PL220620B1 - Sulforaphane derivatives, their precursors and a method for their preparation - Google Patents
Sulforaphane derivatives, their precursors and a method for their preparationInfo
- Publication number
- PL220620B1 PL220620B1 PL401114A PL40111412A PL220620B1 PL 220620 B1 PL220620 B1 PL 220620B1 PL 401114 A PL401114 A PL 401114A PL 40111412 A PL40111412 A PL 40111412A PL 220620 B1 PL220620 B1 PL 220620B1
- Authority
- PL
- Poland
- Prior art keywords
- formula
- polyfluoroalkyl
- alkyl
- sulfides
- defined above
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 22
- SUVMJBTUFCVSAD-UHFFFAOYSA-N sulforaphane Chemical class CS(=O)CCCCN=C=S SUVMJBTUFCVSAD-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000002243 precursor Substances 0.000 title claims abstract description 5
- 150000003457 sulfones Chemical class 0.000 claims abstract description 20
- 150000003462 sulfoxides Chemical class 0.000 claims abstract description 20
- 150000004763 sulfides Chemical class 0.000 claims abstract 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 11
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 10
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 10
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 6
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 6
- 238000004811 liquid chromatography Methods 0.000 claims description 5
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 claims description 5
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 4
- 241001480052 Aspergillus japonicus Species 0.000 claims description 4
- 241000371644 Curvularia ravenelii Species 0.000 claims description 4
- 108090000790 Enzymes Proteins 0.000 claims description 4
- 102000004190 Enzymes Human genes 0.000 claims description 4
- 241000378865 Eutypa lata Species 0.000 claims description 4
- 241000235527 Rhizopus Species 0.000 claims description 4
- 240000004808 Saccharomyces cerevisiae Species 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 241000123213 Trichaptum Species 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 4
- 150000004843 oxaziridines Chemical class 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- -1 sodium hydroxymethyl sulfite-hydrosulfite Chemical compound 0.000 claims description 4
- 241000123650 Botrytis cinerea Species 0.000 claims description 3
- 241000222354 Trametes Species 0.000 claims description 3
- 241000223261 Trichoderma viride Species 0.000 claims description 3
- 241000306282 Umbelopsis isabellina Species 0.000 claims description 3
- IKYOVSVBLHGFMA-UHFFFAOYSA-N dipyridin-2-yloxymethanethione Chemical compound C=1C=CC=NC=1OC(=S)OC1=CC=CC=N1 IKYOVSVBLHGFMA-UHFFFAOYSA-N 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- ASTWEMOBIXQPPV-UHFFFAOYSA-K trisodium;phosphate;dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[O-]P([O-])([O-])=O ASTWEMOBIXQPPV-UHFFFAOYSA-K 0.000 claims description 3
- 108010035722 Chloride peroxidase Proteins 0.000 claims description 2
- 241000222118 Leptoxyphium fumago Species 0.000 claims description 2
- 229910052681 coesite Inorganic materials 0.000 claims description 2
- 229910052906 cristobalite Inorganic materials 0.000 claims description 2
- 108010058646 cyclohexanone oxygenase Proteins 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 235000012239 silicon dioxide Nutrition 0.000 claims description 2
- 229910052682 stishovite Inorganic materials 0.000 claims description 2
- 229910052905 tridymite Inorganic materials 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims 2
- 150000003839 salts Chemical class 0.000 claims 2
- 241000233866 Fungi Species 0.000 claims 1
- 150000003840 hydrochlorides Chemical class 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 9
- SUVMJBTUFCVSAD-JTQLQIEISA-N 4-Methylsulfinylbutyl isothiocyanate Natural products C[S@](=O)CCCCN=C=S SUVMJBTUFCVSAD-JTQLQIEISA-N 0.000 abstract description 5
- 229960005559 sulforaphane Drugs 0.000 abstract description 5
- 235000015487 sulforaphane Nutrition 0.000 abstract description 5
- 230000004071 biological effect Effects 0.000 abstract description 4
- QSLPNSWXUQHVLP-UHFFFAOYSA-N $l^{1}-sulfanylmethane Chemical compound [S]C QSLPNSWXUQHVLP-UHFFFAOYSA-N 0.000 abstract description 2
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 2
- 230000003178 anti-diabetic effect Effects 0.000 abstract description 2
- 239000003472 antidiabetic agent Substances 0.000 abstract description 2
- 229930014626 natural product Natural products 0.000 abstract description 2
- 230000001093 anti-cancer Effects 0.000 abstract 1
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 18
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 14
- 239000001282 iso-butane Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 150000003568 thioethers Chemical class 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 5
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 5
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000012746 preparative thin layer chromatography Methods 0.000 description 4
- OFHCXWMZXQBQMH-UHFFFAOYSA-N trifluoro(trifluoromethylsulfanyl)methane Chemical compound FC(F)(F)SC(F)(F)F OFHCXWMZXQBQMH-UHFFFAOYSA-N 0.000 description 4
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000007790 solid phase Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- QBVJPEFEOJUYLZ-UHFFFAOYSA-N 1-isothiocyanato-4-(trifluoromethylsulfanyl)butane Chemical compound FC(F)(F)SCCCCN=C=S QBVJPEFEOJUYLZ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HHUZEBRBISVTFS-UHFFFAOYSA-N FC(F)(F)S(=O)CCCCN=C=S Chemical compound FC(F)(F)S(=O)CCCCN=C=S HHUZEBRBISVTFS-UHFFFAOYSA-N 0.000 description 2
- 229910004298 SiO 2 Inorganic materials 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- GRWZHXKQBITJKP-UHFFFAOYSA-L dithionite(2-) Chemical compound [O-]S(=O)S([O-])=O GRWZHXKQBITJKP-UHFFFAOYSA-L 0.000 description 2
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- GMWLMJGJIBESBF-UHFFFAOYSA-M sodium;hydroxymethyl sulfite Chemical compound [Na+].OCOS([O-])=O GMWLMJGJIBESBF-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- UXFWTIGUWHJKDD-UHFFFAOYSA-N 2-(4-bromobutyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCCCBr)C(=O)C2=C1 UXFWTIGUWHJKDD-UHFFFAOYSA-N 0.000 description 1
- MKHGVMIXRPGHOO-UHFFFAOYSA-N 2-(benzenesulfonyl)-3-phenyloxaziridine Chemical compound C=1C=CC=CC=1S(=O)(=O)N1OC1C1=CC=CC=C1 MKHGVMIXRPGHOO-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound 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 description 1
- DEBKWVGZUIRRCP-UHFFFAOYSA-N N=C=S.N=C=S.N=C=S.N Chemical group N=C=S.N=C=S.N=C=S.N DEBKWVGZUIRRCP-UHFFFAOYSA-N 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- KURCJVZHJQCRSH-UHFFFAOYSA-N ethyl 3-methyl-6-(trifluoromethyl)-4h-1,4-benzothiazine-2-carboxylate Chemical compound FC(F)(F)C1=CC=C2SC(C(=O)OCC)=C(C)NC2=C1 KURCJVZHJQCRSH-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- QKGYJVXSKCDGOK-UHFFFAOYSA-N hexane;propan-2-ol Chemical compound CC(C)O.CCCCCC QKGYJVXSKCDGOK-UHFFFAOYSA-N 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000004812 organic fluorine compounds Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- QSHJLBYGMJWSEN-UHFFFAOYSA-M sodium;2,2,2-trifluoroethanethiolate Chemical compound [Na+].FC(F)(F)C[S-] QSHJLBYGMJWSEN-UHFFFAOYSA-M 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- OCOTWWSGPAHHQW-UHFFFAOYSA-N trifluoro(trifluoromethylsulfinyl)methane Chemical compound FC(F)(F)S(=O)C(F)(F)F OCOTWWSGPAHHQW-UHFFFAOYSA-N 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Indole Compounds (AREA)
Abstract
Przedmiotem wynalazku są nowe związki – analogi naturalnego produktu, sulforafanu o wzorze CH3S(O)(CH2)4N=C=S, wykazujące właściwości biologiczne, w tym działanie przeciwnowotworowe, przeciwcukrzycowe o przeciwbakteryjne. Nowe związki przedstawione są wzorem ogólnym 1, w którym RF oznacza grupę o wzorze CnF2n+1, gdzie n oznacza liczbę naturalną od 1 do 7, x oznacza liczbę 0, 1 lub 2, z oznacza liczbę 0, 1 lub 2, m oznacza liczbę 0, 1 lub 2, a y oznacza liczbę naturalną od 3 do 6, inaczej mówiąc: sulfidów o wzorze 1 gdy m=0, sulfotlenków o wzorze 1, ich racematów, gdy m=1, oraz sulfonów o wzorze 1 ω-izotiocyjanianoalkilowo-polifluoroalkilowych, gdy m=2. Przedmiotem wynalazku są również prekursory tych związków oraz sposób wytwarzania pochodnych sulforafanu o wzorze ogólnym 1.The subject of the invention are new compounds - analogues of the natural product, sulforaphane of the formula CH3S(O)(CH2)4N=C=S, exhibiting biological properties, including anticancer, antidiabetic and antibacterial activity. The new compounds are represented by the general formula 1, where RF is a group of the formula CnF2n+1, where n is a natural number from 1 to 7, x is a number 0, 1 or 2, z is a number 0, 1 or 2, m is a number 0, 1 or 2, and y is a natural number from 3 to 6, in other words: sulfides of the formula 1 when m=0, sulfoxides of the formula 1, their racemates when m=1, and sulfones of the formula 1 ω-isothiocyanatoalkyl-polyfluoroalkyl when m=2. The subject of the invention are also precursors of these compounds and a method for the preparation of sulforaphane derivatives of the general formula 1.
