PL221299B1 - Cis- (4R, 5R, 6S) -5- (1-iodoethyl) -4- (4'-isopropylphenyl) dihydrofuran-2-one and trans- (4R, 5S, 6R) -5- (1-iodoethyl) -4- (4'-isopropylphenyl) dihydrofuran-2-one and the method of their simultaneous preparation - Google Patents
Cis- (4R, 5R, 6S) -5- (1-iodoethyl) -4- (4'-isopropylphenyl) dihydrofuran-2-one and trans- (4R, 5S, 6R) -5- (1-iodoethyl) -4- (4'-isopropylphenyl) dihydrofuran-2-one and the method of their simultaneous preparationInfo
- Publication number
- PL221299B1 PL221299B1 PL406616A PL40661613A PL221299B1 PL 221299 B1 PL221299 B1 PL 221299B1 PL 406616 A PL406616 A PL 406616A PL 40661613 A PL40661613 A PL 40661613A PL 221299 B1 PL221299 B1 PL 221299B1
- Authority
- PL
- Poland
- Prior art keywords
- isopropylphenyl
- iodoethyl
- dihydrofuran
- cis
- trans
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- -1 (S, E) -3- (4'-isopropylphenyl) -hex-4-enoic acid Chemical compound 0.000 claims description 7
- 238000004440 column chromatography Methods 0.000 claims description 7
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- SLVGTZHVTFYEFE-ZWNMCFTASA-N (E,2S)-4-(4-propan-2-ylphenyl)but-3-en-2-ol Chemical compound C(C)(C)C1=CC=C(C=C1)/C=C/[C@H](C)O SLVGTZHVTFYEFE-ZWNMCFTASA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000005657 iodolactonization reaction Methods 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- HFQMKWCAWQTLTN-UHFFFAOYSA-N CC(C)C1=CC=C(C(CC(O)=O)C=CC)C=C1 Chemical compound CC(C)C1=CC=C(C(CC(O)=O)C=CC)C=C1 HFQMKWCAWQTLTN-UHFFFAOYSA-N 0.000 claims description 2
- 238000005821 Claisen rearrangement reaction Methods 0.000 claims description 2
- 230000005526 G1 to G0 transition Effects 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 230000004048 modification Effects 0.000 claims description 2
- 238000012986 modification Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- LHJUUFQOKBUDCV-UHFFFAOYSA-N CCOC(CC(C=CC)C1=CC=C(C(C)C)C=C1)=O Chemical compound CCOC(CC(C=CC)C1=CC=C(C(C)C)C=C1)=O LHJUUFQOKBUDCV-UHFFFAOYSA-N 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000003480 eluent Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 4
- 238000004611 spectroscopical analysis Methods 0.000 description 4
- 241000282465 Canis Species 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000005918 in vitro anti-tumor Effects 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- NDQXKKFRNOPRDW-UHFFFAOYSA-N 1,1,1-triethoxyethane Chemical compound CCOC(C)(OCC)OCC NDQXKKFRNOPRDW-UHFFFAOYSA-N 0.000 description 1
- 208000004736 B-Cell Leukemia Diseases 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- JVELVWNKDJFWOR-UHFFFAOYSA-N IC(C)C1C(CC(O1)=O)C1=CC=C(C=C1)C(C)C Chemical compound IC(C)C1C(CC(O1)=O)C1=CC=C(C=C1)C(C)C JVELVWNKDJFWOR-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000007398 colorimetric assay Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Opis wynalazkuDescription of the invention
Przedmiotem wynalazku jest optycznie czynny lakton cis-(4R,5R,6S)-5-(1-jodoetylo)-4-(4'-izopropylofenylo)-dihydrofuran-2-on o wzorze 1 przedstawionym na rysunku oraz optycznie czynny lakton trans-(4R,5S,6R)-5-(1-jodoetylo)-4-(4'-zopropylofenylo)-dihydrofuran-2-on o wzorze 2 przedstawionym na rysunku.The present invention relates to the optically active cis- (4R, 5R, 6S) -5- (1-iodoethyl) -4- (4'-isopropylphenyl) -dihydrofuran-2-one lactone of the formula 1 shown in the figure and the optically active trans-lactone (4R, 5S, 6R) -5- (1-iodoethyl) -4- (4'-zopropylphenyl) -dihydrofuran-2-one of the formula 2 shown in the drawing.
