PL224382B1 - 3,4,5-tri-substituted isoxazolines and a method for their preparation - Google Patents
3,4,5-tri-substituted isoxazolines and a method for their preparationInfo
- Publication number
- PL224382B1 PL224382B1 PL401602A PL40160212A PL224382B1 PL 224382 B1 PL224382 B1 PL 224382B1 PL 401602 A PL401602 A PL 401602A PL 40160212 A PL40160212 A PL 40160212A PL 224382 B1 PL224382 B1 PL 224382B1
- Authority
- PL
- Poland
- Prior art keywords
- isoxazoline
- trisubstituted
- dichlorophenyl
- hours
- reaction
- Prior art date
Links
- -1 3,4,5-tri-substituted isoxazolines Chemical class 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006352 cycloaddition reaction Methods 0.000 claims abstract description 20
- 150000002825 nitriles Chemical class 0.000 claims abstract description 16
- 239000000047 product Substances 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- 239000000758 substrate Substances 0.000 claims abstract description 8
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 4
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- XACGZMBUDCYGPB-UHFFFAOYSA-N 2,6-dichlorobenzonitrile oxide Chemical compound [O-][N+]#CC1=C(Cl)C=CC=C1Cl XACGZMBUDCYGPB-UHFFFAOYSA-N 0.000 claims description 9
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims description 9
- 101150065749 Churc1 gene Proteins 0.000 claims description 9
- 102100038239 Protein Churchill Human genes 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 7
- MHHGQWMCVNQHLG-UHFFFAOYSA-N 2-prop-2-enylisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CC=C)C(=O)C2=C1 MHHGQWMCVNQHLG-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- ZRPFJAPZDXQHSM-UHFFFAOYSA-L 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazole;dichloro-[(2-propan-2-yloxyphenyl)methylidene]ruthenium Chemical compound CC(C)OC1=CC=CC=C1C=[Ru](Cl)(Cl)=C1N(C=2C(=CC(C)=CC=2C)C)CCN1C1=C(C)C=C(C)C=C1C ZRPFJAPZDXQHSM-UHFFFAOYSA-L 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 150000003512 tertiary amines Chemical class 0.000 claims description 4
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 2
- 239000011987 hoveyda–grubbs catalyst Substances 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 21
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 abstract description 4
- 150000001413 amino acids Chemical class 0.000 abstract description 4
- 150000002545 isoxazoles Chemical class 0.000 abstract description 3
- 150000001414 amino alcohols Chemical class 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 15
- 150000002547 isoxazolines Chemical class 0.000 description 10
- 238000005649 metathesis reaction Methods 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 5
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 4
- 150000001336 alkenes Chemical group 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 230000000843 anti-fungal effect Effects 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 229910052707 ruthenium Inorganic materials 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 3
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 150000001576 beta-amino acids Chemical class 0.000 description 2
- 239000012973 diazabicyclooctane Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- YBSXDWIAUZOFFV-ONNFQVAWSA-N (ne)-n-[(2,6-dichlorophenyl)methylidene]hydroxylamine Chemical compound O\N=C\C1=C(Cl)C=CC=C1Cl YBSXDWIAUZOFFV-ONNFQVAWSA-N 0.000 description 1
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical class C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 1
- FJRPOHLDJUJARI-UHFFFAOYSA-N 2,3-dihydro-1,2-oxazole Chemical compound C1NOC=C1 FJRPOHLDJUJARI-UHFFFAOYSA-N 0.000 description 1
- UJUOFILOZXIWCO-UHFFFAOYSA-N 2-oxido-4,5-dihydro-1,2-oxazol-2-ium-4-ol Chemical class OC1CO[N+]([O-])=C1 UJUOFILOZXIWCO-UHFFFAOYSA-N 0.000 description 1
- RXXCIBALSKQCAE-UHFFFAOYSA-N 3-methylbutoxymethylbenzene Chemical compound CC(C)CCOCC1=CC=CC=C1 RXXCIBALSKQCAE-UHFFFAOYSA-N 0.000 description 1
- XRLKIVGTUGTLIR-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazol-5-amine Chemical class NC1CC=NO1 XRLKIVGTUGTLIR-UHFFFAOYSA-N 0.000 description 1
- VBOSUKGVZNTUNT-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole zinc Chemical compound [Zn].C1CC=NO1 VBOSUKGVZNTUNT-UHFFFAOYSA-N 0.000 description 1
- 108700023418 Amidases Proteins 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 229940125373 Gamma-Secretase Inhibitor Drugs 0.000 description 1
- JZFPYUNJRRFVQU-UHFFFAOYSA-N Niflumic acid Chemical compound OC(=O)C1=CC=CN=C1NC1=CC=CC(C(F)(F)F)=C1 JZFPYUNJRRFVQU-UHFFFAOYSA-N 0.000 description 1
- 230000004570 RNA-binding Effects 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical class NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 102000005922 amidase Human genes 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- PNPBGYBHLCEVMK-UHFFFAOYSA-N benzylidene(dichloro)ruthenium;tricyclohexylphosphanium Chemical compound Cl[Ru](Cl)=CC1=CC=CC=C1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1 PNPBGYBHLCEVMK-UHFFFAOYSA-N 0.000 description 1
