HRP920760A2 - Process for the preparation of benzocycloalkenyl dihydroxy alkane acid derivatives and medicaments containing them - Google Patents
Process for the preparation of benzocycloalkenyl dihydroxy alkane acid derivatives and medicaments containing them Download PDFInfo
- Publication number
- HRP920760A2 HRP920760A2 HRP-124/90A HRP920760A HRP920760A2 HR P920760 A2 HRP920760 A2 HR P920760A2 HR P920760 A HRP920760 A HR P920760A HR P920760 A2 HRP920760 A2 HR P920760A2
- Authority
- HR
- Croatia
- Prior art keywords
- formula
- phenyl
- compound
- dihydroxy
- erythro
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 41
- 239000002253 acid Substances 0.000 title claims description 18
- 230000008569 process Effects 0.000 title claims description 7
- 239000003814 drug Substances 0.000 title description 6
- 238000002360 preparation method Methods 0.000 title description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 169
- -1 alkyl radicals Chemical class 0.000 claims description 70
- 125000001424 substituent group Chemical group 0.000 claims description 66
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 63
- 125000004432 carbon atom Chemical group C* 0.000 claims description 47
- 239000002904 solvent Substances 0.000 claims description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 29
- 150000002148 esters Chemical class 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- 229910052731 fluorine Inorganic materials 0.000 claims description 22
- 238000010992 reflux Methods 0.000 claims description 20
- 125000000422 delta-lactone group Chemical group 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- 239000011737 fluorine Substances 0.000 claims description 17
- 239000011734 sodium Substances 0.000 claims description 17
- 229910052801 chlorine Inorganic materials 0.000 claims description 16
- 229910052708 sodium Inorganic materials 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 239000000460 chlorine Substances 0.000 claims description 15
- 150000003254 radicals Chemical class 0.000 claims description 15
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 10
- 150000001299 aldehydes Chemical class 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 9
- 150000007513 acids Chemical class 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 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 7
- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 7
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 125000004434 sulfur atom Chemical group 0.000 claims description 6
- 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 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 5
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000012442 inert solvent Substances 0.000 claims description 4
- 238000007273 lactonization reaction Methods 0.000 claims description 4
- HHQJWDKIRXRTLS-UHFFFAOYSA-N n'-bromobutanediamide Chemical compound NC(=O)CCC(=O)NBr HHQJWDKIRXRTLS-UHFFFAOYSA-N 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- 238000006722 reduction reaction Methods 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical group ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 claims description 3
- 238000006136 alcoholysis reaction Methods 0.000 claims description 3
- 238000007098 aminolysis reaction Methods 0.000 claims description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 150000002940 palladium Chemical class 0.000 claims description 3
- 238000005809 transesterification reaction Methods 0.000 claims description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 claims description 2
- 238000006640 acetylation reaction Methods 0.000 claims description 2
- 125000005250 alkyl acrylate group Chemical group 0.000 claims description 2
- 230000029936 alkylation Effects 0.000 claims description 2
- 238000005804 alkylation reaction Methods 0.000 claims description 2
- 238000010531 catalytic reduction reaction Methods 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims description 2
- 239000008139 complexing agent Substances 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims 2
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 claims 1
- GIAYJEKLYCIMQS-UHFFFAOYSA-N 2-[(2-methoxyphenyl)-diphenyl-$l^{5}-phosphanylidene]acetic acid Chemical compound COC1=CC=CC=C1P(=CC(O)=O)(C=1C=CC=CC=1)C1=CC=CC=C1 GIAYJEKLYCIMQS-UHFFFAOYSA-N 0.000 claims 1
- 229930194542 Keto Natural products 0.000 claims 1
- 230000021736 acetylation Effects 0.000 claims 1
- 125000005233 alkylalcohol group Chemical group 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 claims 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims 1
- 229940125904 compound 1 Drugs 0.000 claims 1
- 230000006196 deacetylation Effects 0.000 claims 1
- 238000003381 deacetylation reaction Methods 0.000 claims 1
- XUYJLQHKOGNDPB-UHFFFAOYSA-N phosphonoacetic acid Chemical compound OC(=O)CP(O)(O)=O XUYJLQHKOGNDPB-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 69
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 67
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 50
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- 239000000243 solution Substances 0.000 description 31
- 238000005481 NMR spectroscopy Methods 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 238000004458 analytical method Methods 0.000 description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 229910052938 sodium sulfate Inorganic materials 0.000 description 17
- 235000011152 sodium sulphate Nutrition 0.000 description 17
- 239000000543 intermediate Substances 0.000 description 16
- 239000003921 oil Substances 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 14
- 239000000126 substance Substances 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 13
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 150000001408 amides Chemical class 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 125000005843 halogen group Chemical group 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-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 8
- 229910052763 palladium Inorganic materials 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- 229920005989 resin Polymers 0.000 description 7
- 239000011347 resin Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 5
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical class O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 235000017550 sodium carbonate Nutrition 0.000 description 5
- 239000008096 xylene Substances 0.000 description 5
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 4
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 4
- 125000005530 alkylenedioxy group Chemical group 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 4
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 4
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical class CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 3
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 3
- 229960004844 lovastatin Drugs 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- KJTLQQUUPVSXIM-ZCFIWIBFSA-N (R)-mevalonic acid Chemical compound OCC[C@](O)(C)CC(O)=O KJTLQQUUPVSXIM-ZCFIWIBFSA-N 0.000 description 2
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 2
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- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
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- 230000000843 anti-fungal effect Effects 0.000 description 2
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- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
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- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 description 2
- 239000005516 coenzyme A Substances 0.000 description 2
- 229940093530 coenzyme a Drugs 0.000 description 2
- 239000012024 dehydrating agents Substances 0.000 description 2
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
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- 239000005457 ice water Substances 0.000 description 2
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Područje tehnike The field of technology
Izum je iz područja organske i farmaceutske kemije. The invention is from the field of organic and pharmaceutical chemistry.
Tehnički problem Technical problem
Ovaj izum se odnosi na nove derivate benzocikloalkenil dihidroksi alkanskih kiselina. postupak za njihovo dobivanje i lijekove koji ih sadrže. This invention relates to new derivatives of benzocycloalkenyl dihydroxy alkanoic acids. the procedure for obtaining them and the medicines containing them.
Stanje tehnike State of the art
Poznato je da određeni derivati dihidroksi-3,5-metil-3-pentenoinske kiseline, poznate pod imenom "mevalonska kiselina" su inliibirani enzim hidroksi-3-metil-glutaril koenzim A reduktaze, odgovorne za biosintezu kolesterola (vidi SINGER et Coll. Proc. Se. Exper. Biol. Med, 102,275, 1959). It is known that certain derivatives of dihydroxy-3,5-methyl-3-pentenoic acid, known as "mevalonic acid" inhibit the enzyme hydroxy-3-methyl-glutaryl coenzyme A reductase, responsible for cholesterol biosynthesis (see SINGER et Coll. Proc . Se. Exper. Biol. Med, 102,275, 1959).
Nedavno je derivat mevalonske kiseline pod imenom "Lovastatin", bivši "Mevinolin" predložen kao aktivni princip medikamentskih preparata primjenjivih u tretiranju hiperkolesterolemija (vidi, patent US 4231938 u ime društva MERCK). Recently, a derivative of mevalonic acid under the name "Lovastatin", formerly "Mevinolin", has been proposed as the active principle of medicinal preparations applicable in the treatment of hypercholesterolemia (see, patent US 4231938 in the name of the company MERCK).
Opis rješenja tehničkog problema Description of the solution to the technical problem
Sada je slučajno nađeno da novi derivati benzo ciklo alkenil dihidroksi alkanskih kiselina imaju hipokolesteroelirninatorske, antitrombotične i antifongetične osobine. It has now been found by chance that new derivatives of benzocycloalkenyl dihydroxy alkanoic acids have hypocholesterol-inducing, antithrombotic and antifungal properties.
Točnije, izum se odnosi na spojeve formule I More specifically, the invention relates to compounds of formula I
[image] [image]
u kojoj X predstavlja metilenski niz -CH2-, atom kisika ili sumpora, R1 i R2 mogu također biti identični ili različiti i predstavljaju atome vodika ili alkil radikale sa 1 - 3 atoma ugljika. R1 i R2 mogu također zajedno graditi alkilenski niz -(CH2)n-, koji može biti simetrično supstituiran s jednim ili dva alkil radikala koji sadrže 1-3 atoma ugljika i n može imati vrijednost 4 ili 5. in which X represents a methylene series -CH2-, an oxygen or sulfur atom, R1 and R2 may also be identical or different and represent hydrogen atoms or alkyl radicals with 1-3 carbon atoms. R1 and R2 can also form together an alkylene chain -(CH2)n-, which can be symmetrically substituted with one or two alkyl radicals containing 1-3 carbon atoms and n can have a value of 4 or 5.
R3 i R4 koji mogu biti identični ili različiti i predstavljaju atome vodika, atome halogena (fluor, klor ili brom), radikale: trifluorometil, N,N-dialkilamino sa 1-3 atoma ugljika, alkil sa 1-4 atoma ugljika, alkoksi sa 1 - 5 atoma ugljika, alkiltio sa 1-3 atoma ugljika ili fenil eventualno supstituiran s dva ili više supstituenata koji mogu biti identični ili različiti i predstavljaju radikale: alkil sa 1-3 atoma ugljika, alkoksi sa 1-3 atoma ugljika ili halogene atome (fluora ili klora), u slučaju kada jedan od supstituenata R3 ili R4 predstavlja radikale: trifluorometil, N,N-dialkilamino, fenil ili supstituirani fenil, ovaj se nalazi na vrhovima 3', 4' ili 5' (meta ili para) prema formuli I, a drugi supstituent predstavlja atom vodika. R3 and R4 which can be identical or different and represent hydrogen atoms, halogen atoms (fluorine, chlorine or bromine), radicals: trifluoromethyl, N,N-dialkylamino with 1-3 carbon atoms, alkyl with 1-4 carbon atoms, alkoxy with 1 - 5 carbon atoms, alkylthio with 1-3 carbon atoms or phenyl optionally substituted with two or more substituents that can be identical or different and represent radicals: alkyl with 1-3 carbon atoms, alkoxy with 1-3 carbon atoms or halogen atoms (fluorine or chlorine), in the case when one of the substituents R3 or R4 represents radicals: trifluoromethyl, N,N-dialkylamino, phenyl or substituted phenyl, this is located at the ends 3', 4' or 5' (meta or para) according to formula I, and the second substituent represents a hydrogen atom.
R5 i R6, koji mogu biti identični ili različiti, predstavljaju atome vodika, atome halogena (fluor, klor ili brom), radikale: trifluorometil, alkil sa 1-3 atoma ugljika, alkoksi s 1-3 atoma ugljikaili fenil radikal koji može biti supstituiran s dva ili više supstituenata koji mogu biti identični ili različiti i mogu biti radikali: alkil sa 1 - 3 atoma ugljika, alkoksi sa 1-3 atoma ugljika ili halogeni (klor ili fluor) u slučaju kada jedan od supstituenata R5 ili R6 predstavlja radikale: trifluorometil, fenil ili supstituirani fenil, ovaj se nalazi na vrhovima 6 ili 7 prema formuli I, a drugi supstituent je atom vodika. R5 and R6, which can be identical or different, represent hydrogen atoms, halogen atoms (fluorine, chlorine or bromine), radicals: trifluoromethyl, alkyl with 1-3 carbon atoms, alkoxy with 1-3 carbon atoms or a phenyl radical that can be substituted with two or more substituents that can be identical or different and can be radicals: alkyl with 1-3 carbon atoms, alkoxy with 1-3 carbon atoms or halogens (chlorine or fluorine) in the case when one of the substituents R5 or R6 represents radicals: trifluoromethyl, phenyl or substituted phenyl, this is located at the peaks 6 or 7 according to formula I, and the second substituent is a hydrogen atom.
Supstituenti R3 i R4 odnosno R5 i R6 podnednako mogu graditi cjelinu pod uvjetom da se nalaze na dva susjedna vrha, diradikale: dietilen, alkilen ih alkilendioksi odgovarajućih formula: -CH=CH-CH=CH-, -(CH2)m-, -O(CH2)PO- u kojima m može uzeti vrijednost 3 ih 4, a p vrijednost 1 ih 2 i kada R3 i R4 odnosno R5 i R6 grade alkilendioksi diradikal, ovaj se nalazi vezan na vrhovima 3' i 4' ih 4' i 5' odnosno 6 i 7, prema formuli 1. Substituents R3 and R4, i.e. R5 and R6, can form a whole at the same time, provided that they are located on two adjacent vertices, diradicals: diethylene, alkylene and alkylenedioxy of the corresponding formulas: -CH=CH-CH=CH-, -(CH2)m-, - O(CH2)PO- in which m can take the value 3 and 4, and p the value 1 and 2, and when R3 and R4 or R5 and R6 form an alkylenedioxy diradical, it is attached to the ends 3' and 4' and 4' and 5 ' or 6 and 7, according to formula 1.
Supstituenti R7 i R8 predstavljaju svaki atom vodika ih grade zajedno s postojećom vezom C-C dvostruku vezu trans geometrije (E). Substituents R7 and R8 each represent a hydrogen atom, forming together with the existing C-C bond a double bond of trans geometry (E).
Supstituenti R9 i R10 predstavljaju svaki atom vodika ih grade zajedno dialkilmetilenski ostatak sa 1 - 3 atoma ugljika. Substituents R9 and R10 each represent a hydrogen atom and together they form a dialkylmethylene residue with 1 - 3 carbon atoms.
R11 može predstavljati hidroksilni radikal pri čemu su spojevi formule I karboksilne kiseline u slobodnom obliku. R11 can represent a hydroxyl radical, whereby the compounds of formula I are carboxylic acids in free form.
Spojevi formule I mogu se dobiti također u obliku estera i amida koji podnednako čine dio izuma. The compounds of formula I can also be obtained in the form of esters and amides, which also form part of the invention.
Fiziološki prihvatljivi naročito su poželjni esteri i amidi formule I, u kojoj supstituent R11 predstavlja radikale alkoksi sa 1 - 4 atoma ugljika, benziloksi, alkilamino ih N,N-dialkilamino sa 1 - 3 atoma ugljika, imino sa 4 - 6 atoma ugljika, cikloalkilamino sa 3 do 6 atoma ugljika ih radikale amino ih benzilamino. Physiologically acceptable esters and amides of formula I, in which the substituent R11 represents the radicals alkoxy with 1 - 4 carbon atoms, benzyloxy, alkylamino and N,N-dialkylamino with 1 - 3 carbon atoms, imino with 4 - 6 carbon atoms, cycloalkylamino with 3 to 6 carbon atoms, amino and benzylamino radicals.
Spojevi formule I u obliku soli, tj. formule u kojoj supstituent R11 predstavlja ostatak formule +OM+ u kojoj M+ označava farmaceutski prihvatljiv kation čine također dio izuma; među ovima najpoželjnije su soli natrija, kalija, magnezija ili amonija. Compounds of the formula I in the form of salts, i.e. the formula in which the substituent R11 represents a residue of the formula +OM+ in which M+ denotes a pharmaceutically acceptable cation are also part of the invention; among these, sodium, potassium, magnesium or ammonium salts are most preferred.
Spojevi formule I mogu postojati u obliku delta-laktona, kada supstituent R11 gradi sa supstituentom R9 jednu jednostavnu vezu; spojevi formule I u obliku delta-laktona podjednako čine dio izuma. Compounds of formula I can exist in the form of delta-lactone, when the substituent R11 forms a simple bond with the substituent R9; compounds of formula I in delta-lactone form equally form part of the invention.
Prema poželjnom obliku predmet izuma su spojevi formule I u kojoj su supstituenti R1 i R2 identični ili grade jedan alkilenski lanac: -(CH2)n-, nesupstituiran gdje broj je N 4 ili 5. According to the preferred form, the subject of the invention are compounds of formula I in which the substituents R1 and R2 are identical or form one alkylene chain: -(CH2)n-, unsubstituted where the number N is 4 or 5.
Izvanredno značenje supstituenata R1 i R2 kada ovi označavaju alkil radikale sa 1-3 atoma ugljika je npr. metil. The extraordinary meaning of the substituents R1 and R2 when they denote alkyl radicals with 1-3 carbon atoms is, for example, methyl.
Izvanredna vrijednost n kada supstituenti R1 i R2 grade etilenski lanac -(CH2)n-, je na primjer 4. An extraordinary value of n when the substituents R1 and R2 build an ethylene chain -(CH2)n- is, for example, 4.
Izvanredna značenja za jedan ili oba supstituenta R3 i R4 su data u daljnjem tekstu. Extraordinary meanings for one or both of the substituents R 3 and R 4 are given below.
- kada predstavlja halogen atom (fluor ili klor); - when it represents a halogen atom (fluorine or chlorine);
- kada predstavlja alkil radikal sa 1 - 4 atoma ugljika; metil ili etil; - when it represents an alkyl radical with 1-4 carbon atoms; methyl or ethyl;
- kada predstavlja alkoksi radikal sa 1 - 5 atoma ugljika: metoksi ili etoksi; - when it represents an alkoxy radical with 1 - 5 carbon atoms: methoxy or ethoxy;
- kada predstavlja alkiltio radikal sa 1 do 3 atoma ugljika: metiltio; - when it represents an alkylthio radical with 1 to 3 carbon atoms: methylthio;
- kada predstavlja supstiuirani fenil radikal: fenil para supstituiran s atomom fluora, metil radikalom ili metoksi radikalom. - when it represents a substituted phenyl radical: phenyl para substituted with a fluorine atom, a methyl radical or a methoxy radical.
Izvanredna vrijednost m kada supstituenti R3 i R4 grade diradikal: -(CH2)m- je na primjer 4. The extraordinary value of m when the substituents R3 and R4 form a diradical: -(CH2)m- is, for example, 4.
