used. Since t-butyl alcohol was used as a solvent in our invention, which reduces the basicity of fluoride, potassium hydroxide was used to increase the basicity. It should be noted that by using quaternary ammonium surfactants (cetrimonium bromide, tetrabutylammonium hydrogen sulfate, benzyl-triethylammonium chloride, etc.), we achieved increased utilization and a significant shortening of the reaction time. The catalytic influence of fluoride increases in the sequence from lithium to cesium. The aforementioned synthesis procedure is shown in scheme 1.
Molarni reakcijski omjer reaktanata može biti unutar vrijednosti n (1-(2',4'-difluorfenacil)-1H-1,2,4-triazol (7)) : n (1H-1,2,4-triazol (8)) : n (trimetilsulfoksonijev jodid (9)) ; n (kalijev hidroksid) : n (alkalijski fluorid) = 1 : 1.1 : 1.2-1.5 : 2-2.5 : 1. Reakcija se provodi u t-butil alkoholu kao otapalu na temperaturi povrata otapala tijekom svega 1 sata. Reakcijsko razrjeđenje se može kretati od 1-20 g spoja 7 na 100 ml t-butil alkohola. Ista reakcija se može provesti i bez kalijevog fluorida s nascentnim kalijevim hidroksidom,koji je in situ pripravljen iz kalijevog-t-butoksida i stehiometrijske količine vode. Tako pripremljen nascentni kalijev hidroksid je daleko aktivniji od običnog kalijevog hidroksida. Ohlađena reakcijska smjesa se filtrira, talog se ispire i filtrat upari pod sniženim pritiskom. Dobiveni talog se otopi u vodi, ekstrahira pogodnim otapalom (kloroform, diklormetan, etilacetat i sl.), ekstrakt se suši i upari pod sniženim pritiskom. Iz dobivenog ostatka, dodatkom smjese otapala etilacetat : n-heksan = 1 : 1 na sobnoj temperaturi uz miješanje kristalizira flukonazol (1). Iskorištenja su veća od 50%. Čistoća produkta ovisi o količini dodane smjese otapala i efikasnosti miješanja. The molar reaction ratio of the reactants can be within the value n (1-(2',4'-difluorophenacyl)-1H-1,2,4-triazole (7)) : n (1H-1,2,4-triazole (8) ) : n (trimethylsulfoxonium iodide (9)) ; n (potassium hydroxide) : n (alkaline fluoride) = 1 : 1.1 : 1.2-1.5 : 2-2.5 : 1. The reaction is carried out in t-butyl alcohol as a solvent at the solvent return temperature for only 1 hour. The reaction dilution can range from 1-20 g of compound 7 per 100 ml of t-butyl alcohol. The same reaction can be carried out without potassium fluoride with nascent potassium hydroxide, which is prepared in situ from potassium-t-butoxide and a stoichiometric amount of water. Nascent potassium hydroxide prepared in this way is far more active than ordinary potassium hydroxide. The cooled reaction mixture is filtered, the precipitate is washed and the filtrate is evaporated under reduced pressure. The precipitate obtained is dissolved in water, extracted with a suitable solvent (chloroform, dichloromethane, ethyl acetate, etc.), the extract is dried and evaporated under reduced pressure. Fluconazole (1) crystallizes from the obtained residue by adding a solvent mixture of ethyl acetate : n-hexane = 1 : 1 at room temperature with stirring. Utilization is greater than 50%. The purity of the product depends on the amount of solvent mixture added and the mixing efficiency.
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Pregledom literature [J. H. Clark, Chem. Rev. 80 (1980) 429.] i [G. G. Yakobson i sur, Synthesis (1983) 169.], nađeno je da bazno katalizirane reakcije vođene u prisustvu floridnih iona imaju veća iskorištenja i kraće vrijeme reakcije od onih u kojima fluoridni ion nije prisutan. Ovaj pozitivni utjecaj fluorida iskorišten je u navedenom postupku priprave flukonazola (1). i na taj način je skraćeno vrijeme reakcije i znatno poboljšano iskorištenje. Isto tako smo pronašli da voda u reakcijskoj smjesi nema utjecaj na iskorištenje, ni na brzinu reakcije, te da nije potreban rad uz isključenje vlage. By reviewing the literature [J. H. Clark, Chem. Rev. 80 (1980) 429.] and [G. G. Yakobson et al, Synthesis (1983) 169], base-catalyzed reactions conducted in the presence of fluoride ions were found to have higher yields and shorter reaction times than those in which the fluoride ion was not present. This positive influence of fluoride was used in the mentioned procedure for the preparation of fluconazole (1). and in this way the reaction time is shortened and the utilization is significantly improved. We also found that the water in the reaction mixture has no effect on the yield, nor on the speed of the reaction, and that it is not necessary to work with the exclusion of moisture.