- FCDPQMAOJARMTG-UHFFFAOYSA-M benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichlororuthenium;tricyclohexylphosphanium Chemical compound C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.CC1=CC(C)=CC(C)=C1N(CCN1C=2C(=CC(C)=CC=2C)C)C1=[Ru](Cl)(Cl)=CC1=CC=CC=C1 FCDPQMAOJARMTG-UHFFFAOYSA-M 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 238000005686 cross metathesis reaction Methods 0.000 description 1
- 239000002633 crown compound Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 150000001925 cycloalkenes Chemical class 0.000 description 1
- 150000001470 diamides Chemical class 0.000 description 1
- 125000005610 enamide group Chemical group 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000003540 gamma secretase inhibitor Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 239000011984 grubbs catalyst Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002678 macrocyclic compounds Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- FMXOEQQPVONPBU-UHFFFAOYSA-N methylidene(dioxido)azanium Chemical class [O-][N+]([O-])=C FMXOEQQPVONPBU-UHFFFAOYSA-N 0.000 description 1
- 150000002772 monosaccharides Chemical group 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 238000006772 olefination reaction Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229930001119 polyketide Natural products 0.000 description 1
- 150000003881 polyketide derivatives Chemical class 0.000 description 1
- 239000012063 pure reaction product Substances 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Przedmiotem wynalazku są izoksazoliny 3,4,5-tripodstawione oraz sposób ich otrzymywania z wykorzystaniem związków allilowych typu Q1Q2CHCH=CH2 jako łatwo dostępnych reagentów oraz sekwencji następujących po sobie reakcji: homometatezy (Q1Q2CHCH=CH2 do Q1Q2CHCH=CHCHQ1 Q2), a następnie cykloaddycji dipolarnej tlenków nitryli (ArCNO) do otrzymanych produktów homometatezy, przy czym końcowe produkty reakcji w postaci izoksazolin 3,4,5-tripodstawionych wydziela się za pomocą chromatografii na żelu krzemionkowym. Otrzymane 3,4,5-tripodstawione izoksazoliny mogą być wykorzystane w syntezie organicznej jako substraty do otrzymywania innych związków na przykład izoksazoli, aminoalkoholi lub aminokwasów.The subject of the invention are 3,4,5-trisubstituted isoxazolines and a method of obtaining them using allyl compounds of the Q1Q2CHCH=CH2 type as readily available reagents and sequences of subsequent reactions: homometathesis (Q1Q2CHCH=CH2 to Q1Q2CHCH=CHCHQ1 Q2), followed by dipolar cycloaddition nitrile oxides (ArCNO) to the homometathesis products obtained, with the final reaction products in the form of 3,4,5-trisubstituted isoxazolines being separated by silica gel chromatography. The obtained 3,4,5-trisubstituted isoxazolines can be used in organic synthesis as substrates for the preparation of other compounds, for example isoxazoles, amino alcohols or amino acids.
Description
Opis wynalazkuDescription of the invention
Przedmiotem wynalazku jest izoksazolina 3,4,5-tripodstawiona w postaci cis + trans 3-(2,6-dichlorofenylo)-4,5-bis[N-ftalimido)metylo]izoksazoliny oraz sposób jej otrzymywania z wykorzystaniem jako substratu związku allilowego w postaci N-alliloftalimidu.The subject of the invention is 3,4,5-trisubstituted isoxazoline in the form of cis + trans 3- (2,6-dichlorophenyl) -4,5-bis [N-phthalimido) methyl] isoxazoline and the method of its preparation with the use of an allyl compound as a substrate in the N-allylphthalimide form.
Funkcjonalizowane izoksazoliny (3,4-dihydroizoksazole) są bardzo ważnymi związkami heterocyklicznymi, ze względu na ich liczne zastosowania w syntezie organicznej oraz farmacji. W syntezie organicznej znane jest stosowanie funkcjonalizowanych izoksazolin jako substratów do otrzymywania: β-hydroksyketonów [Bode, J. W.; Carreira, E. M., „A Mild and Chemoselective Method for the Reduction of Conjugated Isoxazolines to 3-hydroxy Ketones”, Org. Lett. 2001, 3, 1587-1590; Bode, J. W.; Fraefel, N.; Muri, D.; Carreira, E. M. „A General Solution to the Modular Synthesis of Polyketide Building Blocks by Kanemasa Hydroxy-Directed Nitrile Oxide Cycloadditions”, Angew. Chem., Int. Ed. 2001,40, 2082-2085], β-aminokwasów [Minter, A. R.; Fuller, A. A.; Mapp, A. K. „A Concise Approach to Structurally Diverse β-Amino Acids“, J. Am. Chem. Soc. 2003, 125, 6846-6847], γ-aminoalkoholi [Marotta, E.; Micheloni, L. M.; Scardovi, N.; Righi, P. „One-Pot Direct Conversion of 2,3-Epoxy Alcohols into Enantiomerically Pure 4-Hydroxy-4,5-dihydroisoxazole 2-Oxides“, Org. Lett. 2001, 3, 727-729; Scott, J. P.; Oliver, S. F.; Brands, K. M. J.; Brewer, S. E.; Davies, A. J.; Gibb, A. D.; Hands, D.; Keen, S. P.; Sheen, F. J.; Reamer, R. A.; Wilson, R. D.; Dolling, U. „Practical Asymmetric Synthesis a γ-Secretase Inhibitor Exploiting Substrate-Controlled Intramolecular