Przedmiotem wynalazku jest także sposób jednoczesnego otrzymywania laktonów o wzorach 1 i 2 z optycznie czynnego alkoholu allilowego (S,E)-4-(4'-izopropylofenylo)-but-3-en-2-olu.The invention also relates to a method for the simultaneous preparation of lactones of formulas 1 and 2 from optically active allyl alcohol (S, E) -4- (4'-isopropylphenyl) -but-3-en-2-ol.
δ-jodo-Y-laktony o wzorach 1 i 2 wykazują aktywność antynowotworową in vitro wobec komórek ludzkiej linii białaczki (Jurkat), psiej białaczki B-komórkowej (GL-1) oraz psiego chłoniaka B-komórkowego (CLBL-1) i mogą znaleźć zastosowanie w farmacji jako składniki leków.The δ-iodo-Y-lactones of formulas 1 and 2 show in vitro anti-tumor activity against human leukemia cells (Jurkat), canine B-cell leukemia (GL-1) and canine B-cell lymphoma (CLBL-1) and can find use in pharmacy as components of drugs.
Dotychczas znany był racemiczny cis-5-(1-jodoetylo)-4-(4'-izopropylofenylo)-dihydrofuran-2-on wykazujący aktywność antynowotworową in vitro w stosunku do komórek psiej linii osteosarkomy (D17) oraz ludzkiej linii białaczki (Jurkat) (Gładkowski W., Skrobiszewski A., Mazur M., Siepka M., Pawlak A., Obmińska-Mrukowicz B., Białońska A., Poradowski D., Drynda A., Urbaniak M. Synthesis and anticancer activity of novel halolactones with β-aryl substituents from simple aromatic aldehydes. Tetrahedron, 2013, 69, 10414-10423).So far, racemic cis-5- (1-iodoethyl) -4- (4'-isopropylphenyl) -dihydrofuran-2-one has been known to show anti-tumor activity in vitro against canine osteosarcoma (D17) and human leukemia (Jurkat) cells (Gładkowski W., Skrobiszewski A., Mazur M., Siepka M., Pawlak A., Obmińska-Mrukowicz B., Białońska A., Poradowski D., Drynda A., Urbaniak M. Synthesis and anticancer activity of novel halolactones with β-aryl substituents from simple aromatic aldehydes. Tetrahedron, 2013, 69, 10414-10423).
Wynalazek dotyczy sposobu jednoczesnego wytwarzania na drodze syntezy chemicznej cis-(4R,5R,6S)-5-(1-jodoetylo)-4-(4'-izopropylofenylo)-dihydrofuran-2-onu o wzorze 1 i trans-(4R,5S,6R) 5-(1-jodoetylo)-4-(4'-izopropylofenylo)-dihydrofuran-2-onu o wzorze 2 z alkoholu allilowego (S,E)-4-(4'-izopropylofenylo)-but-3-en-2-olu będącego przedmiotem zgłoszenia patentowego nr P.405668. Istota wynalazku dotyczącego sposobu polega na tym, że z (S,E)-4-(4'-izopropylofenylo)-but-3-en-2-olu otrzymuje się mieszaninę jodolaktonów w sekwencji trzech następujących kolejno reakcji: przegrupowania Claisena w ortooctanowej modyfikacji Johnsona, hydrolizy powstałego estru w środowisku zasadowym i jodolaktonizacji otrzymanego kwasu. W ostatnim etapie syntezy jodolaktony wydziela się z mieszaniny reakcyjnej metodą chromatografii kolumnowej uzyskując cis-(4R,5R,6S)-5-(1-jodoetylo)-4-(4'-izopropylofenylo)-dihydrofuran-2-on oraz trans-(4R,5S,6R)-5-(1-jodoetylo)-4-(4'-izopropylofenylo)-dihydrofuran-2-on.The invention relates to a process for the simultaneous production by chemical synthesis of cis- (4R, 5R, 6S) -5- (1-iodoethyl) -4- (4'-isopropylphenyl) -dihydrofuran-2-one of the formula 1 and trans- (4R, 5S, 6R) 5- (1-iodoethyl) -4- (4'-isopropylphenyl) -dihydrofuran-2-one of formula 2 from allyl alcohol (S, E) -4- (4'-isopropylphenyl) -but-3 -en-2-ol which is the subject of the patent application No. P.405668. The essence of the invention regarding the method is that from (S, E) -4- (4'-isopropylphenyl) -but-3-en-2-ol a mixture of iodolactones is obtained in the sequence of three sequential reactions: Claisen rearrangement in the orthoacetate modification Johnson, hydrolysis of the resulting ester in a basic environment and iodolactonization of the obtained acid. In the last stage of the synthesis, iodolactones are separated from the reaction mixture by column chromatography to obtain cis- (4R, 5R, 6S) -5- (1-iodoethyl) -4- (4'-isopropylphenyl) -dihydrofuran-2-one and trans- ( 4R, 5S, 6R) -5- (1-iodoethyl) -4- (4'-isopropylphenyl) -dihydrofuran-2-one.