Description
Opis wynalazkuDescription of the invention
Przedmiotem wynalazku są nowe związki - fluorowe analogi naturalnego produktu, sulforafanu o wzorze CH3S(O)(CH2)4N=C=S, posiadające interesujące właściwości biologiczne, w tym działania przeciwcukrzycowe, przeciwnowotworowe i antybakteryjne, w postaci sulfidów, sulfotlenków, ich racematów i enancjomerów, oraz sulfonów ω-izotiocyjanianoalkilowo-polifluoroalkilowych, przedstawionych wzorem 1, (O)mThe subject of the invention are new compounds - fluorine analogs of the natural product, sulforaphane of formula CH3S (O) (CH2) 4N = C = S, having interesting biological properties, including antidiabetic, antitumor and antibacterial activities, in the form of sulfides, sulfoxides, their racemates and enantiomers, and ω-isothiocyanatoalkyl-polyfluoroalkyl sulfones, represented by the formula 1, (O) m
IIII
RF(CHxF2.x)zS-(CH2)y-N=C=S wzór 1 w którym RF oznacza grupę o wzorze CnF2n+i, gdzie n oznacza liczbę naturalną od 1 do 7, x oznacza liczbę 0, 1 lub 2, z oznacza liczbę 0, 1 lub 2, m oznacza liczbę 0, 1 lub 2, a y oznacza liczbę naturalną od 3 do 6, posiadające interesujące właściwości biologiczne, pozwalające na ich zastosowanie do wytwarzania leków przeciwnowotworowych oraz sposób ich wytwarzania.RF (CH x F 2. X ) z S- (CH 2 ) y -N = C = S formula 1 where R F is a group of formula CnF 2n + i, where n is a natural number from 1 to 7, x is the number 0, 1 or 2, z is the number 0, 1 or 2, m is the number 0, 1 or 2, and y is a natural number from 3 to 6, which has interesting biological properties that allow it to be used in the preparation of anticancer drugs and their method manufacturing.
Przedmiotem wynalazku są także nowe prekursory sulforafanu, zwłaszcza w postaci sulfidów, sulfotlenków lub sulfonów ro-N-ftalimido-1-alkilowo-polifluoroalkilowych o wzorze 4, w którym RF, n, x, y, z, i m mają podane wyżej znaczenie.The invention also relates to new sulforaphane precursors, in particular in the form of ro-N-phthalimido-1-alkyl-polyfluoroalkyl sulfides, sulfoxides or sulfones of the formula wherein R F , n, x, y, z, and m are as defined above.
Analogi według wynalazku otrzymano poprzez zastąpienie w cząsteczce sulforafanu prostych podstawników organicznych podstawnikami fluoroorganicznymi oraz ewentualnie zmianę liczby grup metylenowych w łańcuchu łączącym centralny atom siarki z izotiocyjanianowym atomem azotu, a także przez zmianę stopnia utlenienia centralnego atomu siarki.The analogs of the invention were obtained by replacing simple organic substituents in the sulforaphane molecule with organofluorine substituents and possibly by changing the number of methylene groups in the chain connecting the central sulfur atom with the isothiocyanate nitrogen atom, and by changing the oxidation state of the central sulfur atom.
Związki według niniejszego wynalazku nie były dotychczas opisane w literaturze chemicznej.The compounds of the present invention have so far not been described in the chemical literature.
Nieoczekiwanie, w trakcie badań własnych, okazało się, że uzyskano nowe połączenia według wynalazku, odznaczają się wzmocnionym działaniem biologicznym i nowymi właściwościami leczniczymi, w szczególności jako środki zwalczające czerniaka złośliwego skóry (melanomę).Surprisingly, in the course of our own research, it turned out that the new combinations according to the invention were obtained, are distinguished by enhanced biological activity and new therapeutic properties, in particular as agents for combating malignant melanoma (melanoma).
Pochodne sulforafanu, w postaci sulfidów, sulfotlenków, ich racematów i enancjomerów, oraz sulfonów ω-izotiocyjanianoalkilowo-polifluoroalkilowych przedstawione wzorem 1, (O)m ilSulforaphane derivatives, in the form of sulfides, sulfoxides, their racemates and enantiomers, and ω-isothiocyanatoalkyl polyfluoroalkyl sulfones represented by the formula 1, (O) ml
RF(CHxF2.x)zS-(CH2)y-N=C=S wzór 1 w którym RF oznacza grupę o wzorze CnF2n+1, gdzie n oznacza liczbę naturalną od 1 do 7, x oznacza liczbę 0, 1 lub 2, z oznacza liczbę 0, 1 lub 2, m oznacza liczbę 0, 1 lub 2, a y oznacza liczbę naturalną od 3 do 6, w tym sulfidy o wzorze 1 dla m = 0, sulfotlenki, ich racematy oraz enancjomery o wzorze 1, dla m = 1, oraz sulfony ω-izotiocyjanianoalkilowo-polifluoroalkilowe o wzorze 1, dla m = 2.R F (CH x F 2. X ) z S- (CH 2 ) y -N = C = S formula 1 where R F is a group of formula CnF 2n + 1 , where n is a natural number from 1 to 7, x is 0, 1 or 2, z is 0, 1 or 2, m is 0, 1 or 2, and y is a natural number from 3 to 6, including sulfides of formula 1 for m = 0, sulfoxides, their racemates and enantiomers of formula 1 for m = 1, and ω-isothiocyanatoalkyl polyfluoroalkyl sulfones of formula 1 for m = 2.
PL 220 620 B1PL 220 620 B1
Prekursory pochodnych sulforafanu, zwłaszcza w postaci sulfidów, sulfotlenków lub sulfonów ω-N-ftalimido-l-alkilowo-poIifluoroalkilowych o wzorze 4,Precursors of sulforaphane derivatives, especially in the form of ω-N-phthalimido-1-alkyl-polyfluoroalkyl sulfides, sulfoxides or sulfones of the formula 4,
w którym RF, n, x, y, z, i m mają podane wyżej znaczenie.wherein R F , n, x, y, z, and m are as defined above.