Izvanredna vrijednost p kada supstituenti R3 i R4 grade diradikal alkilendioksi: -O(CH2)PO- je naprimjer 1. The extraordinary value of p when the substituents R3 and R4 form an alkylenedioxy diradical: -O(CH2)PO- is, for example, 1.
Izvanredno pogodni rasporedi radikala R3 i R4 su, naprimjer, realizirani kada R3 i R44 predstavljaju radikale alkil sa 1 do 4 atoma ugljika i/ili halogene atome, ili jedan halogen atom i jedan alkoksi radikal sa 1 do 5 atoma ugljika, kada je jedan od supstituenata R3 i R4 atom halogena ih alkil radikal sa 1 do 4 atoma ugljika ih alkoksi radikal sa 1 - 5 atoma ugljika ih alkiltio radikal sa 1 - 3 atoma ugljika, a drugi je atom vodika. Extremely suitable arrangements of radicals R3 and R4 are, for example, realized when R3 and R44 represent alkyl radicals with 1 to 4 carbon atoms and/or halogen atoms, or one halogen atom and one alkoxy radical with 1 to 5 carbon atoms, when one of substituents R3 and R4 are a halogen atom, an alkyl radical with 1 to 4 carbon atoms, an alkoxy radical with 1-5 carbon atoms, an alkylthio radical with 1-3 carbon atoms, and the second is a hydrogen atom.
Specifično pogodni rasporedi radikala R3 i R4 su, na primjer realizirani kada ovi predstavljaju metil radikale u položaju 3' i 5', atom fluora u položaju 4' i metil radikal u položaju 3', atome fluora u položaju 3' i 4', atom fluora u položaju 3' ili 4' i atom vodika, metil ih etil radikal u položaju 4' i atom vodika, metoksi radikal u položaju 3' ili 4' i atom vodika, atom klora u položaju 3' ih 4' i atom vodika ih atome vodika. Izvanredno značenje nekog od supstituenata R5 i R6 je na primjer: Specifically suitable arrangements of the radicals R3 and R4 are, for example, realized when these represent methyl radicals in position 3' and 5', a fluorine atom in position 4' and a methyl radical in position 3', fluorine atoms in position 3' and 4', an atom fluorine in position 3' or 4' and a hydrogen atom, methyl and ethyl radical in position 4' and a hydrogen atom, methoxy radical in position 3' or 4' and a hydrogen atom, chlorine atom in position 3' and 4' and a hydrogen atom hydrogen atoms. An extraordinary meaning of one of the substituents R5 and R6 is, for example:
- kada predstavlja atom halogena: (fluor ih klor); - when it represents a halogen atom: (fluorine and chlorine);
- kada predstavlja alkil radikal sa 1-3 atoma ugljika: metoksi; - when it represents an alkyl radical with 1-3 carbon atoms: methoxy;
- kada predstavlja supstituirani fenil radikal u para položaju s atomom fluora ili klora ili s metoksi radikalom. - when it represents a substituted phenyl radical in the para position with a fluorine or chlorine atom or with a methoxy radical.
Izvanredna vrijednost m kada supstituenti R5 i R6 grade zajedno alkilenski lanac -(CH2)m- je na primjer vrijednost 4. An extraordinary value of m when the substituents R5 and R6 build together an alkylene chain -(CH2)m- is, for example, the value 4.
Izvanredna vrijednost p kada supstituenti R5 i R6 grade zajedno alkilendioksi lanac -O(CH2)pO-je vrijednost 1. The extraordinary value of p when the substituents R5 and R6 build together the alkylenedioxy chain -O(CH2)pO is the value 1.
Izvanredno pogodni rasporedi radikala R5 i R6 su realizirani, naprimjer, kada oni predstavljaju atome halogena (fluor, klor, brom) alkil radikale sa 1 - 3 atoma ugljika ili alkoksi radikale sa 1 - 3 atoma ugljika ili kada jedan od supstituenata R5 i R6 predstavlja atom halogena koji može biti fluor, klor ili brom ili predstavlja alkil radikal sa 1 - 3 atoma ugljika ili alkoksi radikal sa 1 - 3 atoma ugljika, a drugi supstituent je atom vodika. Extremely suitable arrangements of radicals R5 and R6 are realized, for example, when they represent halogen atoms (fluorine, chlorine, bromine), alkyl radicals with 1 - 3 carbon atoms or alkoxy radicals with 1 - 3 carbon atoms or when one of the substituents R5 and R6 represents a halogen atom which can be fluorine, chlorine or bromine or represents an alkyl radical with 1-3 carbon atoms or an alkoxy radical with 1-3 carbon atoms, and the second substituent is a hydrogen atom.
Specifično pogodni rasporedi radikala R5 i R6 su, na primjer, realizirani kada oni predstavljaju metil radikale u položajima 5 i 7, atom klora u položaju 6 i atom vodika, metoksi radikal u položaju 6 i atom vodika, atom fluora u položaju 6 ili 7 atom vodika, radikal metil u položaju 6 ili 7 i atom vodika, radikal fluoro-4 fenil u položaju 6 ili 7 i atom vodika, ili dva atoma vodika. Specifically suitable arrangements of radicals R5 and R6 are, for example, realized when they represent methyl radicals in positions 5 and 7, a chlorine atom in position 6 and a hydrogen atom, a methoxy radical in position 6 and a hydrogen atom, a fluorine atom in position 6 or a 7 atom hydrogen, a methyl radical in position 6 or 7 and a hydrogen atom, a fluoro-4 phenyl radical in position 6 or 7 and a hydrogen atom, or two hydrogen atoms.
Izvanredno značenje supstituenata R9 i R10 koji grade dialkilmetilenski ostatak je na primjer dimetilmetilen. An extraordinary meaning of the substituents R9 and R10 that form a dialkylmethylene residue is, for example, dimethylmethylene.
Izvanredna značenja supstituenta R11 su dana u daljnjem tekstu: Extraordinary meanings of the substituent R11 are given in the following text:
- kada on predstavlja alkoksi radikal sa 1 - 4 atoma ugljika: metoksi ili etoksi; - when it represents an alkoxy radical with 1 - 4 carbon atoms: methoxy or ethoxy;
- kada on predstavlja alkilamino radikal sa 1 - 3 atoma ugljika; - when it represents an alkylamino radical with 1-3 carbon atoms;
- kada on predstavlja radikal N,N-dialkilamino sa 1 - 3 atoma ugljika: dietilamino; - when it represents the N,N-dialkylamino radical with 1-3 carbon atoms: diethylamino;
- kada on predstavlja imino radikal sa 4 do 6 atoma ugljika: pirolidino. - when it represents an imino radical with 4 to 6 carbon atoms: pyrrolidino.
Spojevi formule 1 u kojoj supstituenti R7 i R8 grade zajedno jednu vezu su od poželjnih spojeva formule 1 čiji supstituenti R7 i R8 svaki predstavljaju atom vodika. Compounds of formula 1 in which the substituents R7 and R8 together form one bond are among the preferred compounds of formula 1 whose substituents R7 and R8 each represent a hydrogen atom.
Uzimajući sve drugo isto, spojevi formule I, u kojoj supstituenti R9 i R10 označavaju svaki atom vodika su poželjniji od spojeva u kojima supstituenti R9 i R10 grade dialkihnetilenski ostatak. All else being equal, compounds of formula I in which the substituents R9 and R10 each represent a hydrogen atom are preferred over compounds in which the substituents R9 and R10 form a dialkylene residue.
Uzimajući sve drugo isto, nelaktonski spojevi formule I su poželjniji od delta-laktonskih spojeva. All else being equal, the non-lactone compounds of formula I are preferred over the delta-lactone compounds.
Među spojevima formule I, nelaktonski spojevi, esteri, amidi i soli su uopćeno poželjniji od slobodnih kiselina. Among the compounds of formula I, non-lactone compounds, esters, amides and salts are generally preferred over the free acids.
Uzimajući sve drugo isto, eritro steroizomeri su poželjniji od treo steroizomera (termini eritro i treo se odnose na relativnu orijentaciju grupa OR9 i OR10). All else being equal, erythro stereoisomers are preferred over threo stereoisomers (the terms erythro and threo refer to the relative orientation of the OR9 and OR10 groups).
Među spojevima delta-laktonskim formule I, trans stereoizomeri su poželjniji od cis steroizomera (termini cis i trans se odnose na relativne položaje aksijalne ili ekvatorijalne dva supstituenta delta-laktonskog prstena). Among the delta-lactone compounds of formula I, trans stereoisomers are preferred over cis stereoisomers (the terms cis and trans refer to the relative positions of the axial or equatorial two substituents of the delta-lactone ring).
Specifične grupe spojeva izuma koji su izvanredno poželjne, podrazumijevaju spojeve formule I u kojoj: Specific groups of compounds of the invention that are extremely desirable include compounds of formula I in which:
A) X označava atome kisika ili sumpora ili metilenski lanac, R3 i R4 svaki označavaju metil radikal ili grade zajedno tetrametilenski lanac -(CH2)4-, samo jedan od radikala R3 i R4 grade zajedno vezu i R9 i R10 svaki predstavlja atom vodika. A) X denotes oxygen or sulfur atoms or a methylene chain, R3 and R4 each denote a methyl radical or form together a tetramethylene chain -(CH2)4-, only one of the radicals R3 and R4 form a bond together and R9 and R10 each represent a hydrogen atom.
B) X, R1, R2, R7, R8, R9 i R10 imaju značenja dana neposredno naprijed u A), jedan od supstituenata R3 i R4 označava atom vodika, a drugi atom fluora ili klora i samo jedan od supstituenata R3 i R4 označava atom vodika. B) X, R1, R2, R7, R8, R9 and R10 have the meanings given immediately above in A), one of the substituents R3 and R4 represents a hydrogen atom and the other a fluorine or chlorine atom and only one of the substituents R3 and R4 represents an atom of hydrogen.
C) X, R1, R2, R7, R8, R9 i R1 imaju značenja koja su definirana naprijed u A), jedan od supstituenata R3 i R4 je atom vodika, a drugi označava atom fluora ili klora i svaki od supstituenata R3 i R4 označava atom vodika. C) X, R1, R2, R7, R8, R9 and R1 have the meanings defined above in A), one of the substituents R3 and R4 is a hydrogen atom and the other represents a fluorine or chlorine atom and each of the substituents R3 and R4 represents hydrogen atom.
D) X, R1, R2, R7, R8, R9 i R10 imaju značenja specifično definirana u A), dva supstituenta R3 i R4 su atomi vodika i samo jedan od supstituenata R3 i R4 označava atom vodika. D) X, R 1 , R 2 , R 7 , R 8 , R 9 and R 10 have the meanings specifically defined in A), two substituents R 3 and R 4 are hydrogen atoms and only one of the substituents R 3 and R 4 denotes a hydrogen atom.
E) X, R3, R4, R5, R6, R7, R8, R9, R10 imaju značenja definirana naprijed u C), a R3 i R4 grade zajedno tetrametilenski lanac -(CH2)4-. E) X, R3, R4, R5, R6, R7, R8, R9, R10 have the meanings defined above in C), and R3 and R4 together form a tetramethylene chain -(CH2)4-.
F) X, R1, R2, R7, R8, R9, R10 imaju identična značenja navedena naprijed u E) i svaki od supstituenata R3 i R4 označava atom vodika. F) X, R1, R2, R7, R8, R9, R10 have identical meanings given above in E) and each of the substituents R3 and R4 represents a hydrogen atom.
Svaki spoj formule I sadrži barem dva centra asimetrije koja su atomi ugljika koji nose ostatke OR9 i OR10, kada supstituenti R9 i R10 predstavljaju svaki atom vodika ili zajedno grade dialkilmetilenski ostatak ili koja su ugljik hidroksil i tercijarni atom ugljika postavljen u položaju alfa intracikličnog atoma kisika dok supstituenti R9 i R10 grade zajedno vezu. Each compound of formula I contains at least two centers of asymmetry which are the carbon atoms bearing the residues OR9 and OR10, when the substituents R9 and R10 each represent a hydrogen atom or together form a dialkylmethylene residue or which are the hydroxyl carbon and the tertiary carbon atom placed in the alpha position of the intracyclic oxygen atom while the substituents R9 and R10 form a bond together.
Kako svaki spoj, slobodna kiselina, ester, amid, sol ili delta-lakton dan formulom I može postojati u obliku barem četiri steroizomera dva i dva diasteroizomera, koristi se uobičajene konfiguracijske oznake R i S sa RR, SS, RS i SR ili za oblik racematskih smjesa diasteroizomera, RR-SS i RS-SR. Since each compound, free acid, ester, amide, salt or delta-lactone given by formula I can exist in the form of at least four stereoisomers of two and two diastereomers, the usual configurational designations R and S with RR, SS, RS and SR are used or for the form of racemic mixtures of diastereomers, RR-SS and RS-SR.
Svi ovi izomeri podjednako čine dio izuma. All these isomers equally form part of the invention.
Spojevi formule I mogu sadržavati još dva centra simetrije, kada supstituenti R1 i R2 su različiti, ovo daje dodatne steroizomere koji su također dio izuma. Compounds of formula I may contain two more centers of symmetry, when the substituents R1 and R2 are different, this gives additional stereoisomers which are also part of the invention.
U normalnoj je kompentenciji specijalista da izolira ili sintetizira optički aktivni oblik spojeva formule I, na primjer razdvajanjem racemata ili posebnom sintezom spoja optički aktivnog i da odrede biološke osobine izomera tako izoliranih prateći eksperimente dane u daljnjem tekstu. It is within the normal competence of the specialist to isolate or synthesize the optically active form of the compounds of formula I, for example by separating the racemates or by special synthesis of the optically active compound and to determine the biological properties of the isomers thus isolated following the experiments given below.
Za ester i amid fiziološki prihvatljiv uzima se ester ili amid spoja prema izumu, koji kada hidrolizira u fiziološkim uvjetima, dajući alkohol ili amin fiziološki prihvatljiv, što će reći netoksičan u željenim dozama. For physiologically acceptable ester and amide, the ester or amide of the compound according to the invention is taken, which when hydrolyzed under physiological conditions, gives a physiologically acceptable alcohol or amine, that is, non-toxic in the desired doses.
Termin "alkil" podrazumijeva zasićeni ugljikovodik, linearan ili razgranat, izveden iz odgovarajućeg alkana uklanjanjem jednog atoma vodika. The term "alkyl" refers to a saturated hydrocarbon, linear or branched, derived from the corresponding alkane by the removal of one hydrogen atom.
Termin "alkoksi" podrazumijeva alkil radikal takav kao što je definirano naprijed, koji je za osnovnu molekulu vezan preko atoma kisika. The term "Alkoxy" means an alkyl radical as defined above, which is attached to the basic molecule via an oxygen atom.
Termin "alkilamino" podrazumijeva atom dušika supstituiran s atomom vodika i alkil radikalom takvim kao što je definirano naprijed, i čija je slobodna valencija iskorištena za vezivanje s osnovnom molekulom. The term "alkylamino" refers to a nitrogen atom substituted with a hydrogen atom and an alkyl radical as defined above, and whose free valency has been used for bonding to the parent molecule.
Termin"N,N-dialkilamino" podrazumijeva alkilamino radikal takav kao što je definirano naprijed čiji je atom vodika zamijenjen s alkil radikalom, takvim kao što je prethodno definirano. The term "N,N-dialkylamino" means an alkylamino radical as defined above whose hydrogen atom has been replaced by an alkyl radical as defined above.
Termin "imino" podrazumijeva radikal dialkilamino, takav kao što je definirano naprijed čija dva alkil radikala zajedno grade alkilenski lanac. The term "imino" refers to a dialkylamino radical, as defined above, whose two alkyl radicals together form an alkylene chain.
Izraz "dialkil s jednim do x atoma ugljika" označava svaki od dva alkil radikala koji čine dialkil ostatak koji može neovisno sadržavati od 1 do x atoma ugljika. The term "dialkyl of one to x carbon atoms" means each of two alkyl radicals forming a dialkyl radical which may independently contain from 1 to x carbon atoms.
Kao specifični spojevi izuma mogu se citirati nazivi pojedinih primjera, slijedeći spojevi čije su formule dane u prilogu: As specific compounds of the invention, the names of individual examples can be cited, the following compounds whose formulas are given in the attachment:
Spoj br. 1: (+,-)-6E-eritro-((fluoro-4-fenil)-4-spiro-(2H-benzopiran-1-2,1'-ciklopentil)-3-7-dihidroksi-3,5 -heptan- 6- etilat. Connection no. 1: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3-7-dihydroxy-3,5 - heptane-6-ethylate.
Spoj br. 2: (+,-)-6E-eritro-(dihidro-1,2-dimetil-2,2-fenil-4-naftil-3)-7-dihidroksi-3,5-hepten-6-metilat. Connection no. 2: (+,-)-6E-erythro-(dihydro-1,2-dimethyl-2,2-phenyl-4-naphthyl-3)-7-dihydroxy-3,5-heptene-6-methylate.
Spoj br. 3: (+,-)-6E-eritro-((kloro-4-fenil)-4-dimetil-2,2-2H-benotiapiran-3-il)7-dihidroksi-3,5 -hepten-6-metilat. Connection no. 3: (+,-)-6E-erythro-((chloro-4-phenyl)-4-dimethyl-2,2-2H-benothiapyran-3-yl)7-dihydroxy-3,5-hepten-6-methylate .
Spoj br. 4: (+,-)-eritro-((fluoro-4-fenil)-4-spiro-(2H-benzopiran-1-2,1'-ciklopentil)-3)-7-dihidroksi-3,5-heptan etilat. Connection no. 4: (+,-)-erythro-((fluoro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5-heptane ethylate.