Korzystnie jest, gdy jako fazę stacjonarną w procesie chromatografii kolumnowej stosuje się żel krzemionkowy, a jako fazę ruchomą w procesie rozdziału jodolaktonów stosuje się mieszaninę heksan:aceton w stosunku objętościowym 20:1.Preferably, silica gel is used as the stationary phase in the process of column chromatography and a mixture of hexane: acetone in a volume ratio of 20: 1 as the mobile phase in the process of iodolactone separation.
Korzystnie jest także, gdy reakcję hydrolizy (S,E)-estru etylowego kwasu 3-(4'-izopropylofenylo)-heks-4-enowego prowadzi się w wodnoetanolowym roztworze NaOH.It is also preferred that the hydrolysis reaction of 3- (4'-isopropylphenyl) -hex-4-enoic acid ethyl (S, E) -ester is carried out in an aqueous ethanolic NaOH solution.
Korzystnie jest także, gdy jako reagent w reakcji jodolaktonizacji kwasu (S,E)-3-(4'-izopropylofenylo)-heks-4-enowego stosuje się roztwór jodu w jodku potasu, a reakcję prowadzi się w układzie dwufazowym eter dietylowy/0,5 M roztwór NaHCO3.It is also preferred that a solution of iodine in potassium iodide is used as a reagent in the iodolactonization reaction of (S, E) -3- (4'-isopropylphenyl) -hex-4-enoic acid, and the reaction is carried out in a two-phase system diethyl ether / 0 . 5 M NaHCO3 solution.
Zasadniczą zaletą wynalazku jest jednoczesne otrzymanie optycznie czynnych diastereoizomerycznych e-(4'-izopropylofenylo)-6-jodo-Y-laktonów o wzorach 1 i 2 wykazujących aktywność antynowotworową in vitro z bardzo wysokimi nadmiarami enancjomerycznymi (ee = 99%).The main advantage of the invention is the simultaneous preparation of optically active diastereomeric e- (4'-isopropylphenyl) -6-iodo-Y-lactones of formulas 1 and 2 showing in vitro anti-tumor activity with very high enantiomeric excesses (ee = 99%).
Tabela 1 przedstawia wyniki testów biologicznych in vitro dla otrzymanych laktonów w stosunku do wybranych linii komórek nowotworowych. Testy przeprowadzono według metody opisanej w literaturze (Ferrari M., Fornasiero M.C., Isetta A.M. MTT colorimetric assay for testing macrophage cytotoxic activity in vitro. Journal of Immunological Methods, 1990, 131, 165-172).Table 1 shows the results of the in vitro bioassays for the obtained lactones against selected tumor cell lines. The tests were performed according to the method described in the literature (Ferrari M., Fornasiero M.C., Isetta A.M. MTT colorimetric assay for testing macrophage cytotoxic activity in vitro. Journal of Immunological Methods, 1990, 131, 165-172).
T a b e l a 1T a b e l a 1
IC50 - stężenie związku, przy którym żywotność komórek wynosi 50%. SD - odchylenie standardowe.IC50 - concentration of compound at which cell viability is 50%. SD - standard deviation.
PL 221 299 B1PL 221 299 B1
Wynalazek jest bliżej objaśniony w przykładzie wykonania.The invention is explained in more detail in an exemplary embodiment.