Nitrile Oxide-Olefin Cycloaddition”, J. Org. Chem. 2006, 71, 3086-3092] i innych, ważnych grup związków organicznych, na przykład izoksazoli, β-hydroksyoksymów, N-arylo^-laktamów. Izoksazoliny wykazują także aktywność biologiczną, na przykład przeciwgrzybiczą [Basappa; Sadashiva, M. P.; Mantelingu, K.; Swamy, S. N.; Rangappa, K. E. „Solution-phase synthesis of novel Δ -isoxazoline libraries via 1,3-dipolar cycloaddition and their antifungal properties”, Bioorg. Med. Chem. 2003, 11, 4539-4544] lub antybakteryjną [Pirrung, M. C.; Tumey, L. N.; Raetz, C. R. H.; Jackman, J. E.; Snehalatha, K.; McClerren, A. L.; Fierke, C. A.; Gantt, S. L; Rusche, K. M. „Inhibition of the Antibacterial Target UDP-(3-O-acyl)-N-acetylglucosamine Deacetylase (LpxC): Isoxazoline Zinc Amidase Inhibitors Bearing Diverse Metal Binding Groups”, J. Med. Chem. 2002, 45, 4359-4370].Functionalized isoxazolines (3,4-dihydroisoxazoles) are very important heterocycles due to their numerous applications in organic synthesis and pharmacy. In organic synthesis, it is known to use functionalized isoxazolines as starting materials for the preparation of: β-hydroxy ketones [Bode, J. W .; Carreira, E. M., "A Mild and Chemoselective Method for the Reduction of Conjugated Isoxazolines to 3-hydroxy Ketones", Org. Lett. 2001, 3, 1587-1590; Bode, J. W.; Fraefel, N .; Muri, D .; Carreira, E. M. "A General Solution to the Modular Synthesis of Polyketide Building Blocks by Kanemasa Hydroxy-Directed Nitrile Oxide Cycloadditions", Angew. Chem., Int. Ed. 2001,40, 2082-2085], β-amino acids [Minter, A. R .; Fuller, A. A .; Mapp, A. K. "A Concise Approach to Structurally Diverse β-Amino Acids," J. Am. Chem. Soc. 2003, 125, 6846-6847], γ-amino alcohols [Marotta, E .; Micheloni, L. M .; Scardovi, N .; Righi, P. "One-Pot Direct Conversion of 2,3-Epoxy Alcohols into Enantiomerically Pure 4-Hydroxy-4,5-dihydroisoxazole 2-Oxides", Org. Lett. 2001, 3, 727-729; Scott, J. P .; Oliver, S. F .; Brands, K. M. J .; Brewer, S. E .; Davies, A. J .; Gibb, A. D .; Hands, D .; Keen, S. P .; Sheen, F. J .; Reamer, R. A .; Wilson, R. D .; Dolling, U. "Practical Asymmetric Synthesis a γ-Secretase Inhibitor Exploiting Substrate-Controlled Intramolecular Nitrile Oxide-Olefin Cycloaddition", J. Org. Chem. 2006, 71, 3086-3092] and other important groups of organic compounds, for example isoxazoles, β-hydroxyoximes, N-arylβ-lactams. Isoxazolines also exhibit biological activity, for example antifungal [Basappa; Sadashiva, M. P .; Mantelingu, K .; Swamy, S. N .; Rangappa, K. E. "Solution-phase synthesis of novel Δ -isoxazoline libraries via 1,3-dipolar cycloaddition and their antifungal properties", Bioorg. Med. Chem. 2003, 11, 4539-4544] or antibacterial [Pirrung, M. C .; Tumey, L. N .; Raetz, C. R. H .; Jackman, J.E .; Snehalatha, K .; McClerren, A. L .; Fierke, C. A .; Gantt, S. L; Rusche, K. M. "Inhibition of the Antibacterial Target UDP- (3-O-acyl) -N-acetylglucosamine Deacetylase (LpxC): Isoxazoline Zinc Amidase Inhibitors Bearing Diverse Metal Binding Groups", J. Med. Chem. 2002,45,4359-4370].
Znane są różne reakcje chemiczne stanowiące elementy syntezy izoksazolin. Między innymi znana jest synteza szeregu układów typu QCH2CH=CHCH2Q via metateza związków allilowych typu QCH2CH=CH2. Przykładowo otrzymywanie dieteru typu (E + Z)-ROCH2CH=CHCH2OR (R = zabezpieczony fragment monosacharydowy) via homometateza prostych eterów allilowych typu ROCH2CH=CH2, w obecności katalizatora Grubbsa pierwszej generacji (10 mol% Ru, benzen, 50°C, 41-90% wydajności) znane jest z: A. Kirschning, G. Chen, J. Jaunzems, M. Jesberger, M. Kalesse, M. Lindner, „Synthesis of extended spacer-linked neooligodeoxysaccharides by metathesis olefination and evaluation of their RNA-binding properties”, Tetrahedron, 2004, 60, 3505-3521. Z kolei otrzymywanie dieterów typu (E)-ArOCH2CH=CHCH2OAr (Ar = 2-CH2ClPh or 2-CH2OHPh) via homometateza prostych eterów allilowych o wzorze ArOCH2CH=CH2, w obecności katalizatora Grubbsa drugiej generacji (1 mol% Ru, CH2CI2, ogrzewanie do wrzenia, 2 h) znane jest z: R.N. Malhas, Y.A. Ibrahim, „Synthesis of Olefinic Crown Diamides and their Conversion into Pyrazolino Macrocycles: Promising Photoluminescent Crown Compounds”, Synthesis, 2006, 3261-3269. W pracy: A. J. Vernall, S. Ballet, A.D. Abell, „Cross-metathesis and ring-closing metathesis reactions of amino acid-based substrates”, Tetrahedron, 2008, 64, 3980-3997, opisano także homometatezę homoallilowych substratów zawierających ugrupowanie aminokwasów (Q = RC(O)OCH2, RSC(O)CH2, RNHC(O)CH2, ROC(O)CH2; R = fragment aminokwasowy) do (E)-QCH2CH=CHCH2Q wobec tego samego katalizatora. Zastosowanie rutenowego katalizatora metatezy do wysoce (Z)-stereoselektywnej homometatezy QCH2CH=CH2 (Q = Ph, MeC(O)O, Me3Si, 4,4,5,5-tetrametylodioksoborolan-2-yl, PhNH, HOCH2CH2O) do QCH2CH=CH2CH2Q (2 mol% Ru, THF, 35°C, 1-4 h, od 67 do > 95% wydajności) znane jest z: B.K. Keitz, K. Endo, M.B. Herbert, R.H. Grubbs, „Z-Selective