Keton 7 pripravljen je reakcijom diazotacije 1-(2',4'-difluorifenacil)-4-amino-(1H-1,2,4-triazolium)klorida (6), prikazanoj na shemi 2 u kiselom vodenom mediju dokapavanjem vodene otopine natrijevog nitrita na temperaturi od -1°C do +1°C pri čemu dolazi do izlučivanja ketona 7 u obliku bijelog taloga. Molarni reakcijski omjeri reaktanata su n (1-(2',4'-difluorfenacil)-4-amino-(1H-1,2,4-triazolium)klorid (6)): n (HCl): n (NaNO2) = 1:2:1. Reakcijsko razrjeđenje je 70 g spoja 6 na 500 ml vode. Nakon neutralizacije sa koncentriranim amonijevim hidroksidom, odsisavanja, ispiranja i sušenja dobiven je keton 7 u vrlo visokom iskorištenju. Ketone 7 was prepared by the diazotization reaction of 1-(2',4'-difluorophenacyl)-4-amino-(1H-1,2,4-triazolium) chloride (6), shown in scheme 2, in an acidic aqueous medium by adding an aqueous solution of sodium of nitrite at a temperature of -1°C to +1°C, during which ketone 7 is excreted in the form of a white precipitate. The molar reaction ratios of the reactants are n (1-(2',4'-difluorophenacyl)-4-amino-(1H-1,2,4-triazolium) chloride (6)): n (HCl): n (NaNO2) = 1:2:1. The reaction dilution is 70 g of compound 6 per 500 ml of water. After neutralization with concentrated ammonium hydroxide, suction, washing and drying, ketone 7 was obtained in very high yield.
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1-(2',4'-difluorfenacil)-4-amino-(1H-1,2,4-triazolium)klorid (6) je pripravljen alkiliranjem 4-amino-4H-1,2,4-triazola (5) s α-klor-2,4-difluoracetofenonom (4) u acetonitrilu na temperaturi povrata, kao što je prikazano na shemi 3. Spoj 5 je dodan u 10% molarnom suvišku, a reakcijsko razrjeđenje je 55 g spoja 4 na 500 ml otapala. Spoj 6 je dobiven u iskorištenju većem od 90%. 1-(2',4'-difluorophenacyl)-4-amino-(1H-1,2,4-triazolium) chloride (6) was prepared by alkylating 4-amino-4H-1,2,4-triazole (5) with α-chloro-2,4-difluoroacetophenone (4) in acetonitrile at reflux temperature, as shown in Scheme 3. Compound 5 was added in 10% molar excess, and the reaction dilution was 55 g of compound 4 per 500 ml of solvent. Compound 6 was obtained in a yield greater than 90%.
α-klor-2,4-difluoracetofenon (4) dobiven je aciliranjem 1,3-difluorbenzena (2) sa kloracetil kloridom (3) uz aluminijev(III) klorid, kao što je prikazano na shemi 4. Molarni reakcijski omjer reaktanata je unutar vrijednosti n (1,3-difluorbenzen (2)) : n (kloracetil klorid (3)) : n (aluminijev(III) klorid)= 1 : 1.1-1.3 : 2-2.2. Reakcija se može provesti u 1,2-dikloretanu ili ugljikovom disulfidu kao otapalu na temperaturama od -10°C do sobne. Reakcijsko razrjeđenje je 50 ml spoja 2 na 400 ml otapala. α-Chloro-2,4-difluoroacetophenone (4) was obtained by acylation of 1,3-difluorobenzene (2) with chloroacetyl chloride (3) in the presence of aluminum(III) chloride, as shown in scheme 4. The molar reaction ratio of the reactants is within values of n (1,3-difluorobenzene (2)) : n (chloroacetyl chloride (3)) : n (aluminum(III) chloride)= 1 : 1.1-1.3 : 2-2.2. The reaction can be carried out in 1,2-dichloroethane or carbon disulfide as a solvent at temperatures from -10°C to room temperature. The reaction dilution is 50 ml of compound 2 per 400 ml of solvent.
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U ohlađenu suspenziju spoja 2 i aluminijeva(III) klorida polagano se dodaje spoj 3 i produženo miješa na sobnoj temperaturi, do 24 sata. Reakcijska smjesa se izlije u ledenu vodu, ekstrahira sa pogodnim organskim otapalom (kloroform. diklormetan, etilacetat, eter i sl.), suši, filtrira i uparava pod sniženim pritiskom. Iz dobivenog taloga dodatkom etera kristalizira spoj 4 sa iskorištenjem većim od 75%. Compound 3 is slowly added to the cooled suspension of compound 2 and aluminum(III) chloride and stirred at room temperature for up to 24 hours. The reaction mixture is poured into ice water, extracted with a suitable organic solvent (chloroform, dichloromethane, ethyl acetate, ether, etc.), dried, filtered and evaporated under reduced pressure. Compound 4 crystallizes from the resulting precipitate with the addition of ether with a yield greater than 75%.