PrzykładExample
W kolbie dwuszyjnej zaopatrzonej w termometr umieszcza się 1,90 g (0,01 mol) ( S,E)-4-(4'-izo3 propylofenylo)-but-3-en-2-olu (ee = 99%), 30 cm3 (0,164 mola) ortooctanu trietylu oraz kroplę kwasu propionowego. Mieszaninę ogrzewa się przez okres 24h w temperaturze 138°C pod chłodnicą zwrotną zaopatrzoną w odbieralnik monitorując przebieg reakcji za pomocą chromatografii cienkowarstwowej z zastosowaniem jako eluentu mieszaniny heksan:aceton w stosunku objętościowym 7:1. Produkt oczyszcza się przy użyciu chromatografii kolumnowej na żelu krzemionkowym, stosując jako eluent mieszaninę heksan:aceton w stosunku objętościowym 20:1. Otrzymuje się 2,18 g (84% wydajności teoretycznej) (S,E)-estru etylowego kwasu 3-(4'-izopropylofenylo)-heks-4-enowego.In a two-necked flask equipped with a thermometer are placed 1.90 g (0.01 mol) of (S, E) -4- (4'-iso- 3- propylphenyl) -but-3-en-2-ol (ee = 99%) , 30 cm 3 (0.164 mol) of triethyl orthoacetate and a drop of propionic acid. The mixture was heated for 24 hours at 138 ° C under a reflux condenser equipped with a receiver while monitoring the course of the reaction by thin layer chromatography using a 7: 1 v / v hexane: acetone mixture as eluent. The product was purified by column chromatography on silica gel using 20: 1 v / v hexane: acetone as eluent. 2.18 g (84% of theory) of 3- (4'-isopropylphenyl) -hex-4-enoic acid ethyl (S, E) -ester are obtained.
Dane fizyczne i spektroskopowe otrzymanego (S,E)-estru etylowego kwasu 3-(4'-izopropylofenylo)-heks-4-enowego są następujące:The physical and spectroscopic data of the obtained 3- (4'-isopropylphenyl) -hex-4-enoic acid ethyl (S, E) -ester are as follows:
Żółta ciecz, nD20 = 1,5000;Yellow liquid, nD 20 = 1.5000;
[a]D20 = + 8,35 (c = 4,0, CH2CI2, ee = 99%);[a] D 20 = + 8.35 (c = 4.0, CH 2 Cl 2, ee = 99%);
1H NMR (300 MHz, CDCI3) δ: 1,17 (t, J = 6,9 Hz, 3H, -OCH2CH3), 1,23 (d, J = 6,9 Hz, 6H, (CHhCH-), 1,65 (d, J = 5,7 Hz, 3H, CH3-6), 2,66 (m, 2H, CH2-2), 2,87 (septet, J = 6,9 Hz, 1H, (CHhCH-), 3,77 (m, 1H, H-3), 4,07 (kwartet, J = 6,9 Hz, 2H, -OCH2CH3), 5,50 (dublet kwartetów, J = 15,3 i 5,7 Hz, 1H, H-5), 5,59 (dublet dubletów kwartetów, J = 15,3; 6,9 i 0,9 Hz, 1H, H-4), 7,11-7,17 (dwa m, 4H, p-C6H4); 1 H NMR (300 MHz, CDCl3) δ: 1.17 (t, J = 6.9 Hz, 3H, -OCH2CH3), 1.23 (d, J = 6.9 Hz, 6H, (CHhCH-) 1.65 (d, J = 5.7Hz, 3H, CH3-6), 2.66 (m, 2H, CH2-2), 2.87 (septet, J = 6.9Hz, 1H, (CHhCH -), 3.77 (m, 1H, H-3), 4.07 (quartet, J = 6.9 Hz, 2H, -OCH2CH3), 5.50 (quartet doublet, J = 15.3 and 5, 7 Hz, 1H, H-5), 5.59 (doublet of quartet doublets, J = 15.3; 6.9 and 0.9 Hz, 1H, H-4), 7.11-7.17 (two m , 4H, p-C6H4);
13C NMR (75 MHz, CDCI3) δ: 14,22 (-OCH2CH), 17,96 (C-6), 24,04 ((CHhCH-), 33,71 ((CH)2CH), 41,19 (C-2), 44,68 (C-3), 60,28 (-OCH2CH3), 125,45 (C-5), 126,57 (C-2' i C-6'), 127,26 (C-3' i C-5'), 133,29 (C-4), 140,75 (C-1'), 147,00 (C-4'), 172,19 (C-1); 13 C NMR (75 MHz, CDCl 3) δ: 14.22 (-OCH 2 CH), 17.96 (C-6), 24.04 ((CHhCH-), 33.71 ((CH) 2CH), 41 , 19 (C-2), 44.68 (C-3), 60.28 (-OCH2CH3), 125.45 (C-5), 126.57 (C-2 'and C-6'), 127 , 26 (C-3 'and C-5'), 133.29 (C-4), 140.75 (C-1 '), 147.00 (C-4'), 172.19 (C-1 );
IR (film, cm-1): 1736 (s), 1623 (w), 1510 (m), 1251 (s), 1159 (m), 968 (m), 831 (m).IR (film, cm -1 ): 1736 (s), 1623 (i), 1510 (m), 1251 (s), 1159 (m), 968 (m), 831 (m).