Homodimerization of Terminal Olefins with a Ruthenium Metathesis Catalyst”, J. Am. Chem. Soc., 2011, 133, 9686-9688.Various chemical reactions are known to be involved in the synthesis of isoxazolines. Among other things, the synthesis of a number of QCH 2 CH = CHCH 2 Q systems via the metathesis of allyl compounds of the QCH 2 CH = CH 2 type is known. For example, the preparation of diether of the (E + Z) -ROCH 2 CH = CHCH 2 OR type (R = protected monosaccharide fragment) via homometathesis of simple allyl ethers of the type ROCH 2 CH = CH 2 , in the presence of the first generation Grubbs catalyst (10 mol% Ru, benzene , 50 ° C, 41-90% yield) is known from: A. Kirschning, G. Chen, J. Jaunzems, M. Jesberger, M. Kalesse, M. Lindner, "Synthesis of extended walk-linked neooligodeoxysaccharides by metathesis olefination and evaluation of their RNA-binding properties ”, Tetrahedron, 2004, 60, 3505-3521. In turn, preparation of diethers of the (E) -ArOCH2CH = CHCH2OAr type (Ar = 2-CH2ClPh or 2-CH2OHPh) via homometathesis of simple allyl ethers with the formula ArOCH2CH = CH2, in the presence of second generation Grubbs catalyst (1 mol% Ru, CH 2 Cl 2 boiling, 2 h) is known from: RN Malhas, YA Ibrahim, "Synthesis of Olefinic Crown Diamides and their Conversion into Pyrazolino Macrocycles: Promising Photoluminescent Crown Compounds", Synthesis, 2006, 3261-3269. In the work: AJ Vernall, S. Ballet, AD Abell, "Cross-metathesis and ring-closing metathesis reactions of amino acid-based substrates", Tetrahedron, 2008, 64, 3980-3997, the homometathesis of homoallylic substrates containing the amino acid group ( Q = RC (O) OCH 2 , RSC (O) CH 2 , RNHC (O) CH 2 , ROC (O) CH 2 ; R = amino acid fragment) to (E) -QCH2CH = CHCH2Q in the presence of the same catalyst. Application of a ruthenium metathesis catalyst for highly (Z) -stereoselective homometathesis QCH 2 CH = CH 2 (Q = Ph, MeC (O) O, Me 3 Si, 4,4,5,5-tetramethyldioxoborolan-2-yl, PhNH, HOCH 2 CH 2 O) to QCH 2 CH = CH 2 CH 2 Q (2 mol% Ru, THF, 35 ° C, 1-4 h, from 67 to> 95% yield) known from: BK Keitz, K. Endo , MB Herbert, RH Grubbs, "Z-Selective Homodimerization of Terminal Olefins with a Ruthenium Metathesis Catalyst", J. Am. Chem. Soc., 2011, 133, 9686-9688.
Jednakże reakcja homometateza QCH2CH=CH2 do QCH2CH=CHCH2Q dla Q = N-ftalimidoil, co jest opisane w niniejszym wynalazku nie jest jak dotąd znana.However, the homomethathesis reaction of QCH2CH = CH2 to QCH2CH = CHCH2Q for Q = N-phthalimidoyl, which is described in the present invention, is not known so far.
Znane są również reakcje cykloaddycji dipolarnej tlenków nitryli do różnych dipolarofili typu R CH=CHR , będących analogami QCH2CH=CHCH2Q. Przykładowo cykloaddycja tlenków nitryli: do prostych alkenów i cykloalkenów znana jest z: H. Feuer, „Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis, Wiley-Interscience”: New Jersey, 2007, 1-128, do alkenów wewnętrznych znaPL 224 382 B1 na jest z: D.P. Curran, „Reduction of .DELTA.2-isoxazolines. 3. Raney nickel catalyzed formation of beta-hydroxy ketones”, J. Am. Chem. Soc., 105(18), 1983, 5826-5833, do eterów enoli znana jest z: S. Krompiec, P. Bujak, J. Malarz, M. Krompiec, Ł. Skórka, W. Danikiewicz, P. Kusz, „An isomerization - 1,3-dipolar cycloaddition tandem reaction towards the synthesis of 3-aryl-4-methyl-5-O-substituted isoxazolines from O-allyl compounds”, Tetrahedron, 68, 6018-6031 (2012), do enamin i enamidów znana jest z: P. Bujak, S. Krompiec, J. Malarz, M. Krompiec, M. Filapek, W. Danikiewicz, M. Kania, K. Gębarowska, I. Grudzka, Synthesis of 5-aminoisoxazolines from N-allyl compounds and nitryle oxides via tandem isomerization - 1,3-dipolar cycloaddition, Tetrahedron 66 (2010) 5972-5981.There are also known dipolar cycloaddition reactions of nitrile oxides to various dipolarophiles of the type R CH = CHR, which are analogues of QCH 2 CH = CHCH 2 Q. For example, cycloaddition of nitrile oxides: to simple alkenes and cycloalkenes is known from: H. Feuer, "Nitrile Oxides, Nitrones , and Nitronates in Organic Synthesis, Wiley-Interscience ": New Jersey, 2007, 1-128, for internal alkenes is known from: DP Curran," Reduction of .DELTA.2-isoxazolines. 3. Raney nickel catalyzed formation of beta-hydroxy ketones ”, J. Am. Chem. Soc., 105 (18), 1983, 5826-5833, for enol ethers it is known from: S. Krompiec, P. Bujak, J. Malarz, M. Krompiec, Ł. Skórka, W. Danikiewicz, P. Kusz, " An isomerization - 1,3-dipolar cycloaddition tandem reaction towards the synthesis of 3-aryl-4-methyl-5-O-substituted isoxazolines from O-allyl compounds ”, Tetrahedron, 68, 6018-6031 (2012), to enamines and of enamides is known from: P. Bujak, S. Krompiec, J. Malarz, M. Krompiec, M. Filapek, W. Danikiewicz, M. Kania, K. Gębarowska, I. Grudzka, Synthesis of 5-aminoisoxazolines from N-allyl compounds and nitriles oxides via tandem isomerization - 1,3-dipolar cycloaddition, Tetrahedron 66 (2010) 5972-5981.