Spoj br. 5: (+,-)-6E-eritro-(fluoro-4-fenil)-4-spiro-(2H-benzopiran-1-2,1' -ciklopentil)-3-7-dihidroksi-3,5-hepten-6- ester natrija. Connection no. 5: (+,-)-6E-erythro-(fluoro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3-7-dihydroxy-3,5-heptene -6- sodium ester.
Spoj br. 6: (+,-)-6E-eritro-(fluoro-4-fenil)-4-spiro- (2H-benzopiran-1-2,1'-ciklopentil)-3)- 7-dihidroksi-3,5-hepten-6- benzilat. Connection no. 6: (+,-)-6E-erythro-(fluoro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5- heptene-6-benzilate.
Spoj br. 7: (+,-)-6E-eritro-((fluoro-4-fenil)-4-spiro-(2H-benzopiran-1-2,1'-ciklopentil-3 )-7-dihidroksi-3,5 -N-metil- hepten-6-amid. Connection no. 7: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl-3)-7-dihydroxy-3,5 - N-methyl-hepten-6-amide.
Spoj br. 8: (+,-)-trans-(1E-((fluoro-4-fenil)4-spiro-(2H-benzopiran-1-2,1'-ciklopentil)-3) -2-etenil)-6-hidroksi- 4- tetrahidro-3,4,5,6-piranon-2. Connection no. 8: (+,-)-trans-(1E-((fluoro-4-phenyl)4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-2-ethenyl)-6- hydroxy-4-tetrahydro-3,4,5,6-pyranone-2.
Spoj br. 9: (+,-)-trans-hidroksi-4-tetrahidro-3,4,5,6,-(((fluoro-4-fenil)-4-spiro(2H-benzopiran-1 -2, 1'-ciklopentil)-3) -2-etil)-6-piranon-2. Connection no. 9: (+,-)-trans-hydroxy-4-tetrahydro-3,4,5,6,-(((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1 -2, 1'- cyclopentyl)-3)-2-ethyl)-6-pyranone-2.
Spoj br. 10: (+,-)-eritro-((fluoro-4-fenil)-4-spiro-(2H-benzopiran-1-2,1'-ciklopentil)-3)-7dihidroksi-3,5-heptan ester natrija. Connection no. 10: (+,-)-erythro-((fluoro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7dihydroxy-3,5-heptane sodium ester .
Spoj br. 11: (+,-)-((1E-((fluoro-4-fenil)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3)-2-etenil)-6- dimetil-2,2- dioksan- 1,3-il-4) acetat etila. Connection no. 11: (+,-)-((1E-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-2-ethenyl)-6-dimethyl -2,2-dioxan-1,3-yl-4) ethyl acetate.
Spoj br. 12: (+,-)-6E-eritro-dihidroksi-3,5-(fenil-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3 )-7-hepten-6-etilat. Connection no. 12: (+,-)-6E-erythro-dihydroxy-3,5-(phenyl-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-heptene-6-ethylate.
Spoj br. 13: (+,-)-6E-eritro-((etil-4-fenil)-4-spiro-(2H-benzopiran-1-2,1'-ciklopentil)-3)-7-dihidroksi-3,5-hepten-6-etilat. Connection no. 13: (+,-)-6E-erythro-((ethyl-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5 -heptene-6-ethylate.
Spoj br. 14: (+,-)-6E-eritro-dihidroksi-3,5-(metil-6-fenil-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3)-7-hepten-6-etilat. Connection no. 14: (+,-)-6E-erythro-dihydroxy-3,5-(methyl-6-phenyl-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-heptene- 6-ethylate.
Spoj br. 15: (+,-)-6E-eritro-(fluoro-7-fenil-4-spiro-(2H-benzopiran-1-2,1'-ciklopentil)-3 )-dihidroksi-3,5 –hepten -6- metilat. Connection no. 15: (+,-)-6E-erythro-(fluoro-7-phenyl-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-dihydroxy-3,5-heptene-6 - methylate.
Spoj br. 16: (+,-)-6E-eritro-dibidroksi-3,5-(metil-4-fenil)-4-spiro(2H-benzopiran-1-2,1-ciklopeutil)-3)-7-hepten-6-etilat. Connection no. 16: (+,-)-6E-erythro-dihydroxy-3,5-(methyl-4-phenyl)-4-spiro(2H-benzopyran-1-2,1-cyclopeutil)-3)-7-heptene- 6-ethylate.
Spoj br. 17: (+,-)-6E-eritro-((fluoro-3-fenil)-4-spiro-(2H-benzopiran-1-2,1'-ciklopentil)-3)-7-dihidroksi-3,5 -hepten- 6-etilat. Connection no. 17: (+,-)-6E-erythro-((fluoro-3-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5 -heptene- 6-ethylate.
Spoj br. 18: (+,-)-6E-eritro-dihidroksi-3,5((metoksi-4-fenil)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3)-7 hepten -6- etilat. Connection no. 18: (+,-)-6E-erythro-dihydroxy-3,5((methoxy-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7 heptene - 6- ethylate.
Spoj br. 19: (+,-)-6E-eritro-((kloro-4-fenil)-4-spiro-(2H- benzopiran-1-2,1'-ciklopentil)-3 ) -7-dihidroksi -3,5-hepten -6-etilat. Connection no. 19: (+,-)-6E-erythro-((chloro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5 -heptene-6-ethylate.
Spoj br. 20: (+,-)-6E-eritro-dihidroksi-3,5-((naftil-l-)-4-spiro(2H-benzopiran-l-2,l'-ciklopentil)-3 )-7-hepten-6-etilat. Connection no. 20: (+,-)-6E-erythro-dihydroxy-3,5-((naphthyl-1-)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-heptene -6-ethylate.
Spoj br. 21: (+,-)-6E-eritro-hidroksi-3,5-((dimetil-3,5-fenil)-4-spiro(2H-benzopiran-l-2,1 '-ciklopentil)-3 )-7-hepten- 6-etilat. Connection no. 21: (+,-)-6E-erythro-hydroxy-3,5-((dimethyl-3,5-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)- 7-heptene-6-ethylate.
Spoj br. 22: (+,-)-6E-eritro-((fluoro-4-fenil)-4-dimetil-5,7-spiro(2H-benzopiran-1-2,1 '-ciklopentil)-3 )-7-dihidroksi-3,5 - hepten-6-metilat. Connection no. 22: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-dimethyl-5,7-spiro(2H-benzopyran-1-2,1 '-cyclopentyl)-3 )-7- dihydroxy-3,5-heptene-6-methylate.
Spoj br. 23: (+,-)-6E-eritro-((etoksi-4-fenil)-4-spiro(2H-benzopiran-1-2,1 '-ciklopentil)-3 )-7-dihidroksi-3,5 –hepten -6-metilat. Connection no. 23: (+,-)-6E-erythro-((ethoxy-4-phenyl)-4-spiro(2H-benzopyran-1-2,1 '-cyclopentyl)-3 )-7-dihydroxy-3,5 – heptene-6-methylate.
Spoj br. 24: (+,-)-6E-eritro-dihidroksi-3,5-((izopropiloksi-4-fenil)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3) -7- hepten-6-metilat. Connection no. 24: (+,-)-6E-erythro-dihydroxy-3,5-((isopropyloxy-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3) -7- heptene-6-methylate.
Spoj br. 25: (+,-)-6E-eritro-((fluoro-4-fenil)-4-metoksi-6-spiro(2H-benzopiran-1-2,1'-ciklopentil-3 )-7-dihidroksi-3,5 - hepten-6-metilat. Connection no. 25: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-methoxy-6-spiro(2H-benzopyran-1-2,1'-cyclopentyl-3 )-7-dihydroxy-3 ,5 - heptene-6-methylate.
Spoj br. 26: (+,-)-6E-eritro-((trifluorometil-4-fenil)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3)-7-dihidroksi-3,5-hepten -6-metilat. Connection no. 26: (+,-)-6E-erythro-((trifluoromethyl-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5- heptene-6-methylate.
Spoj br. 27: (+,-)-6E-eritro-dihidroksi-3,5-((n-pentil-oksi-4-fenil)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3)-7- hepten-6-metilat. Connection no. 27: (+,-)-6E-erythro-dihydroxy-3,5-((n-pentyl-oxy-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3 )-7-heptene-6-methylate.
Spoj br. 28: (+,-)-6E-eritro-((fluoro-4-fenil)-4-spiro-(2H-nafto(b)piran-1-2,1'-ciklopentil)-3 )-7-dihidroksi-3,5 -hepten- 6-metilat. Connection no. 28: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-spiro-(2H-naphtho(b)pyran-1-2,1'-cyclopentyl)-3 )-7-dihydroxy -3,5-heptene-6-methylate.
Spoj br. 29: (+,-)-6E-eritro-dihidroksi-3,5-((metiltio-4-fenil)-4-spiro(2H-benzopiran-l-2,1 '-ciklopentil)-3) -7-hepten -6-metilat. Connection no. 29: (+,-)-6E-erythro-dihydroxy-3,5-((methylthio-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7- heptene-6-methylate.
Spoj br. 30: (+,-)-6E-eritro-((terciobutil-4-fenil)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil-3)-7-dihidroksi-3,5-hepten-6 etilat. Connection no. 30: (+,-)-6E-erythro-((tertiobutyl-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl-3)-7-dihydroxy-3,5-heptene -6 ethylate.
Spoj br. 31: (+,-)-6E-eritro-(fluoro-4-fenil)-4-spiro-(2H-benzopiran-1-2,1 '-cikloheksil)-3)-7-dihidroksi-3,5-hepten-6 etilat. Connection no. 31: (+,-)-6E-erythro-(fluoro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclohexyl)-3)-7-dihydroxy-3,5- heptene-6 ethylate.
Spoj br. 32: (+,-)-6E-eritro-((fluoro-4-fenil)-4-izoproksi-7-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3 )-7-dihidroksi-3,5 – hepten-6 metilat. Connection no. 32: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-isoproxy-7-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3 )-7-dihydroxy- 3,5 – heptene-6 methylate.
Spoj br. 33: (+,-)-6E-eritro-((fluoro-4-fenil)-4-spiro-(2H-benzopiran-1-2,1'-ciklopentil)-3 )-7-dihidroksi-3,5 –hepten -6-amid. Connection no. 33: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3 )-7-dihydroxy-3,5 –heptene-6-amide.
Spoj br. 34: (+,-)-6E-eritro-((fluoro-4-fenil)-4-spiro-(2H-benzopiran-1-2,1 '-ciklopentil)-3 )-7-dihidroksi-3,5 -N-izopropil -hepten-6 amid. Connection no. 34: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5 -N-isopropyl-hepten-6 amide.
Spoj br. 35: (+,-)-6E-eritro-((bifenil-1,1-il-4-)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3 )-7-dihidroksi-3,5 -N,N- tetrametilen-hepten-6 amid. Connection no. 35: (+,-)-6E-erythro-((biphenyl-1,1-yl-4-)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3 )-7-dihydroxy -3,5-N,N-tetramethylene-heptene-6 amide.
Spoj br. 36: (+,-)-6E-eritro-((fluoro-4-fenil)-4-spiro-(2H-benzopiran-1-2,1'-ciklopentil)-3 -7-dihidroksi-3,5 -N- cikloheksil-hepten-6 amid. Connection no. 36: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3 -7-dihydroxy-3,5 - N-cyclohexyl-hepten-6 amide.
Spoj br. 37: (+,-)-6E-eritro-N-benzil-((fluoro-4-fenil)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)3 )-7-dihidroksi-3,5 - hepten-6 amid. Connection no. 37: (+,-)-6E-erythro-N-benzyl-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)3 )-7-dihydroxy-3 ,5 - hepten-6 amide.
Spoj br. 38: (+,-)-6E-eritro-(etil-4-fenil)-4-spiro-(2H-benzopiran-1-2,1'-ciklopentil)-3)-7-dihidroksi-3,5-hepten-6 ester natrija. Connection no. 38: (+,-)-6E-erythro-(ethyl-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5- sodium heptene-6 ester.
Spoj br. 39: (+,-)-6E-eritro-dihidroksi-3,5-(metil-6-fenil-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3)-7-hepten-6 ester natrija. Connection no. 39: (+,-)-6E-erythro-dihydroxy-3,5-(methyl-6-phenyl-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-heptene- 6 sodium ester.
Spoj br. 40: (+,-)-6E-eritro-dihidroksi-3,5-((izopropil-4-fenil)-4-spiro(2H-benzopiran-1-2, l'-ciklopentil) -3)-7- hepten-6-ester natrija. Connection no. 40: (+,-)-6E-erythro-dihydroxy-3,5-((isopropyl-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7- sodium heptene-6-ester.
Spoj br. 41: (+,-)-6E-eritro-dihidroksi-3,5-(fenil-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3)-7-6 ester natrija. Connection no. 41: (+,-)-6E-erythro-dihydroxy-3,5-(phenyl-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-6 sodium ester.
Spoj br. 42: (+,-)-6E-eritro-((kloro-4-fenil)-4-spiro-(2H-benzopiran-1-2,1'-ciklopentil)-3)-7-dihidroksi-3,5-hepten-6 ester natrija. Connection no. 42: (+,-)-6E-erythro-((chloro-4-phenyl)-4-spiro-(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5 -heptene-6 ester sodium.
Spoj br. 43: (+,-)-6E-eritro-dihidroksi-3,5-(fenil-4-2H-benzopiran-1-il-3)-7-heptau-6 etilat. Connection no. 43: (+,-)-6E-erythro-dihydroxy-3,5-(phenyl-4-2H-benzopyran-1-yl-3)-7-heptau-6 ethylate.
Spoj br. 44: (+,-)-6E-eritro-((fluoro-4-fenil)-4-dimetil-2,2-2H-benzopiran-1-il-3)-7-dihidroksi-3,5-hepten-6 metilat. Connection no. 44: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-dimethyl-2,2-2H-benzopyran-1-yl-3)-7-dihydroxy-3,5-heptene- 6 methylate.
Spoj br. 45: (+,-)-6E-eritro-((fluoro-4-fenil)-4-izopropil-2-2H-benzopiran-1-il-diliidroksi-3,5-hepten-6 etilat. Connection no. 45: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-isopropyl-2-2H-benzopyran-1-yl-dilyhydroxy-3,5-hepten-6 ethylate.
Spoj br. 46: (+,-)-trans-hidroksi-4-tetrahidro-3,4,5,6-(lE-fenil-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3)- 2-etenil) -6-2H-piranon-2. Connection no. 46: (+,-)-trans-hydroxy-4-tetrahydro-3,4,5,6-(1E-phenyl-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)- 2-ethenyl)-6-2H-pyranone-2.
Spoj br. 47: (+,-)-trans-(1E(dihidro-1,2-dimetil-2,2-fenil-4-naftil-3)-2-etenil)-hidroksi-4-tetrahidro-3,4,5,6-2H-piranon-2. Connection no. 47: (+,-)-trans-(1E(dihydro-1,2-dimethyl-2,2-phenyl-4-naphthyl-3)-2-ethenyl)-hydroxy-4-tetrahydro-3,4,5 ,6-2H-pyranone-2.
Spoj br. 48: (+,-)-trans-(1E(dihidro-1,2-dimetil-2,2-fenil-4-naftil-3)-2-etenil)-hidroksi-4-tetrahidro-3,4,5,6-2H-piranon-2. Connection no. 48: (+,-)-trans-(1E(dihydro-1,2-dimethyl-2,2-phenyl-4-naphthyl-3)-2-ethenyl)-hydroxy-4-tetrahydro-3,4,5 ,6-2H-pyranone-2.
Spoj br. 49: (+,-)-trans-bidroksi-4-tetrahidro-3,4,5,6,-(lE82H-dimetil-2,2-fenil-4 -benzotiapiranil-3)-2 -etenil) -6- 2H-piranon-2. Connection no. 49: (+,-)-trans-bihydroxy-4-tetrahydro-3,4,5,6,-(1E82H-dimethyl-2,2-phenyl-4-benzothiapyranyl-3)-2-ethenyl)-6- 2H-pyranone-2.
Spoj br. 50: (+,-)-eritro-dihidroksi-3,5-(fenil-4-spiro(dibidro-1,2-naftalen-2,r-ciklopentil)-3 )-7-hepten-6-metilat. Connection no. 50: (+,-)-erythro-dihydroxy-3,5-(phenyl-4-spiro(dihydro-1,2-naphthalene-2,r-cyclopentyl)-3 )-7-heptene-6-methylate.
Spoj br. 51: (+,-)-6E-eritro-((fluoro-4-fenil)-4-dihidro-1,2-dimetil-2,2-naftil-3)-7-dihidroksi-3,5-hepten-6 metilat. Connection no. 51: (+,-)-6E-erythro-((fluoro-4-phenyl)-4-dihydro-1,2-dimethyl-2,2-naphthyl-3)-7-dihydroxy-3,5-heptene- 6 methylate.
Spoj br. 52: (+,-)-6E-eritro-(dihidro-l,2-dimetil-2,2-fenil-4-naftil-3)-7-dihidroksi-3,5-kepten-6 metilat. Connection no. 52: (+,-)-6E-erythro-(dihydro-1,2-dimethyl-2,2-phenyl-4-naphthyl-3)-7-dihydroxy-3,5-keptene-6 methylate.
Spoj br. 53: (+,-)-6E-eritro-(fluoro-4-fenil)-4-spiro-(dihidro-1,2-naftalen-2,r-ciklopentil-3)-7-dihidroksi-3,5-hepten-6 metilat. Connection no. 53: (+,-)-6E-erythro-(fluoro-4-phenyl)-4-spiro-(dihydro-1,2-naphthalene-2,r-cyclopentyl-3)-7-dihydroxy-3,5- heptene-6 methylate.