Otrzymany (S,E)-ester etylowy kwasu 3-(4'-izopropylofenylo)-heks-4-enowego w ilości 2,18 g 3 (8,3 mmol) umieszcza się w kolbie okrągłodennej, rozpuszcza w 15 cm3 etanolu, a następnie dodaje 3 cm3 2,5%-owego wodnego roztworu NaOH. Mieszaninę reakcyjną ogrzewa się pod chłodnicą zwrotną, a postęp reakcji monitoruje się za pomocą chromatografii cienkowarstwowej z zastosowaniem jako eluentu mieszaniny heksan:aceton w stosunku objętościowym 7:1. Po całkowitym przereagowaniu substratu całość przenosi się do rozdzielacza i poprzez ekstrakcję chlorkiem metylenu 3 (dwukrotnie po 20 cm3) usuwa się zanieczyszczenia organiczne. Fazę wodną zakwasza się za pomocą 1M HCI wobec papierka wskaźnikowego, po czym ekstrahuje chlorkiem metylenu (trzykrotnie 3 po 40 cm3). Warstwę organiczną zobojętnia się solanką wobec papierka wskaźnikowego i osusza bezwodnym siarczanem magnezu. Po odsączeniu środka suszącego i odparowaniu rozpuszczalnika otrzymuje się 1,63 g (85% wydajności teoretycznej) kwasu (S,E)-3-(4'-izopropylofenylo)-heks-4-enowego.The obtained (S, E) -ethyl ester of 3- (4'-isopropylphenyl) -hex-4-enoic acid in the amount of 2.18 g of 3 (8.3 mmol) is placed in a round-bottom flask, dissolved in 15 cm 3 of ethanol, followed by the addition of 3 cm 3 of a 2.5% aqueous NaOH solution. The reaction mixture is heated to reflux and the progress of the reaction is monitored by thin layer chromatography using 7: 1 v / v hexane: acetone as eluent. When the substrate is completely consumed, it is transferred to a separating funnel and the organic impurities are removed by extraction with methylene chloride 3 (2 × 20 cm 3). The aqueous phase is acidified with 1M HCl against indicator paper and then extracted with methylene chloride ( 3 times 40 cm 3 ). The organic layer was neutralized with brine against a indicator paper and dried with anhydrous magnesium sulfate. After filtering off the drying agent and evaporating the solvent, 1.63 g (85% of theory) of (S, E) -3- (4'-isopropylphenyl) -hex-4-enoic acid are obtained.