Sposób wytwarzania pochodnych sulforafanu o wzorze 1, w którym RF oznacza grupę o wzorze CnF2n+1, gdzie n oznacza liczbę naturalną od 1 do 7, x oznacza liczbę 0, 1 lub 2, z oznacza liczbę 0, 1 lub 2, m oznacza liczbę 0, 1 lub 2, a y oznacza liczbę naturalną od 3 do 6, według wynalazku polega na tym, że ω-N-ftalimidoalkano-l-tiol o wzorze 2, w którym y ma podane wyżej znaczenie, poddaje się reakcji z odpowiednim i-halogenopolifluoroalkanem o wzorze 3, w którym Hal oznacza halogen, a Rf, n, x, z mają podane wyżej znaczenie, w obecności dwunastowodnego fosforanu trisodowego i rozpuszczalnika organicznego, zwłaszcza DMF oraz hydroksymetylosiarczynu sodu (hydrosulfitu), mieszaninę miesza się, a zawartość wylewa do wody i ekstrahuje chloroformem, fazę organiczną suszy MgSO4, odparowuje rozpuszczalnik uzyskując surowy produkt, który oczyszcza się za pomocą chromatografii cieczowej (SiO2, CHCI3), do otrzymania czystego produktu - nowego sulfidu ω-N-ftalimido-l-alkilowo-polifluoroalkilowego o wzorze 4, w którym Rf, n, x, z i y mają podane wyżej znaczenie, a m = 0, z którego blok ftalimidowy usuwa się za pomocą hydrazyny, co prowadzi do nowego sulfidu ro-amino-1-alkilowo-polifluoroalkilowego o wzorze 5, gdzie RF, n, x, z i y mają podane wyżej znaczenie, z którego po potraktowaniu tiofosgenem lub tiowęglanem O,O-di-2-pirydylu otrzymuje się sulfid ro-izotiocyjaniano-1-alkilowo-polifluoroalkilowy 1, gdzie Rf, n, x, z i y mają podane wyżej znaczenie, a m = 0, który, ewentualnie, utlenia się za pomocą odpowiedniego środka utleniającego, wybranego z grupy obejmującej kwas m-chloronadbenzoesowy (m-CPBA), oksazirydyny Davisa, metanadjodan sodu (NalO4), nadtlenek wodoru (H2O2) w obecności katalizatorów, enzymy oksydacyjne wybrane z grupy obejmującej chloroperoksydazę z Caldariomyces fumago, monooksygenazę cykloheksanonu z Actinobacter calcoaceticus lub preparaty komórkowe wybrane z grupy obejmującej grzyby z rodzaju Helminthosporium, Rhizopus, Trichaptum and Trametes species, Mortierella isabellina, Botrytis cinerea, Trichoderma viride Eutypa lata i Aspergillus japonicus ICFC 744/11 oraz drożdże Saccharomyces cerevisiae do utworzenia, w zależności od zastosowanych warunków reakcji, sulfotlenku ro-izotiocyjaniano-1-alkilowo-polifluoroalkilowego 1, gdzie Rf, n, x, z i y mają podane wyżej znaczenie, a m = 1 lub sulfonu ro-izotiocyjaniano-1-alkiIowo-polifluoroalkilowego 1, gdzie Rf, n, x, z i y mają podane wyżej znaczenie, a m = 2.A process for the preparation of sulforaphane of formula 1, wherein RF is a radical of formula C n F 2n + 1 where n is a natural number from 1 to 7, x is 0, 1 or 2, z is 0, 1 or 2; m is 0, 1 or 2 and y is a natural number from 3 to 6, according to the invention, a ω-N-phthalimidoalkane-1-thiol of the formula 2 in which y is as defined above is reacted with with the corresponding i-halogenopolifluoroalkane of formula III in which Hal is halogen and Rf, n, x, z are as defined above, in the presence of trisodium phosphate dodecahydrate and an organic solvent, especially DMF and sodium hydroxymethyl sulfite (hydrosulfite), the mixture is stirred and the content is poured into water and extracted with chloroform, the organic phase is dried over MgSO4, the solvent is evaporated, obtaining a crude product which is purified by liquid chromatography (SiO 2 , CHCl 3 ) to obtain a pure product - a new ω-N-phthalimide-1-alkyl sulfide -polifluoroalkyl where Rf, n, x, z and y are as defined above, m = 0, from which the phthalimide block is removed with hydrazine, leading to the new ro-amino-1-alkyl polyfluoroalkyl sulfide of formula 5 where R F , n, x, z and y are as defined above, whereby treatment with O, O-di-2-pyridyl thiocarbonate with thiophosgene or O, O-di-2-pyridyl thiocarbonate gives ro-isothiocyanato-1-alkyl polyfluoroalkyl sulfide 1, where Rf, n, x, z and y are as defined above, m = 0, which is optionally oxidized with a suitable oxidizing agent selected from the group consisting of m-chloroperbenzoic acid (m-CPBA), Davis oxaziridines, sodium metaperiodate (NalO4), hydrogen peroxide ( H2O2) in the presence of catalysts, oxidative enzymes selected from the group consisting of chloroperoxidase from Caldariomyces fumago, cyclohexanone monooxygenase from Actinobacter calcoaceticus or cell preparations selected from the group consisting of Helminthosporium, Rhizopus, Trichaptum and Trametes species, Morti erella isabellina, Botrytis cinerea, Trichoderma viride Eutypa lata and Aspergillus japonicus ICFC 744/11 and the yeast Saccharomyces cerevisiae to form, depending on the reaction conditions used, ro-isothiocyanato-1-alkyl polyfluoroalkyl sulfoxide 1, where Rf, n z and y are as defined above, am = 1 or ro-isothiocyanato-1-alkyl polyfluoroalkyl sulfone 1, where R f, n, x, z and y are as defined above, and m = 2.
Alternatywnie, nowy sulfid ro-N-ftalimido-1-alkilowo-polifluoroalkilowy o wzorze 4, gdzie RF, n, x, z i y mają podane wyżej znaczenie, a m = 0, najpierw utlenia się do sulfotlenku ro-N-ftalimido-1-alkilowo-polifluoroalkilowego 4 (m = 1), lub sulfonu ro-N-ftalimido-1-alkilowo-polifluoroalkilowego 4 (m = 2), które w reakcji z hydrazyną, a następnie z tiofosgenem lub tiowęglanem O,O-di-2-pirydylu, przekształca się odpowiednio w produkty:Alternatively, the novel ro-N-phthalimido-1-alkyl polyfluoroalkyl sulfide of formula 4, where R F , n, x, z and y are as defined above, and m = 0, is first oxidized to ro-N-phthalimido-1-sulfoxide. alkyl polyfluoroalkyl 4 (m = 1), or ro-N-phthalimido-1-alkyl polyfluoroalkyl sulfone 4 (m = 2), which by reaction with hydrazine followed by thiophosgene or O, O-di-2-thiocarbonate pyridyl transforms into the products:
sulfotlenek ro-izotiocyjaniano-1-alkilowo-polifluoroalkilowy o wzorze 1 (m = 1), lub sulfon ro-izotiocyjaniano-1-alkilowo-polifluoroalkilowy o wzorze 1 (m = 2).ro-isothiocyanato-1-alkyl polyfluoroalkyl sulfoxide of formula 1 (m = 1), or ro-isothiocyanato-1-alkyl polyfluoroalkyl sulfone of formula 1 (m = 2).
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RF(CHxF,x)zHal wzór 3 wzór 4 wzór 2 m-CPBAR F (CH x F, x ) z Hal pattern 3 pattern 4 pattern 2 m-CPBA
H2NNH2, h2oH 2 NNH 2 , h 2 o
RF(CHxF2.x)z-S-(CH2)yNH2 wzór 4 wzór 5 h2nnh2, h,oR F (CH x F 2. X ) z -S- (CH 2 ) yNH 2 formula 4 formula 5 h 2 nnh 2 , h, o
CSCI lub (2-PyO)2C=S,CSCI or (2-PyO) 2 C = S,
CSC!,, NaOHCSC! ,, NaOH
NaOH, r NaOHNaOH, r NaOH
T lub {2-PyO)2C=S m-CPSAT or {2-PyO) 2 C = S m-CPSA
Rp(CHxF2.x)zS—(CH2)y-N=C=S wzór 1 wzór 1Rp (CH x F 2. X ) z S— (CH 2 ) y -N = C = S formula 1 formula 1
SCHEMAT ISCHEME I
Przebieg odpowiednich reakcji ilustrują syntezy nowych związków pokazane na Schemacie I.The course of the respective reactions is illustrated by the syntheses of new compounds shown in Scheme I.