Spoj br. 54: (+,-)-6E-eritro-((-kloro-4-fenil)-4-spiro-(dihidro-1,2-naftalen-2,r-ciklopeutil)-3 )-7-dibidroksi-3,5 -hepten-6 metilat. Connection no. 54: (+,-)-6E-erythro-((-chloro-4-phenyl)-4-spiro-(dihydro-1,2-naphthalene-2,r-cyclopeutil)-3 )-7-dihydroxy-3 ,5 -heptene-6 methylate.
Spoj br. 55: (+,-)-6E-eritro-((-kloro-4-metil)-4-dihidro-1,2-dimetil-2,2-naftil-3)-7-dihidroksi-3,5-hepten-6 metilat. Connection no. 55: (+,-)-6E-erythro-((-chloro-4-methyl)-4-dihydro-1,2-dimethyl-2,2-naphthyl-3)-7-dihydroxy-3,5-heptene -6 methylate.
Spoj br. 56: (+,-)-6E-eritro-((fluoro-3-fenil)-4-spiro-(dihidro-1,2-naftalen-2,r-ciklopentil-3)-7-dihidroksi-3,5-hepten-6 metilat. Connection no. 56: (+,-)-6E-erythro-((fluoro-3-phenyl)-4-spiro-(dihydro-1,2-naphthalene-2,r-cyclopentyl-3)-7-dihydroxy-3,5 -heptene-6 methylate.
Spoj br. 57: (+,-)-6E-eritro-((-fluoro-4-fenil)-4-dihidro-1,2-naftil-3)-7-dihidroksi-3,5-hepten-6 ester natrija. Connection no. 57: (+,-)-6E-erythro-((-fluoro-4-phenyl)-4-dihydro-1,2-naphthyl-3)-7-dihydroxy-3,5-heptene-6 ester sodium.
Spoj br. 58: (+,-)-6E-eritro-(dihidro-1,2-izopropil-2-fenil-4-naftil-3)-7-dihidroksi-3,5-hepten-6 metilat. Connection no. 58: (+,-)-6E-erythro-(dihydro-1,2-isopropyl-2-phenyl-4-naphthyl-3)-7-dihydroxy-3,5-heptene-6 methylate.
Spoj bi. 59: (+,-)-6E-eritro-(dibidro-1,2-metil-2-fenil-4-naftil-3)-7-dihidroksi-3,5-hepten-3,5-hepten-6 metilat. The connection would. 59: (+,-)-6E-erythro-(dihydro-1,2-methyl-2-phenyl-4-naphthyl-3)-7-dihydroxy-3,5-heptene-3,5-heptene-6 methylate .
Spoj br. 60: (+,-)-6E-eritro-dihidroksi-3,5-(metil-8-(metil-4-fenil)-4-spiro(dibidro-1,2-naftalen-2,r-ciklopentil) -3)-7- hepten-6 metilat. Connection no. 60: (+,-)-6E-erythro-dihydroxy-3,5-(methyl-8-(methyl-4-phenyl)-4-spiro(dihydro-1,2-naphthalene-2,r-cyclopentyl) - 3)-7-heptene-6 methylate.
Spoj br. 61: (+,-)-6E-eritro-(kloro-6-(kloro-4-fenil)-4-spiro(dihidro-1,2-naftalen-2,1'-ciklopentil) -3)-7-dihidroksi -3,5- hepten-6 metilat. Connection no. 61: (+,-)-6E-erythro-(chloro-6-(chloro-4-phenyl)-4-spiro(dihydro-1,2-naphthalene-2,1'-cyclopentyl)-3)-7- dihydroxy -3,5- heptene-6 methylate.
Spoj br. 62: (+,-)-6E-eritro-dihidroksi-3,5-(metil-8-(metoksi-4-fenil)-4-spiro(dihidro-1,2-uaftalen-2, 1'-ciklopentil) -3)- 7 -hepten-6 metilat. Connection no. 62: (+,-)-6E-erythro-dihydroxy-3,5-(methyl-8-(methoxy-4-phenyl)-4-spiro(dihydro-1,2-uaphthalene-2, 1'-cyclopentyl) -3)- 7 -heptene-6 methylate.
Spoj br. 63: (+,-)-6E-eritro-(kloro-(fluoro-4-fenil)-4-spiro(dihidro-1,2-naftalen-2,1'-ciklopentil)-3) -7-dibidroksi- 3,5- hepten-6 metilat. Connection no. 63: (+,-)-6E-erythro-(chloro-(fluoro-4-phenyl)-4-spiro(dihydro-1,2-naphthalene-2,1'-cyclopentyl)-3)-7-dihydroxy- 3,5-heptene-6 methylate.
Spoj br. 64: (+,-)-6E-eritro-(dibidro-1,2-dimetil-2,2-metoksi-7-naflil-3)-7-dibidroksi-3,5-hepten-6 metilat. Connection no. 64: (+,-)-6E-erythro-(dihydro-1,2-dimethyl-2,2-methoxy-7-naphthyl-3)-7-dihydroxy-3,5-heptene-6 methylate.
Spoj br. 65: (+,-)-6E-eritro-dihidroksi-3,5-(fenil-4-spiro(2H-benzotiapiran-1-2,1' -ciklopeutil)-3)-7-hepten-6 ester natrija. Connection no. 65: (+,-)-6E-erythro-dihydroxy-3,5-(phenyl-4-spiro(2H-benzothiapyran-1-2,1'-cyclopeutil)-3)-7-heptene-6 sodium ester.
Spoj br. 66: (+,-)-6E-eritro-dihdroksi-3,5-(metil-4-fenil)-4-spiro(2H-benzotiapiran-1-2,1'-ciklopentil)-3)-7-hepten-6 metilat. Connection no. 66: (+,-)-6E-erythro-dihydroxy-3,5-(methyl-4-phenyl)-4-spiro(2H-benzothiapyran-1-2,1'-cyclopentyl)-3)-7-heptene -6 methylate.
Spoj br. 67: (+r)-6E-eritro-dihidroksi-3,5-(fenil-4-dimetil-2,2-2H-benzotiapiraiiil-3)-7-hepten-6 metilat. Connection no. 67: (+r)-6E-erythro-dihydroxy-3,5-(phenyl-4-dimethyl-2,2-2H-benzothiapyrayl-3)-7-heptene-6 methylate.
Spoj br. 68: (+r)-6E-eritro-dihidroksi-3,5-(fenn-4-dimetil-2,2-2H-benzotiapiranil-3)-7-hepten-6 ester natrija. Connection no. 68: (+r)-6E-erythro-dihydroxy-3,5-(phenn-4-dimethyl-2,2-2H-benzothiapyranyl-3)-7-heptene-6 sodium ester.
Izum se također odnosi na postupke za dobivanje spojeva prema izumu okarakteriziranih time što obuhvaćaju barem: The invention also relates to methods for obtaining compounds according to the invention characterized by comprising at least:
a) redukciju ceto-estera opće formule 4, u kojoj X, R1 R2, R3, R4, R5, R6, R7, R8 i R11 imaju značenja opća ili u prethodnom tekstu već definirana, a) reduction of the keto-ester of the general formula 4, in which X, R1, R2, R3, R4, R5, R6, R7, R8 and R11 have the general meanings or those already defined in the previous text,
[image] [image]
i ako bi se dogodilo, and if it happened,
b) transesterifikaciju spojeva formule 1 ili alkolizu spojeva formule 1 u obliku delta-laktoiia ili alkilaciju spoja formule 1 u obliku soli, b) transesterification of compounds of formula 1 or alcoholysis of compounds of formula 1 in the form of delta-lactoil or alkylation of compounds of formula 1 in the form of salts,
c) hidrolizu spoja formule 1 u obliku estera ili delta laktona, c) hydrolysis of the compound of formula 1 in the form of an ester or delta lactone,
d) kada R7 i R8 odnosno R9 i R11 grade jednostavnu vezu; tretiranje odgovarajućih spojeva formule 1 u obliku soli s tercijarnim kloraminom, d) when R7 and R8 or R9 and R11 form a simple connection; treating the corresponding compounds of formula 1 in salt form with tertiary chloramine,
e) kada R7, R8 i R10 označavaju atom vodika, a R9 i R11 grade zajedno jednu vezu; katalitičku redukciju delta laktonskih spojeva formule 1 u kojoj R7 i R8 grade jednu vezu ih laktonizaciju spojeva kiselina odgovarajuće formule 1 u kojoj R7, Rx i R10 označavaju atom vodika; e) when R7, R8 and R10 denote a hydrogen atom, and R9 and R11 form one bond together; catalytic reduction of delta lactone compounds of formula 1 in which R7 and R8 form one bond; lactonization of acid compounds of the corresponding formula 1 in which R7, Rx and R10 denote a hydrogen atom;
f) aminolizu spojeva formule 1 u obliku estera ili delta-laktona; f) aminolysis of compounds of formula 1 in the form of esters or delta-lactones;
g) kada R9 i R10 grade zajedno dialkilmetilenski ostatak; ciklizaciju odgovarajućih spojeva formule 1, u kojoj R9 i R10 svaki označavaju atom vodika s alkoksialkenom. g) when R9 and R10 form together a dialkylmethylene residue; cyclization of the corresponding compounds of formula 1, wherein R 9 and R 10 each represent a hydrogen atom with an alkoxyalkene.
Spojevi formule 1, u kojoj X, R1 R2, R3, R4, R5, R6, R7, R8 imaju opća značenja ih specifično definirana u prethodnom tekstu i u kojoj supstituenti R9 i R10 označavaju svaki atom vodika mogu se dobiti, u obliku estera, prema reakcijskim sekvencama ilustriranih slijedećom shemom I: Compounds of formula 1, in which X, R1, R2, R3, R4, R5, R6, R7, R8 have the general meanings specifically defined in the preceding text and in which the substituents R9 and R10 denote each hydrogen atom can be obtained, in the form of esters, according to reaction sequences illustrated by the following scheme I:
[image] [image]
[image] [image]
Kao što je naznačeno na Shemi I, aldehidski spojevi formule 2 u kojoj supstituenti u kojoj R1 R2, R3, R4, R5, R6, R7, R8 imaju opća ili određena značenja već se definirana podvrgavaju aldolinskoj kondenzaciji s odgovarajućim acetoacetatom u obliku dvojne soli natrija i litija formule 3 u kojoj R11 ima značenja opća ili određena već definirana u sredini polarnog otapala, takvog kao THF (vidi KRAUS et colL J. Org. Cliem. 48, 2111, 1983) radi dobivanja hidroksi-5-okso-3- hepten-6- supstituiranih-7 estera formule 4. As indicated in Scheme I, aldehyde compounds of formula 2 in which the substituents in which R1, R2, R3, R4, R5, R6, R7, R8 have the general or specific meanings already defined are subjected to aldolin condensation with the corresponding acetoacetate in the form of a double sodium salt and lithium of formula 3 in which R 11 has the meanings general or specific already defined in the middle of a polar solvent, such as THF (see KRAUS et colL J. Org. Cliem. 48, 2111, 1983) to obtain hydroxy-5-oxo-3-heptene -6-substituted-7 esters of formula 4.
Esteri formule 4, otopina u inertnom otapalu, takvom kao THF ili eter, tretiranu s alkalnim borhidridom poželjno natrij borohidridom (postupak A) daju spojeve 1 u obliku smjese izomera treo i eritro, koja može biti razdvojena uobičajenim fizikalnokemijskim postupcima takvima kao stoje naprimjer kromatografija. Esters of formula 4, solution in an inert solvent, such as THF or ether, treated with alkaline borohydride, preferably sodium borohydride (method A) give compounds 1 in the form of a mixture of threo and erythro isomers, which can be separated by usual physicochemical methods such as, for example, chromatography.
Jedna varijanta (postupak B) pogodnija od postupka A koja daje spojeve prema izumu u eritro obliku, sastoji se prije svega u redukciji s alkalnim borohidridom, u tretiranju estera 4 u otopini odgovarajućeg otapala takvog kao THF, s kompleksirajućim sredstvom poželjno trialkilboranom kao što je tributil-boran (vidi NARASKA, Chem. Letters, 1415-1418, 1980) ili alkoksi dialkilboran kao što je metoksi dietilboran (vidi CHEN et coll, Tetrahed. Lett. 28(2) 155-158, 1987). One variant (process B) more suitable than process A, which gives the compounds according to the invention in the erythro form, consists first of all in the reduction with alkaline borohydride, in the treatment of ester 4 in a solution of a suitable solvent such as THF, with a complexing agent preferably a trialkylborane such as tributyl .
Spojevi formule 2, u kojoj supstituenti R7 i R8 grade zajedno vezu, mogu se dobiti prema reakcijskim sekvencama ilustriranih slijedećom shemom II: Compounds of formula 2, in which the substituents R7 and R8 form a bond together, can be obtained according to the reaction sequences illustrated in the following scheme II:
[image] [image]
Kao što je naznačeno u Shemi II, spojevi formule 5, u kojima u kojoj X, R1 R2, R3, R4, R5, R6, imaju opća ili određena značenja već definirana su dobivana u Vilsmeier-ovoj reakciji s N,N-dimetil-amino-3-akroleinom (vidi ULLRICH et BREITHAJER, Synthesis 8, 641-645, 1983) u inertnom otapalu takvom kao što je aceto-nitril na temperaturi između 20°C i temperature refluksa radi dobivanja spojeva 2 trans geometrije kao što je pokazano RMN spektroskopijom. As indicated in Scheme II, compounds of formula 5, in which X, R1, R2, R3, R4, R5, R6, have the general or specific meanings already defined were obtained by the Vilsmeier reaction with N,N-dimethyl- with amino-3-acrolein (see ULLRICH et BREITHAJER, Synthesis 8, 641-645, 1983) in an inert solvent such as acetonitrile at a temperature between 20°C and the reflux temperature to give compounds of 2 trans geometry as shown by NMR by spectroscopy.
Drugi postupak dobivanja aldehida formule 2, u kojoj R7 i R8 zajedno grade jednu vezu, ilustriranje slijedećom Shemom IQII Another process for obtaining aldehydes of formula 2, in which R7 and R8 form a single bond together, is illustrated by the following Scheme IQII
[image] [image]
Kao što je naznačeno na Shemi III, spojevi formule 5 se dobivaju u reakciji bromiranja s N-bromosukcinamidom (NBS) u sredini N,N-dimetilformamida (DMF) ili kloriranog otapala, takvog kao što je ugljiktetraklorid ili metilen klorid radi dobivanja odgovarajućih 3-bromiranih spojeva koji se zatim tretiraju s butillitijem u odgovarajućem otapalu, poželjno eteru kao što je, na primjer, dietileter, a zatim s etoksi-3-akroleinom ili N.N-dimetilamino-3-akroleinom radi građenja aldehida 2 u trans obliku kao što je pokazano pomoću RMN spektroskopije. As indicated in Scheme III, compounds of formula 5 are obtained by bromination reaction with N-bromosuccinamide (NBS) in N,N-dimethylformamide (DMF) or a chlorinated solvent such as carbon tetrachloride or methylene chloride to give the corresponding 3- brominated compounds which are then treated with butyllithium in a suitable solvent, preferably an ether such as, for example, diethyl ether, and then with ethoxy-3-acrolein or N,N-dimethylamino-3-acrolein to form aldehyde 2 in the trans form as shown by means of NMR spectroscopy.
Alternativni postupak za dobivanje intermedijernih aldehida formule 2 u kojoj R7 i R8 grade zajedno jednu vezu je ilustriran slijedećom Shemom IV: An alternative procedure for obtaining intermediate aldehydes of formula 2 in which R7 and R8 form a bond together is illustrated by the following Scheme IV:
[image] [image]
Kao što je naznačeno u Shemi IV, spojevi formule 5 se dobivaju Vilsmeir-ovom reakcijom s N,N-dimetilformamidom (vidi JACKSON et Coll. J. Am. Chem. Soc. 103, 533, 1981) u sredini inertnog otapala radi građenja odgovarajućih aldehida koji se koriste u reakciji WITTIG-a s etoksi ih" metoksi karbonil metilen trifenil fosforanom ili još s metil ih etil fosfonacetatom (vidi, Organic Reactions, 14, 273, 1965) radi dobivanja propen 3-supstituiranih estera 8 čija je konfiguracija trans kao što pokazuje RMN spektroskopija. As indicated in Scheme IV, compounds of formula 5 are prepared by Vilsmeir reaction with N,N-dimethylformamide (see JACKSON et Coll. J. Am. Chem. Soc. 103, 533, 1981) in an inert solvent to build the corresponding aldehydes used in the WITTIG reaction with ethoxy"methoxy carbonyl methylene triphenyl phosphorane or with methyl ethyl phosphonoacetate (see, Organic Reactions, 14, 273, 1965) to obtain propene 3-substituted esters 8 whose configuration is trans as as shown by NMR spectroscopy.
Alternativni postupak za dobivanje inermedijernih spojeva formule 8, koji su naročito pogodni kad X označava atom sumpora, sastoji se u reagiranju bromiranog spoja formule 6 s alkil akrilatom, poželjno metil ih etil akrilatom u prisustvu baznog sredstva, takvog kao što je trietilamin ih natrij bikarbonat, paladij dispergjran na ugljiku ih derivat paladija takav kao što je diklorid paladija ih njegov acetat i jednog hganda, poželjno triarilfosfina kao naprimjer triortotolilfosfina u sredini pogodnog otapala, kao što je N,N-dimetilformamida. An alternative procedure for obtaining intermediate compounds of formula 8, which are particularly suitable when X denotes a sulfur atom, consists in reacting the brominated compound of formula 6 with alkyl acrylate, preferably methyl ethyl acrylate in the presence of a base agent, such as triethylamine sodium bicarbonate, palladium dispersed on carbon, a palladium derivative such as palladium dichloride, its acetate, and a ligand, preferably a triarylphosphine such as triorthotolylphosphine, in a suitable solvent, such as N,N-dimethylformamide.