Dane fizyczne i spektroskopowe otrzymanego kwasu (S,E)-3-(4'-izopropylofenylo)-heks-4-enowego są następujące:The physical and spectroscopic data of the obtained (S, E) -3- (4'-isopropylphenyl) -hex-4-enoic acid are as follows:
Brunatna ciecz, nD20 = 1,5183;Brown liquid, nD 20 = 1.5183;
[a]D20 = + 7,90 (c = 1,75, CH2CI2, ee = 99%);[a] D 20 = + 7.90 (c = 1.75, CH 2 Cl 2 , ee = 99%);
1H NMR (300 MHz, CDCI3) δ: 1,23 (d, J = 6,9 Hz, 6H, (CHhCH-), 1,65 (d, J = 5,1 Hz, 3H, CH3-6), 2,72 (m, 2H, CH2-2), 2,88 (septet, J = 6,9 Hz, 1H, (CHhCH-), 3,76 (m, 1H, H-3), 5,51 (dublet kwartetów, J = 15,3 i 5,1 Hz, 1H, H-5), 5,59 (dd, J = 15,3 i 6,9 Hz, 1H, H-4), 7,11-7,18 (dwa m, 4H, p-C6H4); 1 H NMR (300 MHz, CDCl 3) δ: 1.23 (d, J = 6.9 Hz, 6H, (CHhCH-), 1.65 (d, J = 5.1 Hz, 3H, CH3-6) , 2.72 (m, 2H, CH 2 -2), 2.88 (septet, J = 6.9 Hz, 1H, (CHhCH-), 3.76 (m, 1H, H-3), 5. 51 (quartet doublet, J = 15.3 and 5.1 Hz, 1H, H-5), 5.59 (dd, J = 15.3 and 6.9 Hz, 1H, H-4), 7.11 -7.18 (two m, 4H, b-C6H4);
13C NMR (75 MHz, CDCI3) δ: 17,97 (C-6), 24,01 ((CHhCH-), 33,70 ((CHhCH-), 40,61 (C-2), 44,14 (C-3), 125,72 (C-5), 126,66 (C-2' i C-6'), 127,22 (C-3' i C-5'), 133,02 (C-4), 140,45 (C-1'), 147,11 (C-4'), 177,71 (C-1); 13 C NMR (75 MHz, CDCl 3) δ: 17.97 (C-6), 24.01 ((CHhCH-), 33.70 ((CHhCH-), 40.61 (C-2), 44.14 (C-3), 125.72 (C-5), 126.66 (C-2 'and C-6'), 127.22 (C-3 'and C-5'), 133.02 (C -4), 140.45 (C-1 '), 147.11 (C-4'), 177.71 (C-1);
IR (film, cm-1): 3023-2670 (s,b), 1710 (s), 1511 (s), 1419 (s), 1287 (s), 1055 (m), 967 (m), 829 (m).IR (film, cm -1 ): 3023-2670 (s, b), 1710 (s), 1511 (s), 1419 (s), 1287 (s), 1055 (m), 967 (m), 829 ( m).
Uzyskany kwas (S,E)-3-(4'-izopropylofenylo)-heks-4-enowy (1,65 g, 7 mmol) umieszcza się w kolbie okrągłodennej, rozpuszcza w 20 cm3 eteru dietylowego, a następnie dodaje 10 cm3 0,5 M 3 The resulting (S, E) -3- (4'-isopropylphenyl) -hex-4-enoic acid (1.65 g, 7 mmol) is placed in a round bottom flask, dissolved in 20 cm 3 of diethyl ether, and then 10 cm 3 are added. 3 0.5 M 3
NaHCO3. Całość miesza się przez 1 h na mieszadle magnetycznym, po czym wkrapla powoli 20 cm3 wodnego roztworu I2 (3,5 g) w KI (10 g). Przebieg reakcji kontroluje się za pomocą chromatografii cienkowarstwowej z zastosowaniem jako eluentu mieszaniny heksan:aceton w stosunku objętościowym 4:1. Po całkowitym przereagowaniu substratu mieszaninę reakcyjną przenosi się do rozdzielacza, przemywa wodnym roztworem Na2S2O3 i rozdziela warstwy. Warstwę wodną ekstrahuje się ete3 rem dietylowym (dwukrotnie po 40 cm3). Połączone warstwy organiczne suszy się bezwodnym siarczanem magnezu, przesącza, a po odparowaniu rozpuszczalnika otrzymuje 1,94 g mieszaniny jodolaktonów, które rozdziela się metodą chromatografii kolumnowej na żelu krzemionkowym, jako eluentNaHCO3. The mixture was stirred for 1 h with a magnetic stirrer, and treated dropwise with 20 cm 3 of aqueous solution of I2 (3.5 g), KI (10 g). The progress of the reaction is monitored by thin-layer chromatography using a 4: 1 v / v hexane: acetone mixture as eluent. After the substrate reacted completely, the reaction mixture was transferred to a separating funnel, washed with an aqueous Na2S2O3 solution and the layers were separated. The aqueous layer is extracted with 3 rem of diethyl ether ( 2 × 40 cm 3 ). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and after evaporation of the solvent, 1.94 g of a mixture of iodolactones was obtained, which was separated by column chromatography on silica gel as eluent.