Na Schemacie II przedstawiono alternatywną metodę wytwarzania nowych związków, sulfidów o wzorze 4, gdzie RF, n, x, z i y mają podane wyżej znaczenie, a m = 0, polegającą na tym, że ω-N-ftalimido-l-halogenoalkan o wzorze 6 poddaje się reakcji z odpowiednim polifluoroalkanotiolem o wzorze 7, a otrzymany sulfid ro-N-ftalimido-1-alkilowo-polifluoroalkilowy 4, przekształca się następnie w związek o wzorze 1, gdzie Rf, n, z, y i m mają podane wyżej znaczenie, w sposób opisany uprzednio.Scheme II shows an alternative method for the preparation of the novel compounds, sulfides of formula 4, where R F , n, x, z and y are as defined above, m = 0, in that ω-N-phthalimido-1-halogenoalkane of formula 6 is reacted with a suitable polyfluoroalkanethiol of formula 7, and the resulting ro-N-phthalimido-1-alkyl-polyfluoroalkyl sulfide 4 is then converted into a compound of formula 1, where Rf, n, z, and m are as defined above, as defined above previously described.
Alternatywny sposób otrzymywania nowych związków o wzorze 4, według wynalazku, przedstawiony na Schemacie II, stosuje się w zależności dostępności odpowiednich fluorowanych tioli o wzorze 7 oraz ro-N-ftalimido-1-halogenoalkanów o wzorze 6.The alternative method for the preparation of the novel compounds of formula 4 according to the invention, described in Scheme II, is used depending on the availability of the corresponding fluorinated thiols of formula 7 and the r-N-phthalimido-1-halogenoalkanes of formula 6.
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Przedmiot wynalazku ilustrują poniższe przykłady.The following examples illustrate the subject matter of the invention.
P r z y k ł a d I. Synteza sulfidu 4-N-ftalimidobutylowo-trifluorometylowego 4a (Rf = CF3, Z = 0, m = 0, y = 4)Example I. Synthesis of 4-N-phthalimidobutyl trifluoromethyl sulfide 4a (Rf = CF 3 , Z = 0, m = 0, y = 4)
Do ampuły szklanej zawierającej 4-N-ftalimidobutanotiol, wzór 2, y = 4 (1.2 g, 5.1 mmol), dwunastowodny fosforan trisodowy (1.3 g, 5.1 mmol), DMF (9.8 ml) oraz hydroksymetylosiarczyn sodu (hydrosulfit, 2.35 g, 15.3 mmol) wprowadzono gazowy jodotrifluorometan, wzór 3, Rf = CF3, z = 0 (2.0 g, 10.2 mmol). Mieszaninę wytrząsano przez 20 h. Zawartość wylano do wody (50 ml) i ekstrahowano chloroformem. Fazę organiczną suszono MgSO4. Odparowano rozpuszczalnik pod zmniejszonym ciśnieniem uzyskując surowy produkt (1,6 g), który oczyszczono za pomocą chromatografii cieczowej (SiO2, CHCl3). Otrzymano czysty produkt - sulfid 4-N-ftalimidobutylowo-trifluorometylowy 4a (Rf = CF3, z = 0, m = 0, y = 4); wydajność 550 mg (36%).For a glass ampoule containing 4-N-phthalimidobutanethiol, formula 2, y = 4 (1.2 g, 5.1 mmol), trisodium phosphate dodecahydrate (1.3 g, 5.1 mmol), DMF (9.8 ml) and sodium hydroxymethyl sulfite (hydrosulfite, 2.35 g, 15.3 mmol) gas was introduced jodotrifluorometan pattern 3, R f = CF 3, z = 0, (2.0 g, 10.2 mmol). The mixture was shaken for 20 h. The contents were poured into water (50 ml) and extracted with chloroform. The organic phase was dried with MgSO 4 . The solvent was evaporated under reduced pressure to give a crude product (1.6 g) which was purified by liquid chromatography (SiO 2 , CHCl 3 ). Pure product was obtained - 4-N-phthalimidobutyl trifluoromethyl sulfide 4a (R f = CF 3 , z = 0, m = 0, y = 4); yield 550 mg (36%).
1H NMR (CDCI3); δ = 1.70-1,87 (m, 4H, CH2CH2), 2.91 (t, 2H, J = 6.66 Hz, CH2S), 3.70 (t, 2H, J = 6.60 Hz, CH2N), 7.68-7.85 (m, 4H, arom.). 1 H NMR (CDCl3); δ = 1.70-1.87 (m, 4H, CH 2 CH 2 ), 2.91 (t, 2H, J = 6.66 Hz, CH 2 S), 3.70 (t, 2H, J = 6.60 Hz, CH 2 N), 7.68-7.85 (m, 4H, arom).
13C NMR (CDCI3): δ = 26.93, 27.59, 29.47, 37.24, 123.47, 131.24 (q, J = 306 Hz, CF3), 132.19, 134.23, 168.55. 13 C NMR (CDCl3): δ = 26.93, 27.59, 29.47, 37.24, 123.47, 131.24 (q, J = 306 Hz, CF3), 132.19, 134.23, 168.55.
19F NMR (CFCI3): δ = - 40.51 19 F NMR (CFCl3): δ = -40.51
MS (Cl/izobutan): m/z = 304.1 [M+1]MS (Cl / isobutane): m / z = 304.1 [M + 1]
HRMS: dla wzoru: C13H12F3NO2S obliczono: m/z 303.053, znaleziono: m/z 303.054.HRMS: for Formula: C13H12F3NO2S Calculated: m / z 303.053, Found: m / z 303.054.
P r z y k ł a d II. Synteza sulfotlenku 4-N-ftalimidobutylowo-trifluorometylowego 4a (Rf = CF3, z = 0, m = 1, y = 4)P r z x l a d II. Synthesis of 4-N-phthalimidobutyl trifluoromethyl sulfoxide 4a (Rf = CF3, z = 0, m = 1, y = 4)
Do roztworu sulfidu 4-N-ftalimidobutylowo-trifluorometylowego 4a (Rf = CF3, z = 0, m = 0, y = 4), opisanego w Przykładzie I (400 mg, 1.32 mmol), w dichlorometanie (10 ml) dodawano porcjami, mieszając, kwas m-chloronadbenzoesowy (mCPBA) (269 mg, 1.32 mmol) w dichlorometanie. Po 3 dniach dodano stały NaHCO3 (170 mg, 2 mmol) i kontynuowano mieszanie przez 1 h. Po przesączeniu dodano wodę, rozdzielono warstwy i warstwę wodną ekstrahowano CH2CI2. Warstwę organiczną suszono nad MgSO4. Po odparowaniu rozpuszczalników otrzymano surowy produkt (369 mg), który oczyszczono za pomocą chromatografii cieczowej (SiO2, heksan-aceton 6:4) Uzyskano czysty produkt sulfotlenek 4-N-ftalimidobutylowo-trifluorometylowy 4a (Rf = CF3, z = 0, m = 1, y = 4); wydajność: 300 mg (71%).To the solution of 4-N-phthalimidobutyl trifluoromethyl sulfide 4a (Rf = CF 3 , z = 0, m = 0, y = 4) described in Example I (400 mg, 1.32 mmol) in dichloromethane (10 ml) was added portionwise while stirring, m-chloroperbenzoic acid (mCPBA) (269 mg, 1.32 mmol) in dichloromethane. After 3 days, solid NaHCO3 (170 mg, 2 mmol) was added and stirring was continued for 1 h. After filtration, water was added, the layers were separated and the aqueous layer was extracted with CH2Cl2. The organic layer was dried over MgSO4. After evaporation of the solvents, the crude product (369 mg) was obtained, which was purified by liquid chromatography (SiO2, hexane-acetone 6: 4). The pure product 4-N-phthalimidobutyl-trifluoromethyl sulfoxide 4a (Rf = CF 3 , z = 0, m = 1, y = 4); yield: 300 mg (71%).
1H NMR (CDCI3); δ = 1.88 (m, 4H, CH2CH2), 2.89-3.08 (m, 2H, CH2SO), 3.72 (t, 2H, J = 6.12 Hz, 1 H NMR (CDCl3); δ = 1.88 (m, 4H, CH 2 CH 2 ), 2.89-3.08 (m, 2H, CH 2 SO), 3.72 (t, 2H, J = 6.12 Hz,
CH2N), 7,66-7.81 (m, 4H, arom.).CH2N), 7.66-7.81 (m, 4H, arom).