Primjer 1 Example 1
Priprava a-klor-2,4-difluoracetofenona (4) Preparation of a-chloro-2,4-difluoroacetophenone (4)
U suspenziju 1,3-difluorbenzena (2, 0.026 mol, 2.58 ml) i aluminijeva(III) klorida (0.052 mol, 6.93 g) u ugljikovom disulfidu (10 ml) ohlađenu na temperaturu od -10°C i uz snažno miješanje dokapana je otopina kloracetil klorida (3, 0.026 mol, 2.1 ml) u ugljikovom disulfidu (10 ml). Reakcijska smjesa je miješana 1 sat na temperaturi od -10°C i 18 sati na sobnoj temperaturi, a zatim izlivena u smjesu leda (oko 50 g) i vode (50 ml) i miješana do potpunog otapanja leda. Smjesa je ekstrahirana s dietileterom (3 x 50 ml), eterski ekstrakt ispiran sa vodom (3 x 50 ml) i sušen na Na2SO4. Otopina je filtrirana i uparena pod sniženim pritiskom. Into a suspension of 1,3-difluorobenzene (2, 0.026 mol, 2.58 ml) and aluminum(III) chloride (0.052 mol, 6.93 g) in carbon disulfide (10 ml) cooled to a temperature of -10°C and with vigorous stirring was added a solution of chloroacetyl chloride (3, 0.026 mol, 2.1 ml) in carbon disulfide (10 ml). The reaction mixture was stirred for 1 hour at a temperature of -10°C and 18 hours at room temperature, then poured into a mixture of ice (about 50 g) and water (50 ml) and stirred until the ice completely dissolved. The mixture was extracted with diethyl ether (3 x 50 ml), the ether extract washed with water (3 x 50 ml) and dried over Na2SO4. The solution was filtered and evaporated under reduced pressure.
TLC (SiO2): Rf(4) = 0.58 uz diklormetan/n-heksan (7 : 3). TLC (SiO2): Rf(4) = 0.58 with dichloromethane/n-hexane (7 : 3).
Dobiveno je 3.70 g (75.5%) α-klor-2,4-difluoracetofenona (4) u obliku bezbojnih kristala, t.t. 48.4-49.4°C. 3.70 g (75.5%) of α-chloro-2,4-difluoroacetophenone (4) was obtained in the form of colorless crystals, m.p. 48.4-49.4°C.
1H-NMR (CDCl3)δ: 4.70-4.71 (d, 2H, CH2, J=2.74 Hz), 6.9-7.06 (m, 2H, arom.), 7.99-8.08 (m, 1H, arom.). 1H-NMR (CDCl3)δ: 4.70-4.71 (d, 2H, CH2, J=2.74 Hz), 6.9-7.06 (m, 2H, arom.), 7.99-8.08 (m, 1H, arom.).
13C-NMR (CDCl3)δ: 49.64, 49.80, 104.36, 104.70, 104.74, 105.07, 112.57, 112,62, 112.86, 112.91, 133.09, 133.15, 133.23, 133.30, 160.74, 160.74, 160,91 164.31, 164.52, 164.69, 167.95, 168.12, 187.59, 187.66. 13c-NMR (CDCL3) Δ: 49.64, 49.80, 104.36, 104.70, 104.74, 105.07, 112.57, 112,62, 112.86, 112.91, 133.09, 133.15, 133.23, 133.30, 160.74, 160,74, 160,91 164.52, 164.69 , 167.95, 168.12, 187.59, 187.66.
IR (KBr)ν: 3386, 3092, 3054, 3071, 3020, 2957, 1767, 1702, 1612, 1491, 1435, 1393, 1317, 1269, 1233, 1195,1143, 1099, 1002, 971, 919, 884, 822, 795, 756, 728, 707,622,609. IR (KBr)ν: 3386, 3092, 3054, 3071, 3020, 2957, 1767, 1702, 1612, 1491, 1435, 1393, 1317, 1269, 1233, 1195,1143, 1099, 1002, 194,89,89 822, 795, 756, 728, 707,622,609.
Primjer 2 Example 2
Priprava a-klor-2,4-difluoracetofenona (4) Preparation of a-chloro-2,4-difluoroacetophenone (4)
U suspenziju 1,3-difluorbenzena (2, 0.026 mol, 2.58 ml) i aluminijeva(III) klorida (0.052 mol, 6.93 g) u 1,2-dikloretanu (10 ml) ohlađenu na temperaturu od -10°C, uz snažno miješanje dokapana je otopina kloracetil klorida (3, 0.026 mol, 2.1 ml) u 1,2-dikloretanu (10 ml). To a suspension of 1,3-difluorobenzene (2, 0.026 mol, 2.58 ml) and aluminum(III) chloride (0.052 mol, 6.93 g) in 1,2-dichloroethane (10 ml) cooled to a temperature of -10°C, with vigorous stirring, a solution of chloroacetyl chloride (3, 0.026 mol, 2.1 ml) in 1,2-dichloroethane (10 ml) was added dropwise.