Esteri 8 reagiraju s hidridom dizobutilaluminija (DEBAL) u sredini otapala, obično dietilskog etera ih THF, dajući odgovarajuće spojeve 9-propenol 3-supstituirana trans oblika koji se zatim podvrgavaju oksidaciji s oksalil kloridom u DMSO (vidi SWERN et coll, J. Org. Chem. 43 2480, 1978) ih s mangan dioksidom u odgovarajućem otapalu kao što je naprimjer THF, radi dobivanja aldehida formule 2 i geometrije trans. Esters 8 are reacted with diisobutylaluminum hydride (DEBAL) in a solvent medium, usually diethyl ether and THF, to give the corresponding compounds of the 9-propenol 3-substituted trans form which are then subjected to oxidation with oxalyl chloride in DMSO (see SWERN et coll, J. Org. Chem. 43 2480, 1978) with manganese dioxide in a suitable solvent such as, for example, THF, in order to obtain the aldehyde of formula 2 and geometry trans.
Aldehidi formule 2, u kojoj supstituenti R7 i R8 predstavljaju svaki atom vodika, mogu se dobiti prema reakcijskim sekvencama ilustriranima Shemom V koja slijedi: Aldehydes of formula 2, in which the substituents R7 and R8 each represent a hydrogen atom, can be obtained according to the reaction sequences illustrated by Scheme V as follows:
[image] [image]
Prema reakcijskim sekvencama Sheme, aldehidi formule 2 gdje R7 i R8 grade dvostruku vezu se podvrgavaju reakciji acetilacije na primjer s ortolbromiatom formule HC(OR12)3 u kojoj, R12 predstavlja alkil radikal sa 1-4 atoma ugljika, poželjno metil ili etil u prisustvu kisele smole ili još jednoj reakciji acidokatalizirauoj s alkoholom formule R12OH u kojoj R12 ima naprijed dana značenja ili može predstavljati radikal formule -(CH2)qOH, u kojoj q = 2 ili 3 radi građenja spojeva 10, metilenski radikal -R12 ......R11- gradi tada s atomima kisika koji vezuje petočlani šestočlani prsten. According to the reaction sequences of the Scheme, aldehydes of the formula 2 where R7 and R8 form a double bond are subjected to an acetylation reaction, for example with an orthobromomate of the formula HC(OR12)3 in which, R12 represents an alkyl radical with 1-4 carbon atoms, preferably methyl or ethyl in the presence of an acid resin or another acid-catalyzed reaction with an alcohol of the formula R12OH in which R12 has the meanings given above or can represent a radical of the formula -(CH2)qOH, in which q = 2 or 3 to build compounds 10, methylene radical -R12 ...... R11- then builds with the oxygen atoms that bind the five-membered six-membered ring.
Spojevi 10 se zatim hidrogeniziraju, poželjno na niskom tlaku i u prisustvu metalnog katalizatora, kao na primjer paladij dispergiran na ugljiku, u odgovarajućem otapalu kao naprimjer THF ili alkoholu kao što je metanol, u odgovarajuće propanaldehide 3-supstituirane koji mogu biti zatim dezacelizirani u propanaldehide 2 postupcima primjenjiv za dezacetalizaciju koji podrazumijevaju na primjer tretiranje acetala s kiselom smolom u smjesi aceton-voda ili češće s kiselim katalizatorom, u otapalu ili smjesi odgovarajućih otapala. Compounds 10 are then hydrogenated, preferably at low pressure and in the presence of a metal catalyst, such as palladium dispersed on carbon, in a suitable solvent such as THF or an alcohol such as methanol, to the corresponding 3-substituted propanaldehydes which can then be deacylated to propanaldehydes 2 procedures applicable for deacetalization, which include, for example, the treatment of acetals with an acid resin in an acetone-water mixture or, more often, with an acid catalyst, in a solvent or a mixture of suitable solvents.
Alternativa za dobivanje aldehidskih spojeva formule 2, u kojoj supstituenti R7 i R8 predstavljaju svaki atom vodika, sastoji se u reagiranju bromiranih spojeva formule 6 s alilskim alkoholom u prisustvu baznog sredstva takvog kao što je trietilamin ih natrij bikarbonat, paladij dispergiran na ugljiku ili derivat paladija takav kao diklorid paladija ili njegov acetat i liganda, poželjno triarilfosfina kao naprimjer triortotolil fosfin u sredini otapala takvog kao što je N,N-dimetilformamid. An alternative for obtaining aldehyde compounds of formula 2, in which the substituents R7 and R8 each represent a hydrogen atom, consists in reacting brominated compounds of formula 6 with allyl alcohol in the presence of a base agent such as triethylamine, sodium bicarbonate, palladium dispersed on carbon or a palladium derivative such as palladium dichloride or its acetate and a ligand, preferably a triarylphosphine such as triorthotolyl phosphine in a solvent such as N,N-dimethylformamide.
Spojevi formule 5 mogu biti dobiveni prema sekvencama ilustriranima Shemom VI koja slijedi: Compounds of formula 5 may be prepared according to the sequences illustrated in Scheme VI which follows:
[image] [image]
prema kojoj se ketonski spojevi formule 12, u kojoj X, R1, R2, R5 i R6, imaju opća ili određena značenja koja su već definirana, tretiraju spojem litija ili magnezija formule 13, u kojoj R3 i R4 imaju opća ili prethodno definirana određena značenja, radi dodavanjem 1-2 alkohola, odgovarajućeg spoja 14, koji dehidratacijom daje spoj 5 pod djelovanjem dehidracijskog sredstva takvog kao što je kalij sulfat ili paratoluensulfonska kiselina. according to which ketone compounds of the formula 12, in which X, R1, R2, R5 and R6, have the general or specific meanings already defined, are treated with a lithium or magnesium compound of the formula 13, in which R3 and R4 have the general or previously defined specific meanings , works by adding 1-2 alcohols, the corresponding compound 14, which upon dehydration gives compound 5 under the action of a dehydrating agent such as potassium sulfate or paratoluenesulfonic acid.
Spojevi formule 12, u kojoj X predstavlja atome kisika i sumpora, a R1, R2, R5 i R6, imaju opća ili određena prethodno definirana značenja se dobivaju prema postupku KABEE-a et Coll. Synthesis, 12, 886, 1978. Compounds of formula 12, in which X represents oxygen and sulfur atoms, and R1, R2, R5 and R6 have the general or specific previously defined meanings are obtained according to the procedure of KABEE et Coll. Synthesis, 12, 886, 1978.
Spojevi formule 12, u kojoj X predstavlja metilenski lanac, a R1, R2, R5 i R6 s imaju opća ili određena značenja definirana naprijed se dobivaju prema reakcijskim sekvencama ilustriranima slijedećom Shemom VII: Compounds of formula 12, in which X represents a methylene chain and R1, R2, R5 and R6 have the general or specific meanings defined above are obtained according to the reaction sequences illustrated in the following Scheme VII:
[image] [image]
Kao što pokazuje Shema VII, cianoesteri formule 15, u kojoj R1, R2, R5 i R6, imaju opća ili određena značenja koja su već definirana se hidroliziraju i dekarboliziraju pomoću glikolnog kalij hidroksida u odgovarajuće kiseline 16 koje cikliziraju u spojeve 12 zagrijavanjem u kiseloj sredim. Spojevi formule 15 se dobivaju prema postupku koji je opisao PROUT et Coll, Org. Synth, Coll. vol. IV, 93, 1963. As shown in Scheme VII, the cyanoesters of formula 15, in which R1, R2, R5 and R6, have the general or specific meanings already defined, are hydrolyzed and decarbolized with glycolic potassium hydroxide to the corresponding acids 16, which cyclize to compounds 12 by heating in an acidic medium . Compounds of formula 15 are prepared according to the procedure described by PROUT et Coll, Org. Synth, Coll. vol. IV, 93, 1963.
Spojevi formule 1 u obliku estera mogu se jednako dobiti pomoću transesterifikacije spojeva formule I, različitih supstituenata R11, ili alkolizom spojeva formule 1 u obliku delta-laktona ili još O-alkilacijom spojeva formule 1 u obliku soli, poželjno soli natrija s broinidom ili jodidom formule Ru-br(I), u kojoj R11 ima opća ili određena značenja koja su prethodno definirana. Compounds of formula 1 in the form of esters can equally be obtained by means of transesterification of compounds of formula I, various substituents R11, or by alcoholysis of compounds of formula 1 in the form of delta-lactones or also by O-alkylation of compounds of formula 1 in the form of salts, preferably sodium salts with broinide or iodide of the formula Ru-br(I), in which R11 has the general or specific meanings previously defined.
Esteri koji odgovaraju formuli 1, u kojoj supstituenti R7 i R8 svaki predstavlja atom vodika mogu se također dobiti hidrogenizacijom odgovarajućih estera formule 1, u kojoj, supstituenti R7 i R8 grade jednu vezu, poželjno pod sniženim tlakom, u prisustvu metalnog katalizatora kao što je pladij ili platina oksid u pogodnom otapalu kao što je naprimjer THF. Esters corresponding to formula 1, in which the substituents R7 and R8 each represent a hydrogen atom can also be obtained by hydrogenation of the corresponding esters of formula 1, in which the substituents R7 and R8 form a single bond, preferably under reduced pressure, in the presence of a metal catalyst such as palladium or platinum oxide in a suitable solvent such as, for example, THF.
Spojevi formule 1 u obliku soli mogu se dobiti na primjer baznom hidrolizom s natrij ih kalij hidroksidom u pogodnom otapalu, poželjno alkoholu odgovarajućih spojeva formule 1 u obliku estera, poželjno metil ih etil estera ih u obliku delta-laktona. Compounds of formula 1 in the form of salts can be obtained, for example, by basic hydrolysis with sodium potassium hydroxide in a suitable solvent, preferably alcohol, of the corresponding compounds of formula 1 in the form of esters, preferably methyl ethyl esters in the form of delta-lactone.
Delta-laktonski spojevi formule 1, u kojoj supstituenti R7 i R8 grade zajedno jednu vezu, mogu se dobiti reagiranjem odgovarajućih spojeva formule 1 u obliku soli, poželjno soh natrija s kloraminom, poželjno kloro-2-etil-N,N-dietilamin u odgovarajućem otapalu, poželjno karbonilnom kao što je aceton ih butanon. Delta-lactone compounds of formula 1, in which the substituents R7 and R8 together form one bond, can be obtained by reacting the corresponding compounds of formula 1 in the form of salts, preferably sodium hydroxide with chloramine, preferably chloro-2-ethyl-N,N-diethylamine in the appropriate solvent, preferably a carbonyl such as acetone or butanone.
Laktonski spojevi formule 1, u kojoj R7 i R8 i R10 predstavljaju atom vodika, dobivaju se laktonizacijom odgovarajućih kiselina formule 1 što će reći formula u kojima Rn predstavlja hidroksi radikal: reakcija laktonizacije se poželjno izvodi zagrijavanjem kiselina u inertnom aromatičnom otapalu, takvom kao što je benen, toluen, ksilen ih njihova smjesa, slučaj zahtijeva prisustvo dehidracijskog sredstva, kao što je naprimjer paratoluensulfonska kiselina; jedan drugi postupak vrlo prihvatljiv za dobivanje delta-laktonskih spojeva formule 1, u kojoj R7 i R8i R10 predstavljaju atom vodika, sastoji se u hidrogeniziranju u heterogenoj fazi, nezasićenih odgovarajućih spojeva formule 1, što će reći formule u kojima R7 i R8, odnosno R9 i R10 grade zajedno jednu vezu, u prisustvu metalnog katalizatora, poželjno paladija dispergiranog na ugljiku oksida platine, u sredini odgovarajućeg otapala, poželjno etera kao što je THF ih alkohol kao što je metanol ih etanol. Lactone compounds of formula 1, in which R7 and R8 and R10 represent a hydrogen atom, are obtained by lactonization of the corresponding acids of formula 1, that is, formulas in which Rn represents a hydroxy radical: the lactonization reaction is preferably performed by heating acids in an inert aromatic solvent, such as benzene, toluene, xylene and their mixture, the case requires the presence of a dehydrating agent, such as for example paratoluenesulfonic acid; another very acceptable procedure for obtaining delta-lactone compounds of formula 1, in which R7 and R8 and R10 represent a hydrogen atom, consists in hydrogenation in a heterogeneous phase of unsaturated corresponding compounds of formula 1, that is to say formulas in which R7 and R8, respectively R9 and R10 form a single bond together, in the presence of a metal catalyst, preferably palladium dispersed on the carbon of platinum oxide, in the middle of a suitable solvent, preferably an ether such as THF or an alcohol such as methanol or ethanol.
Spojevi, kiseline formule 1 u kojoj R9 i R10 označavaju svaki atom vodika, mogu se dobiti zakiseljavanjem odgovarajućih spojeva formule 1 u obliku soli ih još hidrogenolizom, u prisustvu paladija dispergiranog na ugljiku, odgovarajućih benzilskih estera što će reći spojeva formule 1 u kojoj R11 predstavlja benziloksi ostatak. Compounds, acids of the formula 1 in which R9 and R10 each represent a hydrogen atom, can be obtained by acidifying the corresponding compounds of the formula 1 in the form of salts by further hydrogenolysis, in the presence of palladium dispersed on carbon, of the corresponding benzylic esters, that is, compounds of the formula 1 in which R11 represents benzyloxy residue.
Spojevi formule 1 u obliku amida se dobivaju aminohzom s viškom amina u sredini polarnog otapala poželjno metanola ih etanola, odgovarajućih estera formule 1 poželjno metilenskih ih etilenskih estera ih odgovarajućih spojeva formule 1 u obliku delta-laktona. Compounds of formula 1 in the form of amides are obtained by aminolysis with an excess of amine in the middle of a polar solvent, preferably methanol or ethanol, the corresponding esters of formula 1, preferably methylene or ethylene esters, or the corresponding compounds of formula 1 in the form of delta-lactone.
Spojevi formule 1, u kojoj supstituenti R9 i R10 grade zajedno dialkilmetilensku grupu u Cl-3, dobivaju se reakcijom odgovarajućih spojeva formule 1, u kojoj R9 i R10 svaki predstavlja atom vodika s odgovarajućim alkoksialkenom (termin alkoksiaken označava alken sa 3 do 7 atoma ugljika supstituiran na dvostrukoj vezi s alkoksi radikalom, takvim kao što je definirano naprijed, poželjno metoksi) u odgovarajućem otapalu, takvom kao što je N,N-dimetilformamid naprimjer u prisustvu kiselog katalizatora kao što je paratolensulfonska kiselina. The compounds of formula 1, in which the substituents R9 and R10 together form a dialkylmethylene group in Cl-3, are obtained by the reaction of the corresponding compounds of formula 1, in which R9 and R10 each represent a hydrogen atom with the corresponding alkoxyalkene (the term alkoxyalkene means an alkene with 3 to 7 carbon atoms substituted at the double bond with an alkoxy radical, such as defined above, preferably methoxy) in a suitable solvent, such as N,N-dimethylformamide for example in the presence of an acid catalyst such as paratoluenesulfonic acid.
Pogodno je zapaziti da se spojevi izuma u svojim različitim oblicima : kiselina, sol, ester, amid ili lakton mogu međusobno prevoditi iz jednog oblika u drugi postupcima opisanima naprijed; kao posljedica ovoga ovi različiti oblici su istovremeno intermedijeri u sintezi spojeva prema izumu. It is convenient to note that the compounds of the invention in their various forms: acid, salt, ester, amide or lactone can be mutually converted from one form to another in the procedures described above; as a consequence of this, these different forms are simultaneously intermediates in the synthesis of compounds according to the invention.
Stereoizomerne smjese (cis, trans, treo, eritro, enantiomeri) mogu se razdvojiti uobičajenim postupcima, u stadijima sinteze koji su najpogodniji. Stereoisomeric mixtures (cis, trans, threo, erythro, enantiomers) can be separated by the usual procedures, at the most convenient stages of the synthesis.
Uobičajeni postupci za razdvajanje najčešće su na primjer, rekristalizacija, kromatografija, ili građenje spojeva s optimalno aktivnim spojevima. Common procedures for separation are, for example, recrystallization, chromatography, or building compounds with optimally active compounds.
Intermedijerni spojevi sinteze kojima odgovaraju formule 2, 4, 5, 6, 7, 8, 9, 10, Ili 14 podjednako čine dio izuma, s izuzetkom proizvoda formule 5 gdje R1 i R2 predstavljaju H, a X predstavlja S ili CH2, neki od ovih spojeva bili su poznati ranije, Degani, Ann. Chem (Rim) 1971, 61(2) str. 793-813 i Penn. J. Magn. Reson.1975. 18(1), str. 6-11. Intermediate synthesis compounds corresponding to formulas 2, 4, 5, 6, 7, 8, 9, 10, or 14 equally form part of the invention, with the exception of products of formula 5 where R1 and R2 represent H and X represents S or CH2, some of of these compounds were known earlier, Degani, Ann. Chem (Rome) 1971, 61(2) p. 793-813 and Penn. J. Magn. Reson. 1975. 18(1), p. 6-11.
Ovaj izum se odnosi podjednako na dobivanje i intermedijera sinteze. This invention relates equally to the preparation of synthesis intermediates.
Spojevi formule 1 imaju osobinu inhibiranja hidroksi-3 metil-3glutarnog koenzima A, i stoga pokazuju jaki hipokolesterolemiantni učinak. The compounds of formula 1 have the property of inhibiting hydroxy-3 methyl-3glutaric coenzyme A, and therefore exhibit a strong hypocholesterolemic effect.
Spojevi formule 1 su sposobni kao antagonisti receptora tromboksana A2, što je osobina koja se objašnjava antiagregacijskim djelovanjem pločica. Compounds of formula 1 are capable as antagonists of the thromboxane A2 receptor, which is a feature that is explained by the antiplatelet action of platelets.