19F NMR (CFCI3): δ = -72.9 19 F NMR (CFCl3): δ = -72.9
MS (Cl/izobutan): m/z = 320.1 [M+1]MS (Cl / isobutane): m / z = 320.1 [M + 1]
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Otrzymaną mieszaninę racemiczną rozdzielono na enancjomery stosując technikę HPLC na chiralnej fazie stałej (Chiralcel OJ; heksan - /-PrOH 4 : 6)The resulting racemic mixture was separated into the enantiomers using a chiral solid phase HPLC technique (Chiralcel OJ; hexane - / -PrOH 4: 6)
Dla każdego enancjomeru wykonano badanie rentgenograficzne i przypisano absolutne konfiguracje:X-ray examination was performed for each enantiomer and the absolute configurations were assigned:
(-)-(S)- 4a (Rf = CF3, z = 0, m = 1, y = 4); [a]o - 35 (c = 1.3, AcOEt) (+)-(R)- 4a (Rf = CF3, z = 0, m = 1, y = 4); [a]o + 38.6 (c = 4.0, AcOEt)(-) - (S) - 4a (R f = CF3, z = 0, m = 1, y = 4); [a] O - 35 (c = 1.3, AcOEt) (+) - (R) - 4a (Rf = CF3, z = 0, m = 1, y = 4); [a] o + 38.6 (c = 4.0, AcOEt)
P r z y k ł a d III. Synteza sulfidu 4-izotiocyjanianobutylowo-trifluorometylowego 1a (RF = CF3, z = 0, m = 0, y = 4) (0)mExample III. Synthesis of 4-isothiocyanatobutyl trifluoromethyl sulfide 1a (R F = CF3, z = 0, m = 0, y = 4) (0) m
IIII
CF3-S-(CH2)4N=C=S wzór1aCF 3 -S- (CH 2 ) 4 N = C = S formula 1a
Do roztworu sulfidu 4-N-ftalimidobutylowo-trifluorometylowego 4a (Rf = CF3, z = 0, m = 0, y = 4) (560 mg, 1.85 mmol) w etanolu (1.85 ml) dodano w atmosferze argonu wodzian hydrazyny (120 mg, 2.30 mmol) i całość ogrzewano w temperaturze 75°C. Dodano stężony HCI (aq) (740 μΐ) i ogrzewano przez 1 h w temperaturze 100°C, a następnie pozostawiono roztwór na noc. Dodano wodę (9.5 ml), odsączono osad, przemyto wodą i z uzyskanego roztworu odpędzono rozpuszczalniki pod zmniejszonym ciśnieniem. Do otrzymanego surowego krystalicznego chlorowodorku sulfidu 4-aminobutylowo-trifluorometylowego 5a (Rf = CF3, Z = 0, m = 0, y = 4) dodano chloroform (7 ml) oraz tiofosgen, CSCI2 (230 mg, 2 mmol), a po chwili wodny roztwór NaOH (240 mg, 6 mmol, 2 ml H2O) i całość mieszano przez 20 h. Dodano wodę (3 ml), a produkt ekstrahowano chloroformem. Warstwę organiczną suszono nad MgSO4. Po odparowaniu rozpuszczalnika otrzymano żółto-brązowy olej (356 mg), który oczyszczono za pomocą chromatografii cieczowej (Kolumna Lichroprep). Uzyskano czysty sylfid 4-izotiocyjanianobutylowo-trifluorometylowy 1a (Rf = CF3, z = 0, m = 0, y = 4) z wydajnością 158 mg (40%, w przeliczeniu na wyjściowy sulfid 4a).Hydrazine hydrate (120 ml) was added to a solution of 4-N-phthalimidobutyl trifluoromethyl sulfide 4a (Rf = CF 3 , z = 0, m = 0, y = 4) (560 mg, 1.85 mmol) in ethanol (1.85 ml) under argon atmosphere. mg, 2.30 mmol) and heated to 75 ° C. Concentrated HCl (aq) (740 µΐ) was added and heated for 1 h at 100 ° C, then the solution was left to stand overnight. Water (9.5 ml) was added, the precipitate was filtered off, washed with water and the resulting solution was stripped of solvents under reduced pressure. To the obtained crude crystalline 4-aminobutyl trifluoromethyl sulfide 5a hydrochloride (Rf = CF 3 , Z = 0, m = 0, y = 4) was added chloroform (7 ml) and thiophosgene, CSCl 2 (230 mg, 2 mmol), and after a while, an aqueous NaOH solution (240 mg, 6 mmol, 2 ml of H 2 O) and the mixture was stirred for 20 h. Water (3 ml) was added and the product was extracted with chloroform. The organic layer was dried over MgSO4. Solvent evaporation gave a yellow-brown oil (356 mg) which was purified by liquid chromatography (Lichroprep column). Pure 4-isothiocyanatobutyl-trifluoromethyl sylphide 1a (Rf = CF 3 , z = 0, m = 0, y = 4) was obtained in a yield of 158 mg (40%, based on the starting sulfide 4a).
1H NMR (COCl3): δ = 1.8 (m, 4H, CH2CH2), 2.9 (t, 2H, J = 6.6 Hz, CH2S), 3,6 (t, 2H, J = 6.0 Hz, CH2N). 1 H NMR (COCl 3 ): δ = 1.8 (m, 4H, CH 2 CH 2 ), 2.9 (t, 2H, J = 6.6 Hz, CH 2 S), 3.6 (t, 2H, J = 6.0 Hz , CH2N).
13C NMR (COCI3): δ = 26.53, 28.55, 29.02, 44.41, 130.69 (NCS), 130.86 (q, J = 306 Hz, CF3). 13 C NMR (COCl3): δ = 26.53, 28.55, 29.02, 44.41, 130.69 (NCS), 130.86 (q, J = 306 Hz, CF 3 ).
19F NMR (CFCI3): δ = - 40.4 19 F NMR (CFCI 3 ): δ = - 40.4
MS (Cl/izobutan); m/z = 216 [M+1]MS (Cl / isobutane); m / z = 216 [M + 1]
HRMS: dla wzoru: C6H8F3NS2 obliczono: m/z 215.00527, znaleziono: m/z 215.00503HRMS: for formula: C6H8F3NS2 calculated: m / z 215.00527, found: m / z 215.00503
P r z y k ł a d IV. Synteza sulfotlenku 4-izotiocyjanianobutylowo-trifluorometylowego 1a (Rf = CF3, z = 0, m = 1 ,y = 4) (O)mExample IV. Synthesis of 4-isothiocyanatobutyl trifluoromethyl sulfoxide 1a (Rf = CF 3 , z = 0, m = 1, y = 4) (O) m
IIII
CF3-S-(CH2)4N=C=S wzór 1aCF 3 -S- (CH 2 ) 4 N = C = S formula 1a
Oo roztworu sulfidu 4-izotiocyjanianobutylowo-trifluorometylowego 1a (Rf = CF3, z = 0, m = 0, y = 4) (75 mg, 0.46 mmol) w dichlorometanie (7 ml) dodano porcjami m-CPBA (88 mg, 0.56 mmol).A solution of 4-isothiocyanatobutyl trifluoromethyl sulfide 1a (Rf = CF 3 , z = 0, m = 0, y = 4) (75 mg, 0.46 mmol) in dichloromethane (7 mL) was added portionwise m-CPBA (88 mg, 0.56 mmol).
Postęp reakcji kontrolowano za pomocą 19F NMR. Produkty reakcji rozdzielono za pomocą preparatywnej TLC. Wyizolowano nieprzereagowany substrat (41 mg) oraz oczekiwany produkt, sulfotlenek 4-izotiocyjanianobutylowo-trifluorometylowy 1a (Rf = CF3, z = 0, m = 1, y = 4) (40.4 mg, 49%).The progress of the reaction was monitored by 19 F NMR. The reaction products were separated by preparative TLC. The unreacted starting material (41 mg) and the expected product, 4-isothiocyanatobutyl trifluoromethyl sulfoxide 1a (Rf = CF 3 , z = 0, m = 1, y = 4) (40.4 mg, 49%) were isolated.