Reakcijska smjesa je miješana 1 sat na temperaturi od -10 °C i 67 sati na sobnoj temperaturi, a zatim izlivena u smjesu leda (oko 50 g) i vode (50 ml) uz dodatak koncentrirane kloridne kiseline (10 ml), te ostavljena na miješanju do potpunog otapanja leda. Vodena otopina je ekstrahirana s dietileterom (3 x 50 ml), eterski ekstrakt ispiran sa vodom (3 x 50 ml) i sušen na Na2SO4. Otopina je filtrirana i uparena pod sniženim pritiskom. The reaction mixture was stirred for 1 hour at a temperature of -10 °C and 67 hours at room temperature, then poured into a mixture of ice (about 50 g) and water (50 ml) with the addition of concentrated hydrochloric acid (10 ml), and left at stirring until the ice melts completely. The aqueous solution was extracted with diethyl ether (3 x 50 ml), the ether extract washed with water (3 x 50 ml) and dried over Na2SO4. The solution was filtered and evaporated under reduced pressure.
TLC (SiO2): Rf(4)=0.58 uz diklormetan/n-heksan (7 : 3). TLC (SiO2): Rf(4)=0.58 with dichloromethane/n-hexane (7 : 3).
Dobiveno je 2,80 g (57,1%) α-klor-2,4-difluoracetofenona (4) u obliku bezbojnih kristala, t.t. 48.4-49.4 °C. 2.80 g (57.1%) of α-chloro-2,4-difluoroacetophenone (4) was obtained in the form of colorless crystals, m.p. 48.4-49.4 °C.
IR i NMR spektri identični su onima u primjeru 1. IR and NMR spectra are identical to those of Example 1.
Primjer 3 Example 3
Priprava 1-(2',4'-difluorfenacil)-4-amino-(1H-1,2,4-triazolium)klorida (6) Preparation of 1-(2',4'-difluorophenacyl)-4-amino-(1H-1,2,4-triazolium) chloride (6)
Otopina a-klor-2,4-difluoracetofenona (4, 0.029 mol, 5.54 g) i 4-amino-4H-1,2,4-triazola (5, 0.0155 mol, 1.28 g) u acetonitrilu (50 ml) grijana je uz povrat tijekom 12 sati. U otopinu je dodano još 4-amino-4H-1,2,4-triazola (5, 0.0155 mol, 1.28 g) i grijano uz povrat dodatnih 12 sati. Otapalo je djelomično upareno pod sniženim pritiskom, a nastali kristali odsisani. A solution of α-chloro-2,4-difluoroacetophenone (4, 0.029 mol, 5.54 g) and 4-amino-4H-1,2,4-triazole (5, 0.0155 mol, 1.28 g) in acetonitrile (50 ml) was heated with return within 12 hours. More 4-amino-4H-1,2,4-triazole (5, 0.0155 mol, 1.28 g) was added to the solution and heated under reflux for an additional 12 hours. The solvent was partially evaporated under reduced pressure, and the formed crystals were suctioned off.
TLC (SiO2): Rf(6)=0.14 uz diklormetan/metanol/amonijak (80 : 20 : 1). TLC (SiO2): Rf(6)=0.14 with dichloromethane/methanol/ammonia (80 : 20 : 1).
Dobiveno je 7.45 g (93.4%) 1-(2',4'-difluorfenacil)-4-amino-(1H-1,2,4-triazolium)klorida (6) u obliku bezbojnih kristala, 1.1. 192.8-194.3 °C. 7.45 g (93.4%) of 1-(2',4'-difluorophenacyl)-4-amino-(1H-1,2,4-triazolium) chloride (6) were obtained in the form of colorless crystals, 1.1. 192.8-194.3 °C.
1H-NMR (DMSO-d6)δ: 6.17 (d, 2H, CH2CO, J=2.18 Hz), 7.32-7.37 (m, 1H, arom.), 7.58-7.62 (m, 3H, arom.), 8.07-8.09 (m, 1H, arom.), 9.39 (s, 1H, NH2), 10.44 (s, 1H, NH2). 1H-NMR (DMSO-d6)δ: 6.17 (d, 2H, CH2CO, J=2.18 Hz), 7.32-7.37 (m, 1H, arom.), 7.58-7.62 (m, 3H, arom.), 8.07- 8.09 (m, 1H, arom.), 9.39 (s, 1H, NH2), 10.44 (s, 1H, NH2).