Ponadto w literaturze opisano różne sposoby otrzymywania tripodstawionych izoksazolin stanowiące różne warianty cykloaddycji dipolarnej tlenków nitryli do symetrycznie funkcjonalizowanych alkenów. Przykładowo cykloaddycję tlenków aromatycznych nitryli do układów typu QCH=CHQ (będących analogami QCH2CH=CHCH2Q gdzie Q = CO2Me lub CO2Et opisali Molteni et al. w: G. Molteni,In addition, the literature describes various methods for the preparation of trisubstituted isoxazolines representing different variants of the dipolar cycloaddition of nitrile oxides to symmetrically functionalized alkenes. For example, the cycloaddition of aromatic nitrile oxides to systems of the QCH = CHQ type (which are analogs of QCH 2 CH = CHCH 2 Q where Q = CO 2 Me or CO 2 Et was described by Molteni et al. In: G. Molteni,
P.D. Buttero, „Stable nitrile oxide dipolar cycloadditions in pure water”, Tetrahedron, 67, 2011, 7343-7347. W kolejnej pracy podstawnik Ar to 2,4,6-trimetylofenyl a grupy Q to metoksykarbonyl lub etoksykarbonyl [S.T. Abu-Orabi, N.M. Al-Ghezawi, „1,3-Dipolar Cycloaddition, of Nitrile Oxides with 2 cis- and trans-Ethylene-Substituted Δ-Isoxazolines Derivatives”, Chem. Eng. Data, 1987, 32, 383-384]. Minakata et al otrzymali izoksazolinę, w której Ar = fenyl a Q = etoksykarbonyl [S. Minakata,PD Buttero, "Stable nitrile oxide dipolar cycloadditions in pure water", Tetrahedron, 67, 2011, 7343-7347. In the next work the substituent Ar is 2,4,6-trimethylphenyl and the Q groups are methoxycarbonyl or ethoxycarbonyl [ST Abu-Orabi, NM Al-Ghezawi, "1,3-Dipolar Cycloaddition, of Nitrile Oxides with 2 cis- and trans-Ethylene -Substituted Δ-Isoxazolines Derivatives ”, Chem. Eng. Date, 1987, 32, 383-384]. Minakata et al obtained isoxazoline where Ar = phenyl and Q = ethoxycarbonyl [S. Minakata,
S. Okumura, T. Nagamachi, Y. Takeda, „Generation of Nitrile Oxides from Oximes and Using t-BuOI and their Cycloaddition”, Org. Lett., 13 (11), 2011,2966-2969].S. Okumura, T. Nagamachi, Y. Takeda, "Generation of Nitrile Oxides from Oximes and Using t-BuOI and their Cycloaddition", Org. Lett., 13 (11), 2011, 2966-2969].
Synteza 3,4,5-tripodstawionej izoksazoliny w postaci cis + trans 3-(2,6-dichlorofenylo)-4,5-bis[(N-ftalimido)metylo]izoksazoliny, sposobem według niniejszego wynalazku, w którym substrat allilowy, to jest N-alliloftalimid poddawany byłby homometatezie, a następnie produkt homometatezy uczestniczyłby w cykloaddycji prowadzącej finalnie do tripodstawionej izoksazoliny nie jest znana. Nie jest też znana 3,4,5-tripodstawiona izoksazolina z podstawnikami wymienionymi w niniejszym wynalazku.Synthesis of 3,4,5-trisubstituted isoxazoline as cis + trans 3- (2,6-dichlorophenyl) -4,5-bis [(N-phthalimido) methyl] isoxazoline by the method of the present invention, wherein the allyl substrate is is N-allylphthalimide would be homomethatized and then the homometathesis product would participate in the cycloaddition ultimately leading to the trisubstituted isoxazoline is unknown. The 3,4,5-trisubstituted isoxazoline with the substituents mentioned in the present invention is also not known.