1H NMR (COCI3): δ = 1.88-2.09 (m, 4H, CH2CH2), 2.94 (m, 1H), 3.09 (m, 1H), 3.6 (t, 2H, J = 6.2 Hz, CH2N). 1 H NMR (COCl 3): δ = 1.88-2.09 (m, 4H, CH 2 CH 2 ), 2.94 (m, 1H), 3.09 (m, 1H), 3.6 (t, 2H, J = 6.2 Hz, CH 2 N).
13C NMR (COCI3); δ = 19.4, 29.7, 44.4, 47.5, 125.2 (q, J= 329.5 Hz, CF3), 130.69 (NCS), 19F NMR (CFCI3): δ = - 72.9 13 C NMR (COCl 3); δ = 19.4, 29.7, 44.4, 47.5, 125.2 (q, J = 329.5 Hz, CF3), 130.69 (NCS), 19 F NMR (CFCI3): δ = - 72.9
MS (Cl/izobutan): m/z = 232 [M+1]MS (Cl / isobutane): m / z = 232 [M + 1]
Otrzymaną mieszaninę racemiczną rozdzielono na enancjomery stosując technikę HPLC na chiralnej fazie stałej (Chiralcel OJ; heksan - /-PrOH 4 : 6).The resulting racemic mixture was separated into the enantiomers using a chiral solid phase HPLC technique (Chiralcel OJ; hexane - / -PrOH 4: 6).
Absolutne konfiguracje przypisano na drodze porównania znaków skręcalności uzyskanych enancjomerów ze znakami skręcalności enancjomerycznie wzbogaconych sulfotlenków otrzymanych w reakcji enancjomerów sulfotlenków (-)-(S)-4a i (+)-(R)-4a z hydrazyną.The absolute configurations were assigned by comparing the rotation signs of the obtained enantiomers with the rotation signs of the enantiomerically enriched sulfoxides obtained by reacting the enantiomers of (-) - (S) -4a and (+) - (R) -4a sulfoxides with hydrazine.
PL 220 620 B1 (-)-(S)-1a (Rf= CF3, z = 0, m = 1, y = 4); [a]o - 49.5 (c = 1.3, AcOEt), ee = 95.4% (+)-(R)-1a (Rf= CF3, z = 0, m = 1, y = 4); [a]D + 51.9 (c = 4.0, AcOEt), ee = 100%(-) - (S) -1a (Rf = CF3, z = 0, m = 1, y = 4); [a] o - 49.5 (c = 1.3, AcOEt), ee = 95.4% (+) - (R) -1a (Rf = CF3, z = 0, m = 1, y = 4); [a] D + 51.9 (c = 4.0, AcOEt), ee = 100%
P r z y k ł a d V. Synteza sulfidu 4-N-ftalimidobutylowo-2',2',2'-trifluoroetylowego o wzorze 4b (Rf = CF3, z = 1, x = 2, m = 0, y = 4)Example 5 Synthesis of 2 ', 2', 2'-trifluoroethyl 4-N-phthalimidobutyl sulfide of formula 4b (R f = CF 3 , z = 1, x = 2, m = 0, y = 4)
Przygotowano roztwór metanolanu sodu w metanolu, rozpuszczając sód (0.4 g, 17.225 mmol) w 15 ml MeOH. Roztwór schłodzono do 0°C i w atmosferze azotu wkroplono do niego roztwór 2,2,2-trifluoroetanotiolu, wzór 7, Rf = CF3, x = 2, z = 1 (2 g, 17.225 mmol) w 5 ml MeOH. Mieszano przez 15 min. w temperaturze pokojowej, po czym odpędzono metanol. Otrzymany stały 2,2,2-trifluoroetanotiolan sodu rozpuszczono w 15 ml dimetoksyetanu (DME) i otrzymany roztwór schłodzono do 0°C, utrzymując go w atmosferze azotu. Do tego roztworu wkroplono roztwór N-(4-bromobutylo)ftalimidu, wzór 6, y = 4 (4.86 g, 17.225 mmol) w 10 ml DME i pozostawiono mieszaninę na noc w temperaturze pokojowej. Dodano wodę (50 ml) i rozdzielono warstwy. Warstwę organiczną ekstrahowano wodą. Połączone warstwy wodne ekstrahowano dichlorometanem (4 x 25 ml). Ekstrakt organiczny suszono MgSO4, po czym rozpuszczalnik usunięto pod obniżonym ciśnieniem. Po oczyszczeniu za pomocą chromatografii kolumnowej (CH2CI2) otrzymano sulfid 4-N-ftalimidobutylowo-2',2',2'-trifluoroetylowy 4b (Rf=CF3, X = 2, z = 1, m = 0, y = 4). Wydajność 5.25 g (86%).A solution of sodium methoxide in methanol was prepared by dissolving sodium (0.4 g, 17.225 mmol) in 15 mL of MeOH. The solution was cooled to 0 ° C under nitrogen was added dropwise a solution of 2,2,2-ethanethiol Formula 7, R = CF3, x = 2, z = 1 (2 g, 17.225 mmol) in 5 mL of MeOH. Stirred for 15 min. at room temperature and then the methanol was stripped off. The obtained solid sodium 2,2,2-trifluoroethanethiolate was dissolved in 15 ml of dimethoxyethane (DME) and the resulting solution was cooled to 0 ° C while maintaining it under a nitrogen atmosphere. To this solution was added dropwise a solution of N- (4-bromobutyl) phthalimide, formula 6, y = 4 (4.86 g, 17.225 mmol) in 10 ml of DME, and the mixture was left overnight at room temperature. Water (50 ml) was added and the layers were separated. The organic layer was extracted with water. The combined aqueous layers were extracted with dichloromethane (4 x 25 ml). The organic extract was dried with MgSO 4 , then the solvent was removed under reduced pressure. Purification by column chromatography (CH 2 Cl 2 ) gave 4-N-phthalimidobutyl-2 ', 2', 2'-trifluoroethyl sulfide 4b (R f = CF 3 , X = 2, z = 1, m = 0, y = 4). Yield 5.25 g (86%).
1H NMR (CDCI3): δ = 1.58-1.85 (m, 4H, CH2CH2), 2.69 (t, 2H, J = 7,07 Hz, CH2S), 3.04 (q, 2H, J = 9.33 Hz, CH2CF3), 3.69 (t, 2H, J = 6.81 Hz, CH2N), 7,67-7.86 (m, 4H, aromat) 19F NMR (CFCI3): δ = - 65.82 1 H NMR (CDCl 3 ): δ = 1.58-1.85 (m, 4H, CH 2 CH 2 ), 2.69 (t, 2H, J = 7.07 Hz, CH 2 S), 3.04 (q, 2H, J = 9.33 Hz, CH 2 CF 3 ), 3.69 (t, 2H, J = 6.81 Hz, CH 2 N), 7.67-7.86 (m, 4H, aromat) 19 F NMR (CFCI 3 ): δ = - 65.82
MS (Cl/izobutan): m/z = 318.1 [M+1]MS (Cl / isobutane): m / z = 318.1 [M + 1]
HRMS: dla wzoru: C14H14F3NO2S obliczono: m/z 318.07756, znaleziono: m/z 318.07742.HRMS: for formula: C 14 H 14 F 3 NO 2 S Calculated: m / z 318.07756, Found: m / z 318.07742.