PL 221 299 B1 stosując mieszaninę heksan:aceton w stosunku objętościowym 20:1. Otrzymuje się 719 mg (28% wydajności teoretycznej) cis-(4R,5R,6S)-5-(1-jodoetylo)-4-(4'-izopropylofenylo)-dihydrofuran-2-onu oraz 231 mg (9% wydajności teoretycznej) trans-(4R,5S,6R)-5-(1-jodoetylo)-4-(4'-izopropylofenylo)dihydrofuran-2-onu.Using a 20: 1 v / v hexane: acetone mixture. 719 mg (28% of theory) of cis- (4R, 5R, 6S) -5- (1-iodoethyl) -4- (4'-isopropylphenyl) -dihydrofuran-2-one and 231 mg (9% of theory) are obtained. ) trans- (4R, 5S, 6R) -5- (1-iodoethyl) -4- (4'-isopropylphenyl) dihydrofuran-2-one.
Dane fizyczne i spektroskopowe otrzymanego cis-(4R,5R,6S)-5-(1-jodoetylo)-4-(4'-izopropylofenylo)-dihydrofuran-2-onu są następujące:The physical and spectroscopic data of the obtained cis- (4R, 5R, 6S) -5- (1-iodoethyl) -4- (4'-isopropylphenyl) -dihydrofuran-2-one are as follows:
Białe kryształy, t.t = 50-53°C;White crystals, mp = 50-53 ° C;
[a]D20 = + 1,97 (c = 0,81, CH2CI2, ee = 99%);[a] D 20 = + 1.97 (c = 0.81, CH 2 Cl 2, ee = 99%);
1H NMR (300 MHz, CDCI3) δ: 1,25 (d, J = 6.9 Hz, 6H, (CHa^CH-), 2,00 (d, J = 6,9 Hz, 3H, CH3-7), 2,70 (d, J = 17,7 Hz, 1H, jeden z CH2-3), 2,90 (septet, J = 6,9 Hz, 1H, (CHahCH-), 3,12 (dd, J = 17,7 i 8,4 Hz, 1H, jeden z CH2-3), 3,48 (dublet kwartetów, J = 10,8 i 6,9 Hz, 1H, H-6), 3,88 (dd, J = 8,4 i 5,1 Hz, 1H, H-4), 4,80 (dd, J = 10,8 i 5,1 Hz, 1H, H-5), 7,18 (m, 4H, p-C6H4); 1 H NMR (300 MHz, CDCl 3) δ: 1.25 (d, J = 6.9 Hz, 6H, (CHa ^ CH-), 2.00 (d, J = 6.9 Hz, 3H, CH3-7) , 2.70 (d, J = 17.7 Hz, 1H, one of CH2-3), 2.90 (septet, J = 6.9 Hz, 1H, (CHahCH-), 3.12 (dd, J = 17.7 and 8.4 Hz, 1H, one of CH2-3), 3.48 (quartet doublet, J = 10.8 and 6.9 Hz, 1H, H-6), 3.88 (dd, J = 8.4 and 5.1 Hz, 1H, H-4), 4.80 (dd, J = 10.8 and 5.1 Hz, 1H, H-5), 7.18 (m, 4H, p-C6H4);
13C NMR (75 MHz, CDCI3) δ: 23,64 (C-6), 23,83 i 23,89 ((CHshCH-), 25,52 (C-7), 33,69 ((CH3)2CH-), 38,92 (C-3), 44,57 (C-4), 87,91 (C-5), 126,73 (C-3' i C-5'), 128,45 (C-2' i C-6'), 134,47 (C-1'), 148,59 (C-4'), 176,69 (C-2); 13 C NMR (75 MHz, CDCl3) δ: 23.64 (C-6), 23.83 and 23.89 ((CHshCH-), 25.52 (C-7), 33.69 ((CH3) 2CH -), 38.92 (C-3), 44.57 (C-4), 87.91 (C-5), 126.73 (C-3 'and C-5'), 128.45 (C -2 'and C-6'), 134.47 (C-1 '), 148.59 (C-4'), 176.69 (C-2);
IR (KBr, cm-1): 1789 (s), 1511 (m), 1178 (s), 1135 (s), 962 (s), 838 (s), 527 (s).IR (KBr, cm -1 ): 1789 (s), 1511 (m), 1178 (s), 1135 (s), 962 (s), 838 (s), 527 (s).