Ove osobine spojeva izuma, čine naročito zanimljivim njihovo korištenje kao medikamenata za tretiranje raznih kardiovaskularnih bolesti kao što su, naprimjer, trombotične manifestacije dijabetesa, arterioskleroza, biperlipoproteimemie. These properties of the compounds of the invention make their use as drugs for the treatment of various cardiovascular diseases, such as, for example, thrombotic manifestations of diabetes, arteriosclerosis, biperlipoproteimemia, particularly interesting.
Osim toga, spojevi izuma posjeduju antifongističke osobine što ih čini naročito interesantnima kao medikamenata za antimikotinsko djelovanje. In addition, the compounds of the invention possess antifungal properties, which makes them particularly interesting as drugs for antimycotic activity.
Farmakološke osobine spojeva prema izumu su pokazane slijedećim testovima: The pharmacological properties of the compounds according to the invention were demonstrated by the following tests:
Test A: mjerenjem hepatitske 14C-kolesterogeneze, in vivo, kod štakora prema postupku koji su opisali BUCHER et Coll, J. Biol. Chem, 222, ,1 - 15, 1956 i ELBERTS et Coll, Proc. Natl. Acad. Sci. USA, 77(7), 3957 - 3961, 1980. Test A: by measuring hepatic 14C-cholesterogenesis, in vivo, in rats according to the procedure described by BUCHER et Coll, J. Biol. Chem, 222, ,1-15, 1956 and ELBERTS et Coll, Proc. Natl. Acad. Sci. USA, 77(7), 3957 - 3961, 1980.
Test B: mjerenjem ukupne kolesterolemie, in vivo. kod štakora intravenozno tretiranih s tritonom WR 1339 prema postupku koji je opisao ENDO et Coll, Biochem. Biophvs. Acta, 575, 226 - 276, 1979. Test B: by measuring total cholesterolemia, in vivo. in rats treated intravenously with triton WR 1339 according to the procedure described by ENDO et Coll, Biochem. Biophvs. Acta, 575, 226 - 276, 1979.
Test C: mjerenjem pločaste agregacije izazvane pomoću agonista receptora TXA2 kod morskog praseta na slijedeći način: plazme bogate pločicama (PRP) su dobivene punktiranjem aorte anesteziranih životinja; krv (9 zap.) je stavljena u otopinu koja sadrži 106 mM trinatrij citrata (1 zap.) radi sprječavanja koagulacije. PRP su izolirane laganim centrifugiranjem (10 min, 380 g) i stavljene su na inkubaciju tijekom barem 3 min (37 °C, uz sporo miješanje) u agregometru tipa CHRONOLOG-400. Agregacija pločica je izvedena dodatkom agonista direktnih receptora TXA2, kao na primjer spoja poznatog pod imenom šifre U 46619 (20 nM) prema MALMSTEIN-u, Life Sci, 18, 169, 178, 1976; spojevi izuma su testirani in vitro. Test C: by measuring platelet aggregation induced by TXA2 receptor agonists in guinea pigs in the following manner: platelet-rich plasma (PRP) was obtained by puncturing the aorta of anesthetized animals; blood (9 vol.) was placed in a solution containing 106 mM trisodium citrate (1 vol.) to prevent coagulation. PRPs were isolated by gentle centrifugation (10 min, 380 g) and were incubated for at least 3 min (37 °C, with slow mixing) in a CHRONOLOG-400 type aggregometer. Aggregation of platelets was performed by the addition of TXA2 direct receptor agonists, such as the compound known under the code name U 46619 (20 nM) according to MALMSTEIN, Life Sci, 18, 169, 178, 1976; compounds of the invention have been tested in vitro.
Na primjer pri testiranju spojeva br. 1,2, 19 i 65 prema testu A korišten je DE 50 u količini 0,17 mg/kg, 0,6 mg/kg, 0,09 mg/kg i 0,38 mg/kg respektivno, a za Lovastatin u istim uvjetima 0,39 mg/kg. For example, when testing compounds no. 1,2, 19 and 65 according to test A DE 50 was used in the amount of 0.17 mg/kg, 0.6 mg/kg, 0.09 mg/kg and 0.38 mg/kg respectively, and for Lovastatin in the same conditions 0.39 mg/kg.
Za iste spojeve u testu B, korišten je DE 25 u količini od 29,100,110 i 74 mg/kg respektivno i 130 mg/kg za Lovastatin. U testu C za spojeve br. 1 i 19 korištenje CI 50 od 91 i 28 10-6 mola/L. For the same compounds in test B, DE 25 was used in amounts of 29, 100, 110 and 74 mg/kg respectively and 130 mg/kg for Lovastatin. In test C for compounds no. 1 and 19 use CI 50 of 91 and 28 10-6 mol/L.
Ovaj izum se podjednako odnosi na medikamente koji sadrže spojeve opće formule 1 uzetih takvih, u čistom stanju ih zajedno s drugim proizvodima prihvatljivih s farmaceutskog gledišta koji mogu biti inertni ih fiziološki aktivni. This invention equally relates to medicaments containing compounds of the general formula 1 taken as such, in their pure state together with other products acceptable from a pharmaceutical point of view which may be inert or physiologically active.
Ovi medikamenti se mogu unositi u organizam u raznim oblicima takvim kao što su tablete, dražeje, kapsule, granule, praškovi itd. U ovim preparatima aktivni princip je smjesa u jednom ih više inertnih razrjeđivača takvih kao što je laktoza ih škrob, u drugim preparatima mogu biti prisutne i druge supstancije, a ne samo razrjeđivači, na primjer lubrikanti takvi kao talk ih magnezij stearat; u slučaju vodenih suspenzija, eliksira ih za oralno unošenje, aktivni sastojak može biti vezan s raznim supstancijama za bojenje i aromu, i u slučaju emulzija osi dodataka za suspenzrranje ove mogu sadržavati još i takve razrjeđivače kao što su voda, etanol, propilen glikol i slično. These medications can be taken into the body in various forms such as tablets, dragees, capsules, granules, powders, etc. In these preparations, the active principle is a mixture of several inert diluents such as lactose and starch, in other preparations they can be present and other substances, not only diluents, for example lubricants such as talc and magnesium stearate; in the case of aqueous suspensions, elixirs for oral administration, the active ingredient can be bound with various substances for coloring and flavoring, and in the case of emulsions, the axis of suspension additives can also contain such diluents as water, ethanol, propylene glycol and the like.
Farmaceutski preparati prema izumu, namijenjeni za oralno unošenje i prikazani u obliku pojedinačne doze, sadrže od 1 do 500 mg aktivnog principa. Pharmaceutical preparations according to the invention, intended for oral administration and presented in the form of a single dose, contain from 1 to 500 mg of the active principle.
Slijedeći primjer dan je ne u cilju ograničavanja već ilustriranja jednog preparata ovog tipa. The following example is given not to limit but to illustrate one preparation of this type.
Primjer: Example:
Aktivni princip 10 mg Active principle 10 mg
laktoza 104 mg lactose 104 mg
žitni škrob 30 mg cereal starch 30 mg
talk 2,5 mg talc 2.5 mg
polivinil ekscepient 3 mg polyvinyl excipient 3 mg
magnezij stearat 0,5 mg magnesium stearate 0.5 mg
Izum je ilustriran ne ograničavajućim primjerima danima u daljnjem tekstu, u kojima: The invention is illustrated by non-limiting examples given below, in which:
- su izvršena sva isparavanja, osim ako nije drugačije naznačeno, u rotacijskom uparivaču pod sniženim tlakom; - all evaporations were carried out, unless otherwise indicated, in a rotary evaporator under reduced pressure;
- sve temperature su dane u stupnjevima °C; - all temperatures are given in degrees °C;
- kada je naznačeno "sobna temperatura", podrazumijeva temperaturu između 18 i 25 °C; - when "room temperature" is indicated, it means a temperature between 18 and 25 °C;
- osim kada je drukčije naglašeno, stupanj napredovanja reakcije je kontroliran krornatografski na tankom sloju (CCM); - unless otherwise stated, the degree of progress of the reaction is controlled by thin-layer chromatography (CCM);
- novi spojevi su okarakterizirani svojim fizikalnim konstantama, tahštem tt. ih točkom vrenja tklj. uz eventualno naznačavanje tlaka u mihbarima; - new compounds are characterized by their physical constants, tahšte tt. them by the boiling point, i.e. with possibly indicating the pressure in the mihbars;
prinosi eventualno dani su dani u jednoj vrijednosti koja nije najveća moguća; yields possibly given are given in one value which is not the highest possible;
- spektri nuklearne magnetne rezonance, ako nije drukčije naglašeno, su protonski i dani na 60 Mhz u prisustvu tetrametilsilana kao inertnog etalona; kemijska premještanja su naznačena u ppm, signali su opisani slijedećim skraćenicama, s singulet, d dublet, dd i dublet i dublet, t triplet, q kvartet, m multiplet; - nuclear magnetic resonance spectra, unless otherwise stated, are proton and given at 60 Mhz in the presence of tetramethylsilane as an inert standard; chemical shifts are indicated in ppm, signals are described by the following abbreviations, s singlet, d doublet, dd i doublet i doublet, t triplet, q quartet, m multiplet;
- infracrveni spektri spojeva registrirani na tabletiranoj disperziji kalij bromida u slučaju čvrste supstancije ili filmu u slučaju tekućine. - infrared spectra of compounds registered on tableted dispersion of potassium bromide in the case of a solid substance or film in the case of a liquid.
Primjer 1. Example 1.
(+,-)-6E-eritro-((fluoro-4-fenil)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3)-7-dikidroksi-3,5-hepten-6-etilat (spoj br. 1. formule 1: X = 0, R1 - R2 = (CH2)4-, R3 = 4T, R4 = R5 = R6 = R9 = R10 = H, R7 - R8 = veza, R11 = OC2H5). (+,-)-6E-erythro-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5-heptene- 6-ethylate (compound No. 1 of formula 1: X = 0, R1 - R2 = (CH2)4-, R3 = 4T, R4 = R5 = R6 = R9 = R10 = H, R7 - R8 = bond, R11 = OC2H5).
Stadij 1 Stage 1
(fluoro-4-fenil)-4-dihidro-3,4-hidroksi-4-spiro(2H-benzopiran-1-2,1'-ciklopentan) (Shema VI - formula 14). (fluoro-4-phenyl)-4-dihydro-3,4-hydroxy-4-spiro(2H-benzopyran-1-2,1'-cyclopentane) (Scheme VI - formula 14).
Radi se u atmosferi dušika u reaktoru zaštićenom od vlage. U 6,07 g (0,25 gram atoma) magnezija suspendiranog u 130 cm3 dietileter, dodaje se uz održavanje blagog refluksa etera, 43,75 g (0,25 mola) bromo-l-fluoro-4-benzena otopljenog u 200 cm3 dietiletera. Poslije održavanja smjese na refluksu tijekom 4 sata, smjesa se ohladi do sobne temperature i na ovoj temperaturi se doda 20 g (0,1 mol) spiro(2H-benzopiran-1-2,1'-ciklopentanon-4) (dobivenog prema Kolbe et Coll, Svnthesis 12, 886, 1978) otopljenog u 60 cm3 dietiletera, uz održavanje blagog refluksa etera. It is done in a nitrogen atmosphere in a reactor protected from moisture. To 6.07 g (0.25 gram atoms) of magnesium suspended in 130 cm3 of diethyl ether, while maintaining a slight reflux of ether, 43.75 g (0.25 mole) of bromo-1-fluoro-4-benzene dissolved in 200 cm3 of diethyl ether. After maintaining the mixture at reflux for 4 hours, the mixture was cooled to room temperature and at this temperature 20 g (0.1 mol) of spiro(2H-benzopyran-1-2,1'-cyclopentanone-4) (obtained according to Kolbe) was added et Coll, Synthesis 12, 886, 1978) dissolved in 60 cm 3 of diethyl ether, while maintaining a gentle ether reflux.
Smjesa se miješa tijekom 2 sata na sobnoj temperaturi, a zatim se prelije na smrznutu vodenu otopinu amonij klorida u velikom višku u odnosu na stehiometrijski odnos; doda se dovoljna količina razrijeđene klorovodične kiseline radi potpunog otapanja suspenzije, zatim se dekantira organska faza; ispere se vodom na neutralnom pH i suši na natrij sulfatu, filtrira i otapalo se upari; dobiva se 30 g ulja koje se takvo kakvo je koristi u nastavku sinteze. The mixture is stirred for 2 hours at room temperature and then poured onto a frozen aqueous solution of ammonium chloride in a large excess over the stoichiometric ratio; a sufficient amount of dilute hydrochloric acid is added to completely dissolve the suspension, then the organic phase is decanted; washed with water at neutral pH and dried over sodium sulfate, filtered and the solvent evaporated; 30 g of oil is obtained, which is used as is in the continuation of the synthesis.
Stadij 2: Stage 2:
(Fluoro-4-fenil)4-spiro(2H-benzopiran-1 -2,1 '-ciklopentan) (Shema VI- formula 5). (Fluoro-4-phenyl)4-spiro(2H-benzopyran-1-2,1'-cyclopentane) (Scheme VI - formula 5).
Zagrijava se na sniženom tlaku (16 mm Hg) na temperaturi od 120 °C smjesa 30 g (0,1 mol) proizvoda iz etape 1 i 3 g KHSO4 (1/10 mase spoja koji se razmatra) tijekom 30 minuta. Otopiti ostatak u dovoljnoj količini diklormetana, isprati otopinu vodom, zatim ga sušiti na natrij sulfatu, filtrirati i ispariti otapalo; dobivena čvrsta supstancija se dispergira u metil alkoholu. A mixture of 30 g (0.1 mol) of the product from step 1 and 3 g of KHSO4 (1/10 of the mass of the compound under consideration) is heated under reduced pressure (16 mm Hg) at a temperature of 120 °C for 30 minutes. Dissolve the residue in a sufficient amount of dichloromethane, wash the solution with water, then dry it over sodium sulfate, filter and evaporate the solvent; the obtained solid substance is dispersed in methyl alcohol.
tt. 76-8 ° (diizopropileter) - Prinos 75 %. tt. 76-8 ° (diisopropyl ether) - Yield 75 %.
(CCM: silika gel: etil acetat (AcOEt)-heksan: 5-95: 1 mrlja (CCM: silica gel: ethyl acetate (AcOEt)-hexane: 5-95: 1 spot
Analiza C19H17FO M = 280,33 Analysis C19H17FO M = 280.33
C H F CH F
% izračunato 81,40 6,11 6,78 % calculated 81.40 6.11 6.78
% nađeno 81,53 6,20 6,76 % found 81.53 6.20 6.76
NMR (CDCl3): 1,25 - 2,70 (m, 8H); 5,73 (s, IH); 6,50 - 7,87 (m, 8H) NMR (CDCl 3 ): 1.25 - 2.70 (m, 8H); 5.73 (s, IH); 6.50 - 7.87 (m, 8H)
Stadij 3 Stage 3
2E-((Fluoro-4-fenil)-4-spiro(2H-benzopiran-1-2,1 '-ciklopentil)-3 )-3 -propen-2-al (Shema II - formula 2) 2E-((Fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-3-propen-2-al (Scheme II - formula 2)
Radi se pod atmosferom dušika, u reaktoru zaštićenom od vlage. Ako nije drugačije naglašeno, tijekom slijedećih operacija temperatura reakcijske smjese se održava na -20 °C. U otopinu 20,9 g (0,2 mola) N,N-dimetilamino-3 akroleina u 200 cm3 acetonitrila, dodaje se u razmaku od 30 min uz miješanje, 29,1 g (0,19 mola) fosfor oksiklorida; potrebno je miješanje tijekom 10 min a zatim se dodaje tijekom 15 min 11,2 g (0,04 mola) spoja iz stadija 2 otopljenog u 100 cm3 acetonitrila. Ostaviti zatim smjesu da zauzme sobnu temperaturu i grijati je zatim na refluksu dok se odlazak proizvoda kontrolira kromatografijom na tankom sloju; u ovom slučaju potrebno vrijeme grijanja je 40 sati. It is done under a nitrogen atmosphere, in a reactor protected from moisture. Unless otherwise stated, during the following operations the temperature of the reaction mixture is maintained at -20 °C. In a solution of 20.9 g (0.2 mol) of N,N-dimethylamino-3 acrolein in 200 cm3 of acetonitrile, 29.1 g (0.19 mol) of phosphorus oxychloride is added at intervals of 30 minutes with stirring; stirring is required for 10 min and then 11.2 g (0.04 mol) of the compound from stage 2 dissolved in 100 cm3 of acetonitrile is added over 15 min. Leave the mixture to reach room temperature and then heat it at reflux while the departure of the product is controlled by thin-layer chromatography; in this case, the required heating time is 40 hours.
Smjesa se upari i ostatak se izruči u 1000 cm3 ledene vode, neutralizira (pH = 9) dodavanjem dovoljne količine koncentriranog natrij karbonata, otopina se miješa 15 min i zatim se ekstrahira sa 1000 cm3 metilen klorida (2 x 500 cm3). Organski sloj se ispere vodom i osuši na natrij sulfatu, filtrira, doda se 1000 cm3 heksana i miješa se u prisustvu 100 g silika gela. Poslije filtriranja i uparavanja dobiva se ulje koje kristalizira dajući žutu čvrstu supstanciju dispergiranjem u heksanu, The mixture is evaporated and the residue is poured into 1000 cm3 of ice water, neutralized (pH = 9) by adding a sufficient amount of concentrated sodium carbonate, the solution is stirred for 15 min and then extracted with 1000 cm3 of methylene chloride (2 x 500 cm3). The organic layer is washed with water and dried over sodium sulfate, filtered, 1000 cm3 of hexane is added and mixed in the presence of 100 g of silica gel. After filtration and evaporation, an oil is obtained which crystallizes giving a yellow solid by dispersing in hexane,
tt. 108 - 111 °C (diizopropileter) - prinos 8,4 g = 63 %. tt. 108 - 111 °C (diisopropyl ether) - yield 8.4 g = 63 %.