13C-NMR (DMSO-d6)δ: 60.70, 60.86, 105.31, 105.67, 106.03, 112.93, 112.96, 113.21, 119.09, 119.21, 132.79, 132.82, 132.94, 143.73, 144.89, 160.96, 161.13. 164.38, 164.55, 167.76, 167.93, 187.24, 187.30. 13c-NMR (DMSO-D6) Δ: 60.70, 60.86, 105.31, 105.67, 106.03, 112.93, 112.96, 113.21, 119.09, 119.21, 132.79, 132.82, 132.94, 143.73, 144.89, 160.96, 161.13. 164.38, 164.55, 167.76, 167.93, 187.24, 187.30.
IR (KBr)v: 3390,3130,3070,3040, 2960, 2930, 1690, 1610, 1590. 1505, 1485, 1425, 1270,1260,1240,1205, 1142, 1100, 1020, 1000, 970, 960, 880, 879, 825, 740, 720,670,630,610,601. IR (KBr)v: 3390,3130,3070,3040, 2960, 2930, 1690, 1610, 1590. 1505, 1485, 1425, 1270,1260,1240,1205, 1142, 1100, 1020, 1000, 960,9970 880, 879, 825, 740, 720, 670, 630, 610, 601.
Primjer 4 Example 4
Priprava 1-(2',4'-difluorfenacil)-1H-1,2,4-triazola (7) Preparation of 1-(2',4'-difluorophenacyl)-1H-1,2,4-triazole (7)
Otopina 1-(2',4'-difluorfenacil)-4-amino-(1H-1,2,4-triazolium)klorida (6, 0.0255 mol, 7.00 g) u vodi (40 ml) ohlađena je vodom i ledom na -1 °C. U ohlađenu otopinu je u intervalu od 0.5 sati dokapavana koncentrirana kloridna kiselina (0.051 mol, 4,4 ml), na navedenoj temperaturi i zatim je reakcijska smjesa produljeno miješana još 0.5 sati. U otopinu je zatim dokapana otopina natrijevog nitrita (0.0255 mol, 1.76 g) u vodi (10 ml) u intervalu od 0.5 sati pri čemu je došlo do stvaranja bijelog taloga. Reakcijska smjesa je miješana jedan sat na sobnoj temperaturi, a zatim neutralizirana s koncentriranim amonijevim hidroksidom do pH=7. Talog je odsisan i ispran s vodom (10 ml). A solution of 1-(2',4'-difluorophenacyl)-4-amino-(1H-1,2,4-triazolium)chloride (6, 0.0255 mol, 7.00 g) in water (40 ml) was cooled with water and ice at -1 °C. Concentrated hydrochloric acid (0.051 mol, 4.4 ml) was added dropwise to the cooled solution at intervals of 0.5 hours, at the indicated temperature, and then the reaction mixture was stirred for another 0.5 hours. A solution of sodium nitrite (0.0255 mol, 1.76 g) in water (10 ml) was then added dropwise to the solution at an interval of 0.5 hours, during which a white precipitate was formed. The reaction mixture was stirred for one hour at room temperature and then neutralized with concentrated ammonium hydroxide to pH=7. The precipitate was filtered off and washed with water (10 ml).
TLC (SiO2): Rf(7)=0.65 uz diklormetan/metanol/amonijak (80 : 20 : 1). TLC (SiO2): Rf(7)=0.65 with dichloromethane/methanol/ammonia (80 : 20 : 1).
Dobiveno je 4.9 g (86.1%) 1-(2',4'-difluorfenacil)-1M-1,2,4-triazola (7) u obliku bezbojnih kristala, 1.1. 104-107 °C. 4.9 g (86.1%) of 1-(2',4'-difluorophenacyl)-1M-1,2,4-triazole (7) were obtained in the form of colorless crystals, 1.1. 104-107 °C.
1H-NMR (CDCl3)δ: 5.53-5.54 (d, 2H, CH2, J=3.57 Hz), 6.88-7.02 (m, 2H, arom.), 7.98-8.01 (m, 2H, triazol.), 8.16 (s, 1H, arom.). 1H-NMR (CDCl3)δ: 5.53-5.54 (d, 2H, CH2, J=3.57 Hz), 6.88-7.02 (m, 2H, arom.), 7.98-8.01 (m, 2H, triazol.), 8.16 ( with, 1H, arom.).
13C-NMR (CDCl3)δ: 58.19, 58.36, 104.45, 105.14, 112.84, 112.87, 113.13, 113.16, 132.84, 132.91, 132.99, 133.05, 144.67, 151.69, 161.19, 161.36. 13C-NMR (CDCl3)δ: 58.19, 58.36, 104.45, 105.14, 112.84, 112.87, 113.13, 113.16, 132.84, 132.91, 132.99, 133.05, 144.67, 151.61.19, 16.1619, 16.16.