P r z y k ł a d VI. Synteza sulfidu 4-izotiocyjanianobutylowo-2',2',2'-trifluoroetylowego o wzorze 1b (Rf = CF3, z = 1, x = 2, m = 0, y = 4) (O)m ΪΙExample VI. Synthesis of 2 ', 2', 2'-trifluoroethyl 4-isothiocyanatobutyl sulfide of formula 1b (Rf = CF 3 , z = 1, x = 2, m = 0, y = 4) (O) m ΪΙ
CF3CH2-S-{CH2)4N=C=S wzór1bCF 3 CH 2 -S- {CH2) 4 N = C = S formula 1b
Do kolby zawierającej sulfid 4b (2.024 g, 6.378 mmol) dodano etanol (20 ml) i całość podgrzano w celu rozpuszczenia substratu. Wkroplono wodzian hydrazyny (0.414 g, 6.378 mmol) rozpuszczony w 4 ml etanolu. Roztwór ogrzewano do wrzenia pod chłodnicą zwrotną przez 3 godziny, a następnie pozostawiono na noc w temperaturze pokojowej. Następnego dnia mieszaninę ponownie ogrzewano do wrzenia przez pół godziny. Kontrola 19F NMR wykazała brak substratu. Dodano 1 ml stężonego kwasu solnego i całość ogrzewano do wrzenia przez 1 godzinę. Po ochłodzeniu do temperatury pokojowej dodano 40 ml destylowanej wody, odsączono osad i przemyto go 0.2 N HCI. Z przesączu odparowano wodę pod zmniejszonym ciśnieniem uzyskując surowy chlorowodorek sulfidu 4-aminobutylowo-2',2',2'-trifluoroetylowego 5b (RF = CF3, z = 1 , x = 2 , m = 0, y = 4), 1.483 g. Rozpuszczono go w 25 ml chloroformu. oo roztworu dodano 1.6 g (6.8951 mmol) tiowęglanu O,O-di(2-pirydylu) (DPT) a następnie roztwór 827 mg wodorotlenku sodu w 6.6 ml wody. Całość mieszano intensywnie w temperaturze pokojowej przez weekend. Dodano 10 ml wody destylowanej i mieszaninę ekstrahowano chloroformem (3 x 30 ml). Połączone warstwy organiczne suszono nad bezwodnym MgSO4. Po jego odsączeniu odparowano rozpuszczalnik i inne substancje lotne otrzymując 1,527 g surowego produktu, który oczyszczano za pomocą chromatografii kolumnowej z użyciem dichlorometanu,Ethanol (20 mL) was added to the flask containing sulfide 4b (2.024 g, 6.378 mmol) and heated to dissolve the starting material. Hydrazine hydrate (0.414 g, 6.378 mmol) dissolved in 4 ml ethanol was added dropwise. The solution was heated to reflux for 3 hours and then left overnight at room temperature. The next day, the mixture was refluxed again for half an hour. 19 F NMR control showed no starting material was found. 1 ml of concentrated hydrochloric acid was added and the mixture was heated to reflux for 1 hour. After cooling to room temperature, 40 ml of distilled water was added, the precipitate was filtered off and washed with 0.2 N HCl. Water was evaporated from the filtrate under reduced pressure to give crude 4-aminobutyl-2 ', 2', 2'-trifluoroethyl sulfide 5b hydrochloride (R F = CF 3 , z = 1, x = 2, m = 0, y = 4), 1.483 g. Dissolve in 25 mL of chloroform. About the solution, 1.6 g (6.8951 mmol) of O, O-di (2-pyridyl) thiocarbonate (DPT) was added followed by a solution of 827 mg of sodium hydroxide in 6.6 ml of water. The mixture was stirred vigorously at room temperature over the weekend. 10 ml of distilled water was added and the mixture was extracted with chloroform (3 x 30 ml). The combined organic layers were dried over anhydrous MgSO4. After filtering it, the solvent and other volatiles were evaporated to give 1.527 g of crude product, which was purified by column chromatography using dichloromethane,
PL 220 620 B1 uzyskując 1.07 g (73.1%) czystego sulfidu 4-izotiocyjanianobutylowo-2',2',2'-trifluoroetylowego 1b (Rf = CF3, x = 2, z = 1, m = 0, y = 4).PL 220 620 B1 yielding 1.07 g (73.1%) of pure 2 ', 2', 2'-trifluoroethyl 4-isothiocyanatobutyl sulfide 1b (Rf = CF 3 , x = 2, z = 1, m = 0, y = 4) .
1H NMR (CDCI3): δ = 1,66-1.90 (m, 4H, CH2CH2), 2.72 (t, 2H, J = 6.55 Hz, CH2S), 3.08 (q, 2H, J = 9.91 Hz, CH2CF3), 3.56 (t, 2H, J = 6.05 Hz, CH2N). 1 H NMR (CDCl 3): δ = 1.66-1.90 (m, 4H, CH 2 CH 2 ), 2.72 (t, 2H, J = 6.55 Hz, CH 2 S), 3.08 (q, 2H, J = 9.91 Hz, CH2CF3), 3.56 (t, 2H, J = 6.05 Hz, CH 2 N).
19F NMR (CFCI3): δ = - 65,76 19 F NMR (CFCl3): δ = -65.76
MS (Cl/izobutan); m/z = 230 [M+1]MS (Cl / isobutane); m / z = 230 [M + 1]
P r z y k ł a d VII. Synteza sulfotlenku 4-N-ftalimidobutylowo-2',2',2'-trifluoroetylowego o wzorze 4b (RF = CF3, z = 1, x = 2, m = 1, y = 4) i sulfonu 4-N-ftalimidobutylowo-2',2',2'-trifluoroetylowego o wzorze 4b (RF = CF3, z = 1, x = 2, m = 2, y = 4)Example VII. Synthesis of 4-N-phthalimidobutyl-2 ', 2', 2'-trifluoroethyl sulfoxide of formula 4b (R F = CF 3 , z = 1, x = 2, m = 1, y = 4) and 4-N- sulfone 2 ', 2', 2'-trifluoroethyl phthalimidobutyl of formula 4b (R F = CF 3 , z = 1, x = 2, m = 2, y = 4)
Do roztworu sulfidu 4-N-ftalimidobutylowo- 2',2',2'-trifluoroetylowego 4b (Rf = CF3, z = 1, x = 2, m = 0, y = 4), opisanego w Przykładzie V, (150 mg, 0.4727 mmol) w 5 ml dichlorometanu dodano mCPBA (82 mg, 0.4727 mmol) i całość mieszano w temperaturze pokojowej. Po 10 min kontrola TLC wykazała brak substratu. Roztwór przemyto wodą (5 ml), a następnie nasyconym roztworem NaHCO3 (5 ml). Warstwę organiczną suszono nad bezwodnym MgSO4. Po jego odsączeniu odparowano rozpuszczalnik otrzymując mieszaninę zawierającą dwa produkty. Rozdzielono je za pomocą preparatywnej TLC (CH2CI2 : MeOH, 30 : 1) uzyskując czysty sulfotlenek 4-N-ftalimidobutylowo-2',2',2'-trifluoroetylowy 6b (140 mg, 89%) oraz sulfon 4-N-ftalimidobutylowo-2',2',2'-trifluoroetylowy 7b (18 mg, 11%).For the solution of 4-N-phthalimidobutyl-2 ', 2', 2'-trifluoroethyl sulfide 4b (Rf = CF 3 , z = 1, x = 2, m = 0, y = 4) described in Example 5, (150 mg, 0.4727 mmol) in 5 ml of dichloromethane was added mCPBA (82 mg, 0.4727 mmol) and the mixture was stirred at room temperature. After 10 min, TLC control showed no starting material was found. The solution was washed with water (5 mL) followed by saturated NaHCO3 solution (5 mL). The organic layer was dried over anhydrous MgSO4. After filtering it, the solvent was evaporated to give a mixture containing two products. They were separated by preparative TLC (CH2Cl2: MeOH, 30: 1) to yield pure 2 ', 2', 2'-trifluoroethyl 4-N-phthalimidobutyl sulfoxide (140 mg, 89%) and 4-N-phthalimidobutyl sulfone. 2 ', 2', 2'-trifluoroethyl 7b (18 mg, 11%).
Sulfotlenek 4b (RF = CF3, z = 1, x = 2, m = 1, y = 4):Sulfoxide 4b (R F = CF 3 , z = 1, x = 2, m = 1, y = 4):
1H NMR (CDCI3): δ = 1,64-2,11 (m, 4H, CH2CH2), 2.93 (t, 2H, J = 6.78 Hz, CH2S), 3.45 (q, 2H, J = 10.10 Hz, CH2CF3), 3.76 (t, 2H, J = 6.46 Hz, CH2N), 7.73-7.87 (m, 4H, aromat) 19F NMR (CFCI3): δ = - 60.18 MS (Cl/izobutan); m/z = 334.1 [M+1] 1 H NMR (CDCl 3): δ = 1.64-2.11 (m, 4H, CH 2 CH 2 ), 2.93 (t, 2H, J = 6.78 Hz, CH 2 S), 3.45 (q, 2H, J = 10.10 Hz, CH 2 CF3), 3.76 (t, 2H, J = 6.46 Hz, CH 2 N), 7.73-7.87 (m, 4H, aromat) 19 F NMR (CFCl3): δ = - 60.18 MS (Cl / isobutane); m / z = 334.1 [M + 1]
HRMS: dla wzoru: C14H14F3NO3S obliczono: m/z 334.072475, znaleziono: m/z 334.0724.HRMS: for formula: C14H14F3NO3S calculated: m / z 334.072475, found: m / z 334.0724.