Analiza C22H19FO2 M = 334,37 Analysis C22H19FO2 M = 334.37
C H F CH F
% izračunato 79,02 5,73 5,68 % calculated 79.02 5.73 5.68
% nađeno 78,82 5,75 5,65 % found 78.82 5.75 5.65
IC: IR:
VCHO: 1670 cm-1NMR (CDCl3): 1,25 - 2,87 (m, 8H); 5,98 (dd, IH J = 17 Hz i 7 Hz); 6,37 - 7,5 (m, 9H); 9,25 (d, IH J = 7 Hz). VCHO: 1670 cm -1 NMR (CDCl 3 ): 1.25 - 2.87 (m, 8H); 5.98 (dd, IH J = 17 Hz and 7 Hz); 6.37 - 7.5 (m, 9H); 9.25 (d, IH J = 7 Hz).
Stadij 4: Stage 4:
(+,-)-6E-((fluoro-4-fenil)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3)-7-hidroksi-5-okso-3 -hepten-6-etilat (+,-)-6E-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-hydroxy-5-oxo-3-heptene- 6-ethylate
(Shema I-formule 4). (Scheme I-Formula 4).
Radi se pod atmosferom dušika i u odsustvu vlage, održavajući temperaturu smjese ako nije drugačije naglašeno na -20 °C. U suspenziju 1,2 g (0,05 mola) natrij hidrida u 300 cm3 tetrahidrorarana (THF) doda se 5,6 g (0,043 mola) etil acetoacetata otopljenog u 25 cm3 THF; smjesa se miješa tijekom 20 min zatim poslije 15 - 20 min se dodaje 27 cm3 otopine 1,6 N butillitija u heksanu (0,043 mola BuLi); poslije miješanja smjese tijekom 20 minuta kap po kap se doda u otopinu 8,7 g (0,026 mola) aldehida iz stadija 3 u 140 cm3THF. Poslije miješanja smjese tijekom 3 sata, dodaje se kap po kap 40 ml 3 N otopine klorovodične kiseline na temperaturi između -20 °C i 10 °C. Ekstrahira se u etil acetatu, ispere se vodom organska faza do pH 7, osuši se iznad natrij sulfata, zatim se upari do suhog, dobiva se ulje koje kristalizira dispergiranjem u heksanu. tt: 87 - 90 °C (etil acetat) - Prinos = 110 g = 90,9 % (CCM: silika gel: AcOEt-heksan: 1 - 2: 1 mrlja) It is done under a nitrogen atmosphere and in the absence of moisture, maintaining the temperature of the mixture unless otherwise stated at -20 °C. 5.6 g (0.043 mol) of ethyl acetoacetate dissolved in 25 cm3 of THF is added to a suspension of 1.2 g (0.05 mol) of sodium hydride in 300 cm3 of tetrahydrofuran (THF); the mixture is stirred for 20 min, then after 15 - 20 min, 27 cm3 of a solution of 1.6 N butyllithium in hexane (0.043 mol of BuLi) is added; after stirring the mixture for 20 minutes, 8.7 g (0.026 mol) of aldehyde from stage 3 in 140 cm3THF was added drop by drop. After stirring the mixture for 3 hours, 40 ml of 3 N hydrochloric acid solution is added drop by drop at a temperature between -20 °C and 10 °C. It is extracted in ethyl acetate, the organic phase is washed with water to pH 7, dried over sodium sulfate, then evaporated to dryness, an oil is obtained which crystallizes by dispersing in hexane. mp: 87 - 90 °C (ethyl acetate) - Yield = 110 g = 90.9 % (CCM: silica gel: AcOEt-hexane: 1 - 2: 1 spot)
Analiza C28H29FO5 M = 464,51 Analysis C28H29FO5 M = 464.51
C H F CH F
% izračunato 72,40 6,29 4,09 % calculated 72.40 6.29 4.09
% nađeno 72,33 6,31 4,05 % found 72.33 6.31 4.05
IC: IR:
VOH: 3420 cm-1 VOH: 3420 cm-1
VCO: 1740 i 1710 cm-1 VCO: 1740 and 1710 cm-1
NMR (CDCl3): 1,32 (3, 3H); 1,5 - 2,35 (m, 8H); 2,52 (d, 2H); 3,92 - 4,65 (m, 39H); 5,30 (dd, IH J =15, 8 Hz); 6,25 - 7,50 (m, 8H). NMR (CDCl 3 ): 1.32 (3, 3H); 1.5 - 2.35 (m, 8H); 2.52 (d, 2H); 3.92 - 4.65 (m, 39H); 5.30 (dd, IH J =15, 8 Hz); 6.25 - 7.50 (m, 8H).
Stadij 5: Stage 5:
(+,-)-6E-((fluoro-4-fenil)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil))-3)-7-dihidroksi-3,5-hepten-etilat (spoj br. 1). (+,-)-6E-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl))-3)-7-dihydroxy-3,5-heptene-ethylate (compound no. 1).
Radi se pod atmosferom dušika u reaktoru zaštićenom od vlage. Ako nije drugačije naglašeno, tijekom slijedećih operacija temperature reakcijske smjese se održava na -70°C. U otopinu 3,25 g (0,007 mola) četo estera iz stadija 4 u smjesi sa 65 cm3 THF i 15 cm3 metanola se s pauzom od 5 min uz miješanje doda 7,7 cm3 otopine 1 N dietilmetoksiboran u THF (0,007 mola + 10 % borana). It is done under a nitrogen atmosphere in a reactor protected from moisture. Unless otherwise stated, during the following operations the temperature of the reaction mixture is maintained at -70°C. In a solution of 3.25 g (0.007 mol) of the cheto ester from stage 4 in a mixture with 65 cm3 of THF and 15 cm3 of methanol, 7.7 cm3 of a solution of 1 N diethylmethoxyborane in THF (0.007 mol + 10 % wrinkle).
Poslije miješanja smjese tijekom 40 min doda se 0,29 g (0,007 mola + 10 % natrij borohidrida. Poslije miješanja smjese tijekom 5 sati ova se zakiseljava dodatkom 6,5 cm3 octene kiseline, poslije čega se dodaje 80 cm3 etil acetata. Smjesa se ostavi da zauzme sobnu temperaturu; zatim se smjesa ispere sa zasićenom vodenom otopinom bikarbonata natrija (2 x 200 cm3) i zatim s vodom; dekantira se organska faza, osuši se iznad natrij sulfata i zatim se upari otapalo. Dobiveno zaostalo ulje se otopi u 60 cm3metanola; ova otopina se miješa tijekom 20 min na 35 °C i zatim se upari do suhog. Ova operacija se ponavlja do postizanja konstantne mase, u ovom slučaju operacija je ponavljana četiri puta. After stirring the mixture for 40 min, 0.29 g (0.007 mol + 10% sodium borohydride) is added. After stirring the mixture for 5 hours, it is acidified by adding 6.5 cm3 of acetic acid, after which 80 cm3 of ethyl acetate is added. The mixture is left to take room temperature; then the mixture is washed with a saturated aqueous solution of sodium bicarbonate (2 x 200 cm3) and then with water; the organic phase is decanted, dried over sodium sulfate and then the solvent is evaporated. The residual oil obtained is dissolved in 60 cm3 of methanol ; this solution is stirred for 20 min at 35 °C and then evaporated to dryness. This operation is repeated until a constant mass is reached, in this case the operation was repeated four times.
Zatim se dobiva 3,1 g čvrste supstancije koja se dispergira u diizopropileteru. tt. 112 - 114 °C (etil acetat) - Prinos = 2,48 g = 76 %. (CCM: silika gel: AcOEt-heksan: 1-1:1 mrlju) Then 3.1 g of a solid substance is obtained which is dispersed in diisopropyl ether. tt. 112 - 114 °C (ethyl acetate) - Yield = 2.48 g = 76 %. (CCM: silica gel: AcOEt-hexane: 1-1:1 stain)
Analiza C28H31FO5 M - 466,55 Analysis C28H31FO5 M - 466.55
C H F CH F
% izračunato 72,08 6,70 4,07 % calculated 72.08 6.70 4.07
% nađeno 72,82 6,83 3,90 % found 72.82 6.83 3.90
IC: IR:
VOH: 3390 cm-1 VOH: 3390 cm-1
VCO =1715 cm-1 VCO = 1715 cm-1
NMR (CDCl3) -200 MHz: 1,275 (t, 3H); 1,20 - 1,58 (m, 2H) 1,60 - 2,29 (m, 8H); 2,36 - 2,44 (m, 2H); 4,17 (q, 2H); 4,00 - 4,29 (m, 2H); 5,34 (dd, IH J = 16,1 Hz i J = 6,3 Hz); 5,94 (dd, IH J = 16, 1 Hz i 1,2 Hz); 6,54 (dd IH J = 7,7 Hz i 1,5 Hz); 6,70 - 6,85 (m, 2H); 7,00 - 7,20 (m, 5H). NMR (CDCl 3 ) -200 MHz: 1.275 (t, 3H); 1.20 - 1.58 (m, 2H) 1.60 - 2.29 (m, 8H); 2.36 - 2.44 (m, 2H); 4.17 (q, 2H); 4.00 - 4.29 (m, 2H); 5.34 (dd, IH J = 16.1 Hz and J = 6.3 Hz); 5.94 (dd, IH J = 16, 1 Hz and 1.2 Hz); 6.54 (dd IH J = 7.7 Hz and 1.5 Hz); 6.70 - 6.85 (m, 2H); 7.00 - 7.20 (m, 5H).
HPLC: HPLC:
Silicij dioksidna kolona 5 sferna 25 cm Silicon dioxide column 5 spherical 25 cm
Detekcija UV - 254 nm UV detection - 254 nm
Pokretna faza: AcOEt-heksan-AcOH: 35-65-0,01 Mobile phase: AcOEt-hexane-AcOH: 35-65-0.01
1 pik: (11,1 min) 1 peak: (11.1 min)
Primjer 2. Example 2.
(+)-6E-eritro-(dihidro-1,2-dimetil-2,2-fenil-4-naftil-3)-7-dihidroksi-3,5 -hepten-6-metilat (+)-6E-erythro-(dihydro-1,2-dimethyl-2,2-phenyl-4-naphthyl-3)-7-dihydroxy-3,5-heptene-6-methylate
(Spoj br. 2 - formule 1 : X = CH2; R1 = R2 = CH3; R3 = R4 = R5; R6 = R9 = R10 = H; R7 i Ks = veza; R11 = OCH3) (Compound no. 2 - formula 1: X = CH2; R1 = R2 = CH3; R3 = R4 = R5; R6 = R9 = R10 = H; R7 and Ks = bond; R11 = OCH3)
Stadij 1: Stage 1:
Etil(dimetil-2,2-fenil-3-propil)-2-cianoacetat (Shema VII-formula 15) Ethyl (dimethyl-2,2-phenyl-3-propyl)-2-cyanoacetate (Scheme VII-formula 15)
U suspenziju 19,2 g (0,79 gram atoma) magnezija u 100 cm3 etera dodaje se uz održavanje blagog refluksa otopina 100 g (0,79 mola) benzil klorida u 400 cm3 etera. Smjesa se na refluksu zagrijava 15 min a zatim se dodaje uz održavanje blagog refluksa otopina 101,1 g (0,66 mola) etil izopropiliden cianacetata u 130 cm3 etera. Smjesa se na refluksu grije tijekom 2 sata, zatim se ohladi i polako se dodaje 400 cm3 vode i zatim 100 cm3 20 % otopine H2SO4. A solution of 100 g (0.79 mol) of benzyl chloride in 400 cm3 of ether is added to a suspension of 19.2 g (0.79 gram atoms) of magnesium in 100 cm3 of ether while maintaining a slight reflux. The mixture is heated at reflux for 15 min and then a solution of 101.1 g (0.66 mol) of ethyl isopropylidene cyanoacetate in 130 cm3 of ether is added while maintaining a slight reflux. The mixture is heated at reflux for 2 hours, then cooled and 400 cm3 of water and then 100 cm3 of 20% H2SO4 solution are slowly added.
Smjesa se zatim miješa tijekom 20 minuta, a zatim se dekantira organska faza. The mixture is then stirred for 20 minutes and the organic phase is then decanted.
Ekstrahira se vodena faza s eterom i sjedinjene eterske faze se suše iznad natrij sulfata, filtrira se i destilira. The aqueous phase is extracted with ether and the combined ether phases are dried over sodium sulfate, filtered and distilled.
t klj. 115- 121 °C - prinos 147 g = 90 %. t key 115-121 °C - yield 147 g = 90 %.
IC: IR:
VC=O: 1740 cm-1, VCN : 2250 cm-1 VC=O: 1740 cm-1, VCN: 2250 cm-1
NMR (CDCCl3): 1-1,5 (m, 9H); 2,75 (s, 2H); 3,25 (s, IH; 4,2 (q, 2H); 6,7 - 7,6 (m, 5H). NMR (CDCCl 3 ): 1-1.5 (m, 9H); 2.75 (s, 2H); 3.25 (s, 1H; 4.2 (q, 2H); 6.7-7.6 (m, 5H).
Stadij 2: Stage 2:
Dimetil-3,3-fenil-4-butanoinska kiselina (Shema VII - formula 16) Dimethyl-3,3-phenyl-4-butanoic acid (Scheme VII - formula 16)
U 70 g (0,285 mola) spoja stadija 1 dodaje se bez hlađenja otopina 70 g kalij hidroksida u 230 cm3 etilenglikola. A solution of 70 g of potassium hydroxide in 230 cm3 of ethylene glycol is added without cooling to 70 g (0.285 mol) of the compound of stage 1.
Smjesa se grije na refluksu (140 °C) tijekom 3 sata i 15 minuta. Pod sniženim tlakom od 15 mm Hg ispari isparljivo otapalo i zatim se smjesa grije na refluksu (197 °C) tijekom 6 sati. Smjesa se ohladi i doda se 500 cm3 vode i ekstrahira se eterom. Vodena faza se zakiseli dodatkom koncentrirane klorovodične kiseline i ekstrahira se u benzenu. Benzenska faza se ispere vodom, osuši se na natrij sulfatu, filtrira i upari se do suhog. Tako se izolira 48,7 g ulja koje se kao takvo koristi u slijedećoj sintezi. Prinos = 89 %. The mixture is heated at reflux (140 °C) for 3 hours and 15 minutes. The volatile solvent was evaporated under reduced pressure of 15 mm Hg and then the mixture was heated at reflux (197 °C) for 6 hours. The mixture is cooled and 500 cm3 of water is added and extracted with ether. The aqueous phase is acidified by the addition of concentrated hydrochloric acid and extracted into benzene. The benzene phase is washed with water, dried over sodium sulfate, filtered and evaporated to dryness. Thus, 48.7 g of oil is isolated, which is used as such in the following synthesis. Yield = 89%.
IC: IR:
VCO: 1700 cm-1 VCO: 1700 cm-1
NMR (CDCl3): 1 (s, 6H); 2,2 (s, 2H); 2,65 (s, 2H); 6,8 - 7,5 (m, 5H). NMR (CDCl 3 ): 1 (s, 6H); 2.2 (s, 2H); 2.65 (s, 2H); 6.8 - 7.5 (m, 5H).
Stadij 3: Stage 3:
Tetrahidro-1,2,3,4-dimetil-3,3-okso-1-naftalen (Shema VII - formula 12) Tetrahydro-1,2,3,4-dimethyl-3,3-oxo-1-naphthalene (Scheme VII - formula 12)
Zagrije se smjesa 292 g polifosforne kiseline i 860 cm3 ksilena na temperaturu između 70 i 80 °C i doda se na ovoj temperaturi 48,7 g (0,253 mola) spoja iz stadija 2 otopljenog u 550 cm3 ksilena. Smjesa se zagrijava na refluksu tijekom 6 sati i 30 minuta, zatim se ohladi, dekantira se ksilenska faza; na preostalom mineralnom dijelu doda se 2000 cm3 i ekstrahira se ksilenom. Ponovo se ujedine organske faze, isperu se sa 10 % vodenom otopinom Na2CO3, zatim vodom i onda se osuše iznad natrij sulfata. Zatim se izvrši filtriranje i uparavanje otapala i predestiHra se zaostalo ulje. A mixture of 292 g of polyphosphoric acid and 860 cm 3 of xylene is heated to a temperature between 70 and 80 °C and at this temperature 48.7 g (0.253 mol) of the compound from stage 2 dissolved in 550 cm 3 of xylene is added. The mixture is heated at reflux for 6 hours and 30 minutes, then cooled, the xylene phase is decanted; 2000 cm3 is added to the remaining mineral part and extracted with xylene. The organic phases are combined again, washed with 10% aqueous Na2CO3 solution, then with water and then dried over sodium sulfate. Then the solvent is filtered and evaporated and the residual oil is distilled.
t klj.0,2 = 72 - 90 °C - prinos 87,5 %. t klj.0.2 = 72 - 90 °C - yield 87.5 %.
IC: IR:
VC=O: 1680 cm-1 VC=O: 1680 cm-1
NMR (CDCl3) 0,8 - 1,2 (m, 6H); 2,5 (s, 2H); 2,8 (s, 2H); 7 - 7,7 (m, 3H); 8 (dd, IH). NMR (CDCl 3 ) 0.8 - 1.2 (m, 6H); 2.5 (s, 2H); 2.8 (s, 2H); 7 - 7.7 (m, 3H); 8 (dd, IH).