IR (KBr)v: 3115, 3090, 3060, 3040, 2980, 2960, 2940, 1685, 1610, 1590, 1505, 1485, 1425, 1375, 1360, 1315, 1270, 1240, 1200, 1095, 1000, 970, 965, 895, 880, 825, 740, 720, 670, 640, 620, 610. IR (KBr)v: 3115, 3090, 3060, 3040, 2980, 2960, 2940, 1685, 1610, 1590, 1505, 1485, 1425, 1375, 1360, 1315, 1270, 1240, 1200, 10,095, 1095 965, 895, 880, 825, 740, 720, 670, 640, 620, 610.
Primjer 5 Example 5
Priprava2-(2,4-difluorfenil)-1,3-bis(1H-1,2,4-triazol-1-il)propan-2-ol, Preparation of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol,
FLUKONAZOL(I) FLUCONAZOLE(S)
Suspenzija 1-(2',4'-difluorfenacil)-1H-1,2,4-triazola (7, 0.00224 mol, 0.5 g), 1H-1,2,4-triazola (8, 0.00246 mol, 0.17 g), trimetilsulfoksonijevog jodida (9, 0.00336 mol, 0.74 g), kalijevog hidroksida (0.00448 mol, 0.25 g) i kalijevog fluorida (0.00224 mol, 0.13 g) u t- butil alkoholu (10 ml) grijana je u povrat 1 sat. Nastali talog je odsisan i ispran sa t-butil alkoholom (10 ml). Otopina je uparena do suha pod sniženim pritiskom, te ostatak otopljen u vodi (10 ml). Vodena otopina je ekstrahirana s etilacetatom (4 x 25ml), sušena na Na2S04, filtrirana i uparena pod sniženim pritiskom. Na dobiveni ostatak dodana je smjesa otapala etilacetat/n-heksan (1 : 1) (10 ml), te ostavljena kristalizirati na sobnoj temperaturi uz miješanje. Suspension of 1-(2',4'-difluorophenacyl)-1H-1,2,4-triazole (7, 0.00224 mol, 0.5 g), 1H-1,2,4-triazole (8, 0.00246 mol, 0.17 g) , trimethylsulfoxonium iodide (9, 0.00336 mol, 0.74 g), potassium hydroxide (0.00448 mol, 0.25 g) and potassium fluoride (0.00224 mol, 0.13 g) in t-butyl alcohol (10 ml) was heated under reflux for 1 hour. The resulting precipitate was suctioned off and washed with t-butyl alcohol (10 ml). The solution was evaporated to dryness under reduced pressure, and the residue was dissolved in water (10 ml). The aqueous solution was extracted with ethyl acetate (4 x 25ml), dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. A solvent mixture of ethyl acetate/n-hexane (1 : 1) (10 ml) was added to the obtained residue and allowed to crystallize at room temperature with stirring.
TLC (SiO2): Rf(1)=0.29 uz diklormetan/metanol (9 : 1). TLC (SiO2): Rf(1)=0.29 with dichloromethane/methanol (9 : 1).
Dobiveno je 0.39 g (56,9%) 2-(2,4-difluorfenil)-1,3-bis(1H-1,2,4-triazol-1-il)propan-2-ol (1) u obliku bezbojnih kristala, 1.1. 138-140 °C. 0.39 g (56.9%) of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol (1) was obtained in the form colorless crystals, 1.1. 138-140 °C.
1H-NMR (CDCl3)δ: 4.43-4.48 (m, 2H, CH2), 4.69-4.74 (m, 2H, CH2), 5.65 (s, 1 H, OH), 6.72-6.81 (m, 2H, arom.), 7.36-7.44 (m, 1H, arom.), 7.79(s, 1H arom.), 8.03 ( s, 1H, arom.). 1H-NMR (CDCl3)δ: 4.43-4.48 (m, 2H, CH2), 4.69-4.74 (m, 2H, CH2), 5.65 (s, 1H, OH), 6.72-6.81 (m, 2H, arom. ), 7.36-7.44 (m, 1H, arom.), 7.79 (s, 1H arom.), 8.03 (s, 1H, arom.).
13C-NMR (CDCl3)δ: 54.71, 54.78, 75.10, 75.15, 103.85, 104.21, 104.57, 111.87, 111.91, 112.14, 112.18, 129,80, 129.87, 129.92, 130.00, 144.46, 151.67, 156.61, 156.77, 161.24, 161.39, 164.57, 164.74. 13c-NMR (CDCl3) Δ: 54.71, 54.78, 75.10, 75.15, 103.85, 104.21, 104.57, 111.87, 111.91, 112.14, 112.18, 129.80, 129.87, 129.92, 130.00, 144.46, 151.67, 156.61, 156.77, 161.24 161.39, 164.57, 164.74.