Celem niniejszego wynalazku było poszerzenie bazy pochodnych zawierających układ dihydroizoksazolu poprzez opracowanie nowej, tripodstawionej izoksazoliny o pożądanych właściwościach, przydatnych przede wszystkim do dalszej syntezy organicznej oraz wskazanie nowych możliwości w syntezie tripodstawionych izoksazolin, jakie stwarza wykorzystanie prostych związków allilowych typu QCH2CH=CH2 oraz zastosowanie nieznanego dotychczas tandemu ich przemian.The aim of the present invention was to broaden the base of derivatives containing the dihydroisoxazole system by developing a new, trisubstituted isoxazoline with the desired properties, useful primarily for further organic synthesis, and to indicate new possibilities in the synthesis of trisubstituted isoxazolines, resulting from the use of simple allyl compounds of the QCH2CH = CH2 type and the use of a previously unknown a tandem of their transformations.
Istotę wynalazku stanowi izoksazolina 3,4,5-tripodstawiona w postaci cis + trans 3-(2,6-dichlorofenylo)-4,5-bis[(N-ftalimido)metylo]izoksazoliny przedstawiona wzorem 1:The essence of the invention is the 3,4,5-trisubstituted isoxazoline in the form of cis + trans 3- (2,6-dichlorophenyl) -4,5-bis [(N-phthalimido) methyl] isoxazoline represented by the formula 1:
ClCl
Wzór ίFormula ί
Istotę wynalazku stanowi również sposób otrzymywania izoksazoliny 3,4,5-tripodstawionej w postaci cis + trans 3-(2,6-dichlorofenylo)-4,5-bis[(N-ftalimido)metylo]lizoksazoliny, przedstawionej wzorem 1, charakteryzujący się tym, że substrat w postaci łatwo dostępnego związku allilowego, to jest N-alliloftalimidu poddaje się sekwencji następujących po sobie reakcji: homometatezie do związku o wzorze QCH2CH=CHCH2Q, gdzie Q oznacza N-ftalimidoil, a następnie cykloaddycji tlenku 2,6-dichlorobenzonitrylu do otrzymanego produktu homometatezy.The essence of the invention is also a method of obtaining 3,4,5-trisubstituted isoxazoline in the cis + trans form of 3- (2,6-dichlorophenyl) -4,5-bis [(N-phthalimido) methyl] lysoxazoline, represented by the formula 1, characterized by in that the substrate in the form of a readily available allyl compound, i.e. N-allylphthalimide, is subjected to a sequence of successive reactions: homometathesis to the compound of formula QCH2CH = CHCH2Q, where Q is N-phthalimidoyl, and then cycloaddition of 2,6-dichlorobenzonitrile oxide to the obtained homomethathesis product.
W pierwszym etapie prowadzi się reakcję homometatezy, w której mieszaninę związku allilowego, w postaci N-alliloftalimidu z katalizatorem Hoveydy-Grubbsa drugiej lub korzystnie pierwszej gene4In the first stage, a homometathesis reaction is carried out in which the mixture of the allyl compound in the form of N-allylphthalimide with Hoveyda-Grubbs catalyst of the second or preferably the first gene4
PL 224 382 B1 racji, w proporcjach molowych od 5 : 1 do 50 : 1, korzystnie 30 : 1 ogrzewa się do wrzenia w roztworze chlorku metylenu, w ilości od 5 do 50 mL, korzystnie 30 mL na 1 mmol substratu, przez czas od 3 do 48 godzin, korzystnie 24 godziny, w warunkach ściśle bezwodnych i beztlenowych.In molar proportions from 5: 1 to 50: 1, preferably 30: 1, the mixture is boiled in a methylene chloride solution in an amount of 5 to 50 mL, preferably 30 mL per 1 mmol of substrate, for a period of time from 3 to 48 hours, preferably 24 hours, under strictly anhydrous and anaerobic conditions.
Następnie produkt homometatezy w postaci związku o wzorze QCH2CH=CHCH2Q, gdzie Q oznacza N-ftalimidoil wydziela się z mieszaniny poreakcyjnej na drodze chromatografii kolumnowej na żelu krzemionkowym. Wydzielony produkt homometatezy poddaje się następnie reakcji cykloaddycji dipolarnej z trwałym tlenkiem nitrylu ArCNO, to jest z tlenkiem 2,6-dichlorobenzonitrylu, w stosunku QCH2CH=CHCH2Q : ArCNO = od 2:1 do 1 : 2, korzystnie 1,2 : 1, przy czym tlenek 2,6-dichlorobenzonitrylu otrzymuje się uprzednio oddzielnie, z chlorku oksymoilowego. Reakcję cykl oaddycji prowadzi się w czasie od 4 do 48 godzin, korzystnie 24 godziny, w temperaturze mieszczącej się w przedziale od 10°C do 60°C, korzystnie w temperaturze pokojowej, w rozpuszczalniku w postaci chlorku metylenu, tetrahydrofuranu lub DMF, przy czym rozpuszczalnika stosuje się od 2 do 50 mL, korzystnie 5 mL na 1 mmol tlenku nitrylu. Końcowy produkt reakcji, to jest izoksazolinę 3,4,5-tripodstawioną w postaci cis + trans 3-(2,6-dichlorofenylo)-4,5-bis[(N-ftalimido)metylo]izoksazoliny wydziela się za pomocą chromatografii na żelu krzemionkowym.Then, the homomethathesis product, in the form of a compound of formula QCH 2 CH = CHCH 2 Q, where Q is N-phthalimidoyl, is separated from the reaction mixture by silica gel column chromatography. The separated homomethathesis product is then subjected to a dipolar cycloaddition reaction with stable nitrile oxide ArCNO, i.e. 2,6-dichlorobenzonitrile oxide, in the ratio QCH 2 CH = CHCH 2 Q: ArCNO = from 2: 1 to 1: 2, preferably 1.2 : 1, with 2,6-dichlorobenzonitrile oxide being prepared separately previously from oximoyl chloride. The addition cycle is carried out for 4 to 48 hours, preferably 24 hours, at a temperature ranging from 10 ° C to 60 ° C, preferably at room temperature, in a solvent such as methylene chloride, tetrahydrofuran or DMF, and 2 to 50 mL of solvent is used, preferably 5 mL per 1 mmol of nitrile oxide. The final reaction product, i.e. the 3,4,5-trisubstituted cis + trans isoxazoline of 3- (2,6-dichlorophenyl) -4,5-bis [(N-phthalimido) methyl] isoxazoline is isolated by gel chromatography silica.