Dane fizyczne i spektroskopowe otrzymanego trans-(4R,5S,6R)-5-(1-jodoetylo)-4-(4'-izopropylofenylo)-dihydrofuran-2-onu są następujące:The physical and spectroscopic data of the obtained trans- (4R, 5S, 6R) -5- (1-iodoethyl) -4- (4'-isopropylphenyl) -dihydrofuran-2-one are as follows:
Gęsta ciecz;Thick liquid;
[α]0 = -8,26 (c = 2,5; CH2CI2, ee = 99%);[α] 0 = -8.26 (c = 2.5; CH2Cl2, ee = 99%);
1H NMR (300 MHz, CDCI3) δ: 1,24 (d, J = 6,9 Hz, 6H, (CHbhCH-), 1,86 (d, J = 7,2 Hz, 3H, CH3-7), 2,66 (dd, J = 18,3 i 6,6 Hz, 1H, jeden z CH2-3), 2,90 (septet, J = 6,9 Hz, 1H, (CH3)2CH-), 3,13 (dd, J = 18,3 i 9,9 Hz, 1H, jeden z CH2-3), 3,60 (ddd, J = 9,9, 6,6 i 5,4 Hz, 1H, H-4), 4,26 (t, J = 5,4 Hz, 1H, H-5), 4,38 (kwartet dubletów, J = 7,2 i 5,4 Hz, 1H, H-6), 7,16-7,24 (dwa m, 4H, p-C6H4); 1 H NMR (300 MHz, CDCl 3) δ: 1.24 (d, J = 6.9 Hz, 6H, (CHbhCH-), 1.86 (d, J = 7.2 Hz, 3H, CH3-7) , 2.66 (dd, J = 18.3 and 6.6 Hz, 1H, one of CH 2 -3), 2.90 (septet, J = 6.9 Hz, 1H, (CH3) 2 CH-) 3.13 (dd, J = 18.3 and 9.9 Hz, 1H, one of CH 2 -3), 3.60 (ddd, J = 9.9, 6.6 and 5.4 Hz, 1H , H-4), 4.26 (t, J = 5.4 Hz, 1H, H-5), 4.38 (doublet quartet, J = 7.2 and 5.4 Hz, 1H, H-6) , 7.16-7.24 (two m, 4H, p-C6H4);
13C NMR (75 MHz, CDCI3) δ: 23,35 (C-7), 23,88 ((CH3)2CH-), 28,27 (C-6), 33,72 ((CH3)2CH-), 37,71 (C-3), 44,98 (C-4), 89,63 (C-5), 126,93 (C-2' i C-6'), 127,34 (C-3' i C-5'), 138,58 (C-1'), 148,51 (C-4'), 174,96 (C-2); 13 C NMR (75 MHz, CDCl3) δ: 23.35 (C-7), 23.88 ((CH3) 2 CH-), 28.27 (C-6), 33.72 ((CH3) 2 CH -), 37.71 (C-3), 44.98 (C-4), 89.63 (C-5), 126.93 (C-2 'and C-6'), 127.34 (C -3 'and C-5'), 138.58 (C-1 '), 148.51 (C-4'), 174.96 (C-2);
IR (film, cm-1): 1785 (s), 1513 (m), 1184 (s), 1150 (s), 1028 (s), 829 (m), 564 (s).IR (film, cm -1 ): 1785 (s), 1513 (m), 1184 (s), 1150 (s), 1028 (s), 829 (m), 564 (s).
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