IR (KBr)v: 3122, 3014, 2962, 2792, 2480, 2229, 1917, 1774, 1739, 1620, 1598, 1524, 1502, 1464, 1453, 1417, 1272, 1253, 1235, 1209, 1137, 1117,1075,1091, 1026,1011,999,967,960,870,854, 768, 733, 674, 652, 615. IR (KBr)v: 3122, 3014, 2962, 2792, 2480, 2229, 1917, 1774, 1739, 1620, 1598, 1524, 1502, 1464, 1453, 1417, 1272, 1253, 1235, 117, 117, 1209 1075,1091, 1026,1011,999,967,960,870,854, 768, 733, 674, 652, 615.
Primjer 6 Example 6
Priprava 2-(2,4-difluorfenil)-1,3-bis(1H-1,2,4-triazol-1-il)propan-2-ol. Preparation of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol.
FLUKONAZOL(I) FLUCONAZOLE(S)
Suspenzija 1-(2',4'-difluorfenacil)-1H-1,2,4-triazola (7, 0.00224 mol, 0.5 g), 1H-1,2,4-triazola (8, 0.00246 mol, 0.17 g), trimetilsulfoksonijevog jodida (9, 0.00336 mol, 0.74 g), kalijevog hidroksida (0.00448 mol, 0.25 g), i vode (0.00437 mol, 0.079 g) u t-butil alkoholu (10 ml) grijana je u povrat 5,5 sati i miješana na sobnoj temperaturi 18 sati. Nastali talog je odsisan i ispran sa t-butil alkoholom (10 ml). Otopina je uparena do suha pod sniženim pritiskom, te ostatak otopljen u vodi (10 ml). Vodena otopina je ekstrahirana s etilacetatom (4 x 25 ml), sušena na Na2SO4, filtrirana i uparena pod sniženim pritiskom. Na dobiveni ostatak dodana je smjesa otapala etilacetat/n-heksan (1 : 1) (10 ml), te ostavljena kristalizirati na sobnoj temperaturi uz miješanje. Suspension of 1-(2',4'-difluorophenacyl)-1H-1,2,4-triazole (7, 0.00224 mol, 0.5 g), 1H-1,2,4-triazole (8, 0.00246 mol, 0.17 g) , trimethylsulfoxonium iodide (9, 0.00336 mol, 0.74 g), potassium hydroxide (0.00448 mol, 0.25 g), and water (0.00437 mol, 0.079 g) in t-butyl alcohol (10 ml) was heated to reflux for 5.5 hours and stirred at room temperature for 18 hours. The resulting precipitate was suctioned off and washed with t-butyl alcohol (10 ml). The solution was evaporated to dryness under reduced pressure, and the residue was dissolved in water (10 ml). The aqueous solution was extracted with ethyl acetate (4 x 25 ml), dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. A solvent mixture of ethyl acetate/n-hexane (1 : 1) (10 ml) was added to the obtained residue and allowed to crystallize at room temperature with stirring.
TLC (SiO2): Rf(1)=0.29 uz diklormetan/metanol (9 : 1). TLC (SiO2): Rf(1)=0.29 with dichloromethane/methanol (9 : 1).
Dobiveno je 0.38 g (55.4%) 2-(2,4-difluorfenil)-1,3-bis(1H-1,2,4-triazol-1-il)propan-2-ol (1) u obliku bezbojnih kristala, 1.1. 138-140 °C. IR i NMR spektri identični su onima u primjeru 5. 0.38 g (55.4%) of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol (1) was obtained in the form of colorless crystals , 1.1. 138-140 °C. The IR and NMR spectra are identical to those of Example 5.
Primjer 7 Example 7
Priprava 2-(2,4-difluorfenil)-1,3-bis(1H-1,2,4-triazol-1-il)propan-2-ol, Preparation of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol,
FLUKONAZOL (1) FLUCONAZOLE (1)
Suspenzija 1-(2',4'-difluorfenacil)-1H-1,2,4-triazola (7, 0.00224 mol, 0.5 g), 1H-1,2,4-triazola (8, 0.00246 mol, 0.17 g), trimetilsulfoksonijevog jodida (0.00336 mol, 0.74 g), kalijevog hidroksida (0.00448 mol, 0.25 g), kalijevog fluorida (0.00224 mol, 0.13 g) i trietil-benzilamonijevog klorida (0.000224 mol, 0.05 g) u t-butil alkoholu (10 ml) grijana je u povrat 1 sat. Nastali talog je odsisan i ispran sa t-butil alkoholom (10 ml). Otopina je uparena do suha pod sniženim pritiskom, te ostatak otopljen u vodi (10 ml). Vodena otopina je ekstrahirana s etilacetatom (4 x 25ml), sušena na Na2SO4, filtrirana i uparena pod sniženim pritiskom. Na dobiveni ostatak dodana je smjesa otapala etilacetat/n-heksan (1 : 1) (10 ml), te ostavljena kristalizirati na sobnoj temperaturi uz miješanje. Suspension of 1-(2',4'-difluorophenacyl)-1H-1,2,4-triazole (7, 0.00224 mol, 0.5 g), 1H-1,2,4-triazole (8, 0.00246 mol, 0.17 g) , trimethylsulfoxonium iodide (0.00336 mol, 0.74 g), potassium hydroxide (0.00448 mol, 0.25 g), potassium fluoride (0.00224 mol, 0.13 g) and triethyl-benzylammonium chloride (0.000224 mol, 0.05 g) in t-butyl alcohol (10 ml). ) was reheated for 1 hour. The resulting precipitate was suctioned off and washed with t-butyl alcohol (10 ml). The solution was evaporated to dryness under reduced pressure, and the residue was dissolved in water (10 ml). The aqueous solution was extracted with ethyl acetate (4 x 25ml), dried over Na2SO4, filtered and evaporated under reduced pressure. A solvent mixture of ethyl acetate/n-hexane (1 : 1) (10 ml) was added to the obtained residue and allowed to crystallize at room temperature with stirring.