Korzystnie, trwały tlenek 2,6-dichlorobenzonitrylu stosowany do reakcji cykloaddycji dipolarnej otrzymuje się w reakcji chlorku 2,6-dichlorofenylo-oksymoilowego z trzeciorzędowymi aminami, korzystnie DABCO - 1,4-diazabicyklo[2.2.2]oktanem, przy czym proporcje molowe chlorek : trzeciorzędowa amina mieszczą się w przedziale od 1 : 1 do 1 : 2, korzystnie 1 : 1,2.Preferably, the stable 2,6-dichlorobenzonitrile oxide used for the dipolar cycloaddition reaction is obtained by reacting 2,6-dichlorophenyl oximoyl chloride with tertiary amines, preferably DABCO-1,4-diazabicyclo [2.2.2] octane, the molar ratio of chloride being The tertiary amine ranges from 1: 1 to 1: 2, preferably 1: 1.2.
Ideę sposobu według wynalazku pokazano na schemacie 3, natomiast poszczególne etapy syntezy na schematach 1 i 2.The concept of the process according to the invention is shown in Scheme 3, while the individual steps of the synthesis are shown in Schemes 1 and 2.
Schemat 1. Homometateza związku allilowego typu QCH2CH=CH2 do związku allilowego typu QCH2CH=CHCH2Q (Q = N-ftalimidoil).Scheme 1. Homometathesis of an allyl compound of QCH 2 CH = CH 2 type to an allyl compound of QCH 2 CH = CHCH 2 Q type (Q = N-phthalimidoyl).
+ H2C=CH2 a = katalizator Hoveydy-Grubbsa drugiej lub pierwszej generacji, chlorek metylenu, temperatura wrzenia, czas od 3 do 48 godzin.+ H 2 C = CH 2 a = Hoveyda-Grubbs 2nd or 1st generation catalyst, methylene chloride, boiling point, time from 3 to 48 hours.
Schemat 2. Cykloaddycja dipolarna tlenku 2,6-dichlorobenzonitrylu do produktu homometatezy w postaci związku allilowego typu QCH2CH=CHCH2Q (Q = N-ftalimidoil).Scheme 2. Dipolar cycloaddition of 2,6-dichlorobenzonitrile oxide to the homomethathesis product in the form of an allyl compound of the type QCH 2 CH = CHCH 2 Q (Q = N-phthalimidoyl).
gdzie: b = chlorek metylenu, tetrahydrofuran lub DMF, temperatura od 10 do 60°C, czas od 4 do 48 godzin.where: b = methylene chloride, tetrahydrofuran or DMF, temperature 10 to 60 ° C, time 4 to 48 hours.
Schemat 3. Synteza izoksazoliny 3,4,5-tripodstawionej ze związku allilowego typu QCH2CH=CH2 via homometateza-cykloaddycja dipolarna.Scheme 3. Synthesis of 3,4,5-trisubstituted isoxazoline from an allyl compound of the type QCH 2 CH = CH 2 via homometathesis-dipolar cycloaddition.
PL 224 382 B1PL 224 382 B1
Sposób syntezy izoksazoliny 3,4,5-tripodstawionej w postaci cis + trans 3-(2,6-dichlorofenylo)-4,5-bis[(N-ftalimido)metylo]izoksazoliny według wynalazku pozwala na stosunkowo łatwe otrzymanie związku należącego do nowej grupy tych związków z podstawnikami typu QCH2 w pozycjach 4 i 5 oraz podstawnikiem arylowym w pozycji 3. Sposób stanowi istotny wkład w syntezę organiczną, na przykład w otrzymywanie izoksazoli lub aminoketonów, oraz zważywszy na liczne zastosowania izo ksazolin i produktów, które można z nich otrzymać. Istotnym elementem nowości jest zastosowanie do syntezy dipola, to jest tlenku 2,6-dichlorobenzonitrylu DABCO, to jest 1,4-diazabicyklo[2.2.2]oktanu w miejsce powszechnie stosowanej, lotnej i toksycznej trietyloaminy.The method of synthesizing 3,4,5-trisubstituted isoxazoline in the cis + trans form of 3- (2,6-dichlorophenyl) -4,5-bis [(N-phthalimido) methyl] isoxazoline according to the invention allows for relatively easy preparation of the compound belonging to the new group of these compounds with type QCH 2 substituents at positions 4 and 5, and aryl substituent at position 3. the method represents a significant contribution in organic synthesis, for example in the preparation of isoxazoles or aminoketones, and in view of the numerous applications and iso ksazolin products that can be one get. An important element of the novelty is the use of the dipole, i.e. DABCO 2,6-dichlorobenzonitrile oxide, i.e. 1,4-diazabicyclo [2.2.2] octane in the synthesis, in place of the commonly used, volatile and toxic triethylamine.