Sulfon 4b (Rf = CF3, z = 1, x = 2, m = 2, y = 4):Sulfone 4b (R f = CF3, z = 1, x = 2, m = 2, y = 4):
1H NMR (CDCI3): δ = 1.84-2.16 (m, 4H, CH2CH2), 3,25 (t, 2H, J = 7.37 Hz, CH2S), 3.71-3.87 (m, 4H, CH2N i CH2CF3), 7.7-7.86 (m, 4H, aromat) 19F NMR (CFCI3): δ = - 60.53 MS (Cl/izobutan): m/z = 350.1 [M+1] 1 H NMR (CDCl 3 ): δ = 1.84-2.16 (m, 4H, CH 2 CH 2 ), 3.25 (t, 2H, J = 7.37 Hz, CH 2 S), 3.71-3.87 (m, 4H, and CH2CF3 CH 2 N), 7.7-7.86 (m, 4H, aromatic) 19 F NMR (CFCI 3): δ = - 60.53 MS (Cl / isobutane): m / z = 350.1 [m + 1]
HRMS: dla wzoru: C14H14F3NO4S obliczono: m/z 350.06739, znaleziono: m/z 350.06753.HRMS: for formula: C 14 H 14 F 3 NO 4 S Calculated: m / z 350.06739, Found: m / z 350.06753.
PL 220 620 B1PL 220 620 B1
Przykład VIII. Synteza sulfotlenku 4-izotiocyjanianobutylowo-2',2',2'-trifluoroetylowego o wzorze 1b (RF = CF3, z = 1, x = 2, m = 1, y = 4) (O)m IIExample VIII. Synthesis of 2 ', 2', 2'-trifluoroethyl 4-isothiocyanatobutyl sulfoxide of formula 1b (R F = CF 3 , z = 1, x = 2, m = 1, y = 4) (O) m II
CF3CH2-S-(CH2)4N=C=S wzór 1 bCF 3 CH 2 -S- (CH 2 ) 4 N = C = S formula 1 b
a) Do roztworu sulfidu 4-izotiocyjanianobutylowo-2',2',2'-trifluoroetylowego 1b (RF = CF3, x = 2, z = 1, m = 0, y = 4) (200 mg, 0.8734 mmol) w 7 ml dichlorometanu dodano mieszając mCPBA (150 mg, 0.8734 mmol). Roztwór silnie się rozgrzał. Po upływie 1 godziny kontrola TLC wykazała brak substratu. Odparowano rozpuszczalnik i surowy produkt oczyszczano za pomocą preparatywnej TLC (CH2CI2 : MeOH, 60 : 1). Uzyskano sulfotlenek 4-izotiocyjanianobutylowo-2',2',2'-trifluoroetylowy 1b (RF = CF3, x = 2, z = 1, m = 1, y = 4), 189 mg (88.3%).a) For a solution of 2 ', 2', 2'-trifluoroethyl 4-isothiocyanatobutyl sulfide 1b (R F = CF 3 , x = 2, z = 1, m = 0, y = 4) (200 mg, 0.8734 mmol) in 7 ml of dichloromethane, mCPBA (150 mg, 0.8734 mmol) was added with stirring. The solution has become very hot. After 1 hour, TLC control showed no starting material was found. The solvent was evaporated and the crude product was purified by preparative TLC (CH 2 Cl 2 : MeOH, 60: 1). 2 ', 2', 2'-trifluoroethyl sulfoxide 1b 4-isothiocyanatobutyl sulfoxide 1b (RF = CF3, x = 2, z = 1, m = 1, y = 4), 189 mg (88.3%) was obtained.
b) Do roztworu sulfidu 4-izotiocyjanianobutylowo-2',2',2'-trifluoroetylowego 1b (Rf = CF3, x = 2, z = 1, m = 0, y = 4) (200 mg, 0.8734 mmol) w tetrachloroetanie (5 ml) dodano oksazirydynę Davisa, (+) lub (-)-8,8-dichlorokamforosulfonylooksazirydynę, 260 mg (0.8734 mmol) w 2 ml tetrachloroetanu. Mieszano w temperaturze pokojowej przez 12 dni aż do zaniku substratu (TLC). Odparowano rozpuszczalnik i surową mieszaninę oczyszczano za pomocą preparatywnej TLC jak w podpunkcie a). Otrzymano sulfotlenek 4-izotiocyjanianobutylowo-2',2',2'-trifluoroetylowy 1b (Rf = CF3, x = 2, z = 1, m = 1, y = 4), 200 mg (93.4%).b) To a solution of 2 ', 2', 2'-trifluoroethyl 4-isothiocyanatobutyl sulfide 1b (Rf = CF 3 , x = 2, z = 1, m = 0, y = 4) (200 mg, 0.8734 mmol) in tetrachloroethane (5 ml) Davis oxaziridine, (+) or (-) - 8,8-dichlorocamphorsulfonyloxaziridine, 260 mg (0.8734 mmol) in 2 ml tetrachloroethane was added. Stirred at room temperature for 12 days until no more starting material (TLC). The solvent was evaporated and the crude mixture was purified by preparative TLC as in a). 2 ', 2', 2'-trifluoroethyl 4-isothiocyanatobutyl sulfoxide 1b (Rf = CF 3 , x = 2, z = 1, m = 1, y = 4), 200 mg (93.4%) was obtained.
1H NMR (CDCis): δ = 1.80-2.07 (m, 4H, CH2CH2), 2.78-3.01 (m, 2H, CH2S), 3.47 (q, 2H, J= 10.07 Hz, CH2CF3), 3.61 (t, 2H, J = 6.01 Hz, CH2N). 1 H NMR (CDCl): δ = 1.80-2.07 (m, 4H, CH 2 CH 2), 2.78-3.01 (m, 2H, CH2 S), 3.47 (q, 2H, J = 10.07 Hz, CH2CF3), 3.61 (t, 2H, J = 6.01Hz, CH 2 N).
19F NMR (CFCI3): δ = - 60.08 13C NMR (CDCI3): δ = 19.67, 28.73, 44.49, 52.56, 55.93 (q, J = 28.84 Hz), 123.15 (q, J= 277.36 Hz), 131,09 19 F NMR (CFCl3): δ = - 60.08 13 C NMR (CDCl3): δ = 19.67, 28.73, 44.49, 52.56, 55.93 (q, J = 28.84 Hz), 123.15 (q, J = 277.36 Hz), 131, 09
MS (Cl/izobutan): m/z = 246 [M+1]MS (Cl / isobutane): m / z = 246 [M + 1]
HRMS: dla wzoru: C14H14F3NO4S obliczono; m/z 246.023418, znaleziono: m/z 246.02342.HRMS: for formula: C14H14F3NO4S calculated; m / z 246.023418, found: m / z 246.02342.
Otrzymaną mieszaninę racemiczną rozdzielono na enancjomery stosując technikę HPLC na chiralnej fazie stałej (Chirobiotic V2; heksan - i-PrOH 50%).The resulting racemic mixture was separated into the enantiomers using a chiral solid phase HPLC technique (Chirobiotic V2; hexane - i-PrOH 50%).
(-)-1b (Rf = CF3, z =1, x = 2, m = 1, y = 4); [a]D- 44.7 (c = 0.84, /-PrOH), ee = 99.9% (+)-1b (Rf = CF3, Z = 1, x = 2, m = 1, y = 4); [a]D + 43.2 (c = 0.94, /-PrOH), ee = 93.9%(-) - 1b (Rf = CF3, z = 1, x = 2, m = 1, y = 4); [a] D- 44.7 (c = 0.84, i -PrOH), ee = 99.9% (+) - 1b (Rf = CF3, Z = 1, x = 2, m = 1, y = 4); [a] D + 43.2 (c = 0.94, i -PrOH), ee = 93.9%
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