TLC (SiO2): Rf(1)=0.29 uz diklormetan/metanol (9:1). TLC (SiO2): Rf(1)=0.29 with dichloromethane/methanol (9:1).
Dobiveno je 0.10 g (14.6%) 2-(2,4-difluorfenil)-1,3-bis(1H-1,2,4-triazol-1-il)propan-2-ol (1) u obliku bezbojnih kristala, 1.1. 138-140 °C. 0.10 g (14.6%) of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol (1) was obtained in the form of colorless crystals , 1.1. 138-140 °C.
IR i NMR spektri identični su onima u primjeru 5. The IR and NMR spectra are identical to those of Example 5.
Primjer 8 Example 8
Priprava 2-(2,4-difluorfenil)-1,3-bis(1H-1,2,4-triazol-1-il)propan-2-ol, Preparation of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol,
FLUKONAZOL (1) FLUCONAZOLE (1)
Suspenzija 1-(2',4'-difluorfenacil)-1H-1,2,4-triazola (7, 0.00224 mol, 0.5 g), 1H-1,2,4-triazola (8, 0.00246 mol, 0.17 g), trimetilsulfoksonijevog jodida (9, 0.00336 mol, 0.74 g), kalijevog hidroksida (0.00448 mol, 0.25 g), kalijevog fluorida (0.00224 mol, 0.13 g) i kalcijevog hidrida (0.09 g, 0.00224 mol) u t-butil alkoholu (10 ml) grijana je uz povrat 2,5 sata. Nastali talog je odsisan i ispran sa t-butil alkoholom (10 ml). Otopina je uparena do suha pod sniženim pritiskom, te ostatak otopljen u vodi (10 ml). Vodena otopina je ekstrahirana s etilacetatom (4 x 25 ml), sušena na Na2SO4, filtrirana i uparena pod sniženim pritiskom. Na dobiveni ostatak dodana je smjesa otapala etilacetat/n-heksan (1 : 1) (10 ml), te ostavljena kristalizirati na sobnoj temperaturi uz miješanje. Suspension of 1-(2',4'-difluorophenacyl)-1H-1,2,4-triazole (7, 0.00224 mol, 0.5 g), 1H-1,2,4-triazole (8, 0.00246 mol, 0.17 g) , trimethylsulfoxonium iodide (9, 0.00336 mol, 0.74 g), potassium hydroxide (0.00448 mol, 0.25 g), potassium fluoride (0.00224 mol, 0.13 g) and calcium hydride (0.09 g, 0.00224 mol) in t-butyl alcohol (10 ml ) is heated with return for 2.5 hours. The resulting precipitate was suctioned off and washed with t-butyl alcohol (10 ml). The solution was evaporated to dryness under reduced pressure, and the residue was dissolved in water (10 ml). The aqueous solution was extracted with ethyl acetate (4 x 25 ml), dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. A solvent mixture of ethyl acetate/n-hexane (1 : 1) (10 ml) was added to the obtained residue and allowed to crystallize at room temperature with stirring.
TLC (SiO2); Rf(1)=0.29 uz diklormetan/metanol (9 : 1). TLC (SiO2); Rf(1)=0.29 with dichloromethane/methanol (9 : 1).
Dobiveno je 0.29 g (42.3%) 2-(2,4-difluorfenil)-1,3-bis(1H-1,2,4-triazol-1-il)propan-2-ol (1) u obliku bezbojnih kristala, 1.1. 138-140 °C. 0.29 g (42.3%) of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol (1) was obtained in the form of colorless crystals , 1.1. 138-140 °C.
IR i NMR spektri identični su onima u primjeru 5. The IR and NMR spectra are identical to those of Example 5.
Claims (4)
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