Otrzymanie związku przedstawionego wzorem 1 inną metodą niż według niniejszego wynalazku byłoby bardzo trudne lub praktycznie niemożliwe do zrealizowania.The preparation of the compound represented by the formula 1 by a method other than that of the present invention would be very difficult or practically impossible to achieve.
Sposób otrzymywania izoksazoliny 3,4,5-tripodstawionej w postaci cis + trans 3-(2,6-dichlorofenylo)-4,5-bis[(N-ftalimido)metylo]izoksazoliny według wynalazku ilustruje poniższy przykład.The method for the preparation of the 3,4,5-trisubstituted isoxazoline in the cis + trans form of 3- (2,6-dichlorophenyl) -4,5-bis [(N-phthalimido) methyl] isoxazoline according to the invention is illustrated in the following example.
P r z y k ł a dP r z k ł a d
Otrzymywanie cis + trans 3-(2,6-dichlorofenylo)-4,5-bis[(N-ftalimido)metylo]izoksazolinyPreparation of cis + trans 3- (2,6-dichlorophenyl) -4,5-bis [(N-phthalimido) methyl] isoxazoline
[inna nazwa: cis + trans 3-(2,6-dichIorofenylo)-4,5-dihydro-4,5-di(N-ftalimido)metylo]izoksazolu].[other name: cis + trans 3- (2,6-dichlorophenyl) -4,5-dihydro-4,5-di (N-phthalimido) methyl] isoxazole].
a = katalizator Hoveydy-Grubbsa drugiej generacji, chlorek metylenu, temperatura wrzenia, 24 godzinya = Hoveyda-Grubbs 2nd generation catalyst, methylene chloride, boiling point, 24 hours
b = DMF, 40°C, 24 hb = DMF, 40 ° C, 24 h
Związek allilowy w postaci N-alliloftaIimidu (10 mmoli) ogrzewano do wrzenia z katalizatorem Hoveydy-Grubbsa drugiej generacji (1 mmol), w roztworze chlorku metylenu (10mL/1 mmol) przez 24 godziny, w warunkach ściśle bezwodnych i beztlenowych. Następnie produkt metatezy wydzielono z mieszaniny poreakcyjnej za pomocą chromatografii kolumnowej na żelu krzemionkowym, przy czym eluentem był chlorek metylenu. Wydzielony produkt metatezy poddano następnie reakcji cykloaddycji dipolarnej z tlenkiem 2,6-dichlorobenzonitrylu (5 mmoli), który otrzymano uprzednio z 2,6-dichlorobenzaldoksymu, poprzez chlorek oksymoilowy i reakcję tego ostatniego z DABCO. Reakcję cykloaddycji prowadzono w roztworze DMF, w temperaturze mieszczącej się od 30 do 40°C przez 24 godziny, mieszając ciągle i intensywnie mieszaninę reakcyjną. Po zakończeniu reakcji odparowano DMF na próżniowej wyparce rotacyjnej a pozostałość rozpuszczono w chlorku metylenu i poddano chromatografii kolumnowej na żelu krzemionkowym. Zastosowano 20 g żelu na 1 g surowego produktu oraz chlorek metylenu jako eluent. Czysty produkt reakcji w postaci cis + trans 3-(2,6-dichlorofenylo)-4,5-bis[(N-ftalimido)metylo]izoksazoliny otrzymano w ilości 3.6 mmola, czyli z wydajnością 72%, w przeliczeniu na wyjściowy związek allilowy.The allyl compound in the form of N-allylphthalimide (10 mmol) was refluxed with a second generation Hoveyda-Grubbs catalyst (1 mmol) in methylene chloride solution (10 mL / 1 mmol) for 24 hours under strictly anhydrous and anaerobic conditions. Then, the metathesis product was isolated from the reaction mixture by means of column chromatography on silica gel, the eluent being methylene chloride. The separated metathesis product was then subjected to a dipolar cycloaddition reaction with 2,6-dichlorobenzonitrile oxide (5mmol), which had previously been obtained from 2,6-dichlorobenzaldoxime, via oximoyl chloride and reacting the latter with DABCO. The cycloaddition reaction was carried out in a DMF solution at a temperature ranging from 30 to 40 ° C for 24 hours while the reaction mixture was continuously and vigorously stirred. After completion of the reaction, DMF was evaporated on a vacuum rotary evaporator, and the residue was dissolved in methylene chloride and subjected to silica gel column chromatography. 20 g of gel per 1 g of crude product and methylene chloride as eluent were used. The pure reaction product in the form of cis + trans 3- (2,6-dichlorophenyl) -4,5-bis [(N-phthalimido) methyl] isoxazoline was obtained in the amount of 3.6 mmol, i.e. 72% yield, based on the starting allyl compound .
Otrzymana sposobem według wynalazku 3,4,5-tripodstawiona izoksazolina może być wykorzystane w syntezie organicznej jako substrat do otrzymywania innych, ważnych związków, na przykład izoksazolu, aminoalkoholu lub aminokwasu. Potencjalnie może też być wykorzystana do wytwarzania preparatów farmaceutycznych o właściwościach przeciwgrzybicznych, przeciwbakteryjnych lub antywirusowych.The 3,4,5-trisubstituted isoxazoline obtained by the process according to the invention can be used in organic synthesis as a starting material for the preparation of other important compounds, for example isoxazole, amino alcohol or amino acid. Potentially, it can also be used for the production of pharmaceutical preparations with antifungal, antibacterial or antiviral properties.
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