Stadij 4: Stage 4:
Tetrahidro-1,2,3,4-hidroksi-1 -dimetil-3,3 -fenil-1 naftalen (Shema VI - formula 14). Tetrahydro-1,2,3,4-hydroxy-1-dimethyl-3,3-phenyl-1-naphthalene (Scheme VI - formula 14).
U 8,07 g (1,16 gr atoma) lidija suspendiranog u 200 cm3 etera, dodaje se uz održavanje blagog refluksa etera, otopina 86,95 g (0,55 mola) bromobenzena u 150 cm3 etera. Smjesa se zagrije na refluksu tijekom 45 minuta i ohladi se na temperaturu između 5 i 10 °C i na ovoj temperaturi se doda 38,6 g (0,19 mola) spoja iz stadija 3 otopljenog u 150 cm3 etera. A solution of 86.95 g (0.55 mol) of bromobenzene in 150 cm3 of ether is added to 8.07 g (1.16 g atoms) of lydium suspended in 200 cm3 of ether, while maintaining a gentle reflux of the ether. The mixture was heated at reflux for 45 minutes and cooled to a temperature between 5 and 10 °C and at this temperature 38.6 g (0.19 mol) of the compound from step 3 dissolved in 150 cm 3 of ether was added.
Smjesa se miješa tijekom 4 sata na sobnoj temperaturi i zatim se doda 150 cm3 vode održavanjem temperature između 5 i 10 °Ć. Smjesa se miješa tijekom 15 minuta i zatim se dekantira organska faza, ispere se vodom i osuši se iznad natrij sulfata i otapalo se upari. The mixture is stirred for 4 hours at room temperature and then 150 cm3 of water is added, maintaining the temperature between 5 and 10 °C. The mixture is stirred for 15 minutes and then the organic phase is decanted, washed with water and dried over sodium sulfate and the solvent is evaporated.
Dobiva se čvrsta juta supstancija koja se dispergira u heksanu, zatim se cijedi i suši. tt. = 107-110 °C - prinos = 47,4 g = 85 %. A solid jute substance is obtained, which is dispersed in hexane, then strained and dried. tt. = 107-110 °C - yield = 47.4 g = 85 %.
Stadij 5. Stage 5.
Dihidro-1,2-dimetil-2,2-fenil-4-naftalen (Shema VI-formula 5) dobiveno iz spoja stadija 4 prema postupku stadija 2 primjera1. Dihydro-1,2-dimethyl-2,2-phenyl-4-naphthalene (Scheme VI-formula 5) obtained from the compound of stage 4 according to the procedure of stage 2 of example 1.
tklj 0,1 103-105 °C tt 82-84°C Prinos 89 % tklj 0.1 103-105 °C tt 82-84°C Yield 89 %
Analiza: C18H18 M = 234,34 Analysis: C18H18 M = 234.34
C H CH
% izračunato 92,26 7,74 % calculated 92.26 7.74
% nađeno 92,42 7,64. % found 92.42 7.64.
NMR (CDCl3): 1,05 (s, 6H); 2,7 (s, 2H); 5,7 (s, IH); 6,75 - 7,4 (m, 9H). NMR (CDCl 3 ): 1.05 (s, 6H); 2.7 (s, 2H); 5.7 (s, IH); 6.75 - 7.4 (m, 9H).
Stadij 6: Stage 6:
Bromo-3-dihidro-1,2-dimetil-2,2-fenil-4-naftalen (Shema III - formula 6). Bromo-3-dihydro-1,2-dimethyl-2,2-phenyl-4-naphthalene (Scheme III - formula 6).
U smjesu 27,3 g (0,117 mola) spoja stadija 5 u 120 cm3 DMF dobro miješanu, dodaje se tako da temperatura smjese ne pređe 30 °C, 25 g (0,14 mola) N-bromosukcinamida otopljenog u 120 cm3 DMF. To a mixture of 27.3 g (0.117 mol) of the compound of stage 5 in 120 cm3 of DMF, well mixed, is added so that the temperature of the mixture does not exceed 30 °C, 25 g (0.14 mol) of N-bromosuccinamide dissolved in 120 cm3 of DMF.
Poslije miješanja smjese na sobnoj temperaturi tijekom 24 sata i stajanja na istoj temperaturi tijekom 48 sati, smjesa se izlije na 800 cm3 zaleđene vode, ekstrahira se sa 400 cm3 etera (2 x 200 cm ). Ekstrakti od ispiranja se ujedine i suše na natrij sulfatu. Eter se upari i preostalo ulje se kromatografira na gelu silicij dioksida korištenjem heksana kao eluanta. Dobiveno poslije uparavanja heksana, ulje se koristi kao takvo u slijedećoj sintezi. Prinos = 32,4 g = 89 %. NMR (CDCl3): 1,2 (s, 6H); 2,95 (s, 2H); 6,3 - 7,5 (m, 9H). After mixing the mixture at room temperature for 24 hours and standing at the same temperature for 48 hours, the mixture is poured into 800 cm3 of ice water, extracted with 400 cm3 of ether (2 x 200 cm). The washing extracts are combined and dried over sodium sulfate. The ether is evaporated and the residual oil is chromatographed on silica gel using hexane as eluent. Obtained after evaporation of hexane, the oil is used as such in the next synthesis. Yield = 32.4 g = 89%. NMR (CDCl 3 ): 1.2 (s, 6H); 2.95 (s, 2H); 6.3 - 7.5 (m, 9H).
Stadij 7: Stage 7:
3E-( dihidro-1,2-dimetil-2,2-fenil-4-naftil-3 )-3 -propen-2-al (Shema III - formula 2) 3E-(dihydro-1,2-dimethyl-2,2-phenyl-4-naphthyl-3)-3-propen-2-al (Scheme III - formula 2)
Ako nije drugačije naznačeno, operacije koje slijede izvode se na temperaturi od -50 °C. U otopinu 6,26 g (0,02 mola) spoja iz stadija 6 u 100 cm3 etera ohlađenog na -50 °C i dobro miješan dodaje se 13,8 cm3 1,6 N otopine butillitija u heksanu (0,022 mola BuLi). Zatim poslije podizanja temperature smjese na sobnu temperaturu, smjesa se grije na refluksu tijekom 1 sata i 20 minuta i zatim se ohladi na temperaturu između -50 i -60 °C i dodaje se 2 g N,N-dimetil-amino-3 akroleina otopljenog u 30 cm3 etera. Unless otherwise indicated, the following operations are performed at a temperature of -50 °C. To a solution of 6.26 g (0.02 mol) of the compound from stage 6 in 100 cm3 of ether cooled to -50 °C and well stirred is added 13.8 cm3 of a 1.6 N solution of butyllithium in hexane (0.022 mol of BuLi). Then, after raising the temperature of the mixture to room temperature, the mixture is heated at reflux for 1 hour and 20 minutes and then cooled to a temperature between -50 and -60 °C and 2 g of dissolved N,N-dimethyl-amino-3 acrolein is added in 30 cm3 of ether.
Poslije miješanja smjesa na -50 °C tijekom 1 sata i 30 minuta, smjesa se ostavi radi dostizanja sobne temperature; a zatim se miješa 30 min poslije čega se smjesa ulije u 300 cm3 10 % otopine klorovodične kiseline uz miješanje. Dekantira se organska faza i ispere se vodom; vodena faza se ekstrahira metilen kloridom, ekstrakt se ispere vodom i zatim se ujedine sve organske faze; suši se na natrij sulfatu; otapala se upare i preostalo ulje kristalizira u pentanu. After mixing the mixtures at -50 °C for 1 hour and 30 minutes, the mixture is left to reach room temperature; and then it is mixed for 30 minutes, after which the mixture is poured into 300 cm3 of 10% hydrochloric acid solution while stirring. The organic phase is decanted and washed with water; the aqueous phase is extracted with methylene chloride, the extract is washed with water and then all organic phases are combined; dried on sodium sulfate; the solvents are evaporated and the remaining oil crystallizes in pentane.
tt 105 - 108 °C Prinos 2,6 g = 45 %. mp 105 - 108 °C Yield 2.6 g = 45 %.
IC: IR:
Vc=o: 1680 cm-1 Vc=o: 1680 cm-1
NMR (CDCl3): 1,2 (s, 6H); 2,8 (s, 2H); 6,05 (dd; J = 16,5 i 7,5, IH); 6,4 - 7,5 (m, 10H); 9,5 (D:J =7,5, IH) NMR (CDCl 3 ): 1.2 (s, 6H); 2.8 (s, 2H); 6.05 (dd; J = 16.5 and 7.5, IH); 6.4 - 7.5 (m, 10H); 9.5 (D:J =7.5, IH)
Stadij 8: Stage 8:
(+)-6E-(dihidro-l,2-dimetil-2,2-fenil-4-naftil-3)-7-hidroksi-5-okso-3-hepten-6-metilat(Shema I - formula 4). (+)-6E-(dihydro-1,2-dimethyl-2,2-phenyl-4-naphthyl-3)-7-hydroxy-5-oxo-3-heptene-6-methylate (Scheme I - formula 4) .
Dobiva se polazeći od spoja stadija 7 prema postupku stadija 4 primjera 1. It is obtained starting from the compound of stage 7 according to the procedure of stage 4 of example 1.
Spoj je predstavljen u obliku ulja. Prinos = 87 %. The compound is presented in the form of an oil. Yield = 87%.
NMR (CDCl3): 1,1 (s, 6H); 1,9 - 2,6 (m, 3H); 2,72 (s, 2H); 3,3 (s, 2H); 3,65 (s, 3H); 3,45 (m, 2H); 4,8 - 5,35 (m, IH); 6 (d : J = 15,75; IH); 6,35 - 7,5 (m, 5H). NMR (CDCl 3 ): 1.1 (s, 6H); 1.9 - 2.6 (m, 3H); 2.72 (s, 2H); 3.3 (s, 2H); 3.65 (s, 3H); 3.45 (m, 2H); 4.8 - 5.35 (m, IH); 6 (d : J = 15.75; IH); 6.35 - 7.5 (m, 5H).
Stadij 9: Stage 9:
(+,-)-6E-eritro-(dihidro-1,2-dimetil-2,2-fenil-4-naftil-3)-7-dihidroksi-3,5-hepten-6-metilat (spoj br. 2). (+,-)-6E-erythro-(dihydro-1,2-dimethyl-2,2-phenyl-4-naphthyl-3)-7-dihydroxy-3,5-heptene-6-methylate (compound no. 2 ).
Dobiva se polazeći od spoja stadija 8 prema postupku stadija 5 primjera 1. It is obtained starting from the compound of stage 8 according to the procedure of stage 5 of example 1.
Čvrsta supstancija žute boje. Yellow solid substance.
tt: 101 - 103 °C - Prinos 2,2 g = 67 %. mp: 101 - 103 °C - Yield 2.2 g = 67 %.
Analiza za: C26H30O4 M = 406,52 Analysis for: C26H30O4 M = 406.52
C N C N
% izračunato 76,82 7,44 % calculated 76.82 7.44
% nađeno 76,57 7,43 % found 76.57 7.43
Primjer 3. Example 3.
(±)-6E-eritro((kloro-4-fenil)-4-dimetil-2,2-2H-benzotiapiran-3 -il)-7-dihidroksi-3,5 -hepten-6-metilat (±)-6E-erythro((chloro-4-phenyl)-4-dimethyl-2,2-2H-benzothiapyran-3-yl)-7-dihydroxy-3,5-hepten-6-methylate
(spoj br. 3 - formula 1: X = S, R1 R2 = CH3, R3 = 401, R4 = R5 = R6 = R9 = R10 = H, R7 i R8 = veza, R11=OCH3). (compound no. 3 - formula 1: X = S, R1 R2 = CH3, R3 = 401, R4 = R5 = R6 = R9 = R10 = H, R7 and R8 = bond, R11=OCH3).
Stadij 1: (Kloro-4-fenil)-4-dihidro-3,4-hidroksi-4-dimetil-2,2-2H-benzotiapiran (Shema VI - formula 14) dobiveno polazeći od dihidro-2,3dimetil-2,2-4H benzotia-piranom-4 prema postupku stadija 4 primjera 2; koristi se ne prerađeno u slijedećoj sintezi. Stage 1: (Chloro-4-phenyl)-4-dihydro-3,4-hydroxy-4-dimethyl-2,2-2H-benzothiapyran (Scheme VI - formula 14) obtained starting from dihydro-2,3dimethyl-2, 2-4H benzothia-pyran-4 according to the procedure of step 4 of example 2; it is used unprocessed in the next synthesis.
Stadij 2: Stage 2:
(kloro-4-fenil)-4-dimetil-2,2-2H-benzotiapiran (Shema VI - formula 5) dobiva se polazeći od spoja stadija 1 prema postupku stadija 2 primjera 1). (chloro-4-phenyl)-4-dimethyl-2,2-2H-benzothiapyran (Scheme VI - formula 5) is obtained starting from the compound of stage 1 according to the procedure of stage 2 of example 1).
tt: 100-102 °C (diizopropileter) - Prinos = 50 %. Analiza za C17H15CIS M = 286,81 mp: 100-102 °C (diisopropyl ether) - Yield = 50 %. Analysis for C17H15CIS M = 286.81
C H Cl S C H Cl S
% izračunato 71,19 5,27 12,36 11,18 % calculated 71.19 5.27 12.36 11.18
% nađeno 70,94 5,42 12,60 10,90 % found 70.94 5.42 12.60 10.90
NMR (CDCl3): 2 (s, 6H); 5,75 (s, IH); 6,75 - 7,5 (m, 8H). NMR (CDCl 3 ): 2 (s, 6H); 5.75 (s, IH); 6.75 - 7.5 (m, 8H).
Stadij 3: Stage 3:
Bromo-3-(kloro-4-fenil)-4-dimetil-2,2-2H-benzotiapiran (Shema III - formula 6) dobiveno polazeći od spoja stadija 2 prema postupku stadija 6 primjera 2; poslije uparavanja etera, dobivena čvrsta supstancija se dispergira u dovoljnoj količini metanola ohlađenog na -20 °C, zatim se cijedi i suši tako da daje čvrstu supstanciju. Bromo-3-(chloro-4-phenyl)-4-dimethyl-2,2-2H-benzothiapyran (Scheme III - formula 6) obtained starting from the compound of stage 2 according to the procedure of stage 6 of example 2; after evaporation of the ether, the resulting solid is dispersed in a sufficient amount of methanol cooled to -20 °C, then filtered and dried to give a solid.
tt: 150 - 156 °C - prinos 88 %. mp: 150 - 156 °C - yield 88 %.
NMR (CDCl3): 1,6(s,6H);6,2-7,8(m,8H). NMR (CDCl 3 ): 1.6(s, 6H); 6.2-7.8(m, 8H).
Radi se pod atmosferom dušika, u reaktoru zaštićenom od sobne vlage. It is done under a nitrogen atmosphere, in a reactor protected from room humidity.
Grije se na refluksu smjesa 20,1 g (0,055 mola) spoja iz stadija 3, 27,5 cm3 (0,254 mola) etil akrilata, 130 cm3 N,N-dimetilformamida, 130 cm3 paladij diacetata; smjesa se ulije na smjesu vode i leda i ekstrahira se s dovoljnom količinom etera; alternativno se eterski ekstrakt pere u klorovodičnoj kiselini i vodi do pH = 7 i zatim se suši na natrij sulfatu, filtrira se i ostatak se dispergira u heksanu ohlađenom na -20 °C poslije čega se cijedi kao čvrsta supstancija u suši. A mixture of 20.1 g (0.055 mol) of the compound from stage 3, 27.5 cm3 (0.254 mol) of ethyl acrylate, 130 cm3 of N,N-dimethylformamide, 130 cm3 of palladium diacetate is heated at reflux; the mixture is poured onto a mixture of water and ice and extracted with a sufficient amount of ether; alternatively, the ether extract is washed in hydrochloric acid and water to pH = 7 and then dried over sodium sulfate, filtered and the residue dispersed in hexane cooled to -20 °C, after which it is filtered as a dry solid.
tt: 97 - 99 °C (CH3OH) - Prinos = 91 %. Analiza za C22H21CI02S M = 384,91 mp: 97 - 99 °C (CH3OH) - Yield = 91 %. Analysis for C 22 H 21 ClO 2 S M = 384.91
C H Cl S % izračunato 68,65 5,50 9,21 8,33 % nađeno 68,58 5,79 9,45 8,30 C H Cl S % calculated 68.65 5.50 9.21 8.33 % found 68.58 5.79 9.45 8.30
NMR (CDCl3): 1 - 1,75 (m, 9H); 3,75 - 4,5 (9, 2H); 5,3 - 5,75 (d, IH); 6,5 - 7,5 (m, 9H). NMR (CDCl 3 ): 1 - 1.75 (m, 9H); 3.75 - 4.5 (9.2H); 5.3 - 5.75 (d, 1H); 6.5 - 7.5 (m, 9H).
Stadij 5: Stage 5:
2E-((kloro-4-fenil)-4-dimetil-2,2-2H-benzotiapiran-3il)-3-propen-2-ol (Shema IV - formula 9). 2E-((chloro-4-phenyl)-4-dimethyl-2,2-2H-benzothiapyran-3yl)-3-propen-2-ol (Scheme IV - formula 9).
Radi se pod atmosferom dušika u reaktoru zaštićenom od sobne vlage. U otopinu 18,9 g (0,049 mola) spoja stadija 4 u 180 cm3 tetrahidrofurana ohlađenog na -20 °C, dodaje se 196 cm3 1N otopine diizobutilaluminij hidrida u tetrahidrofurauu (0,049 x 4 mola DIABAL-a); smjesa se miješa na sobnoj temperaturi tijekom 1 sata, zatim se smjesi dodaje 200 ml vode; ovo dodavanje je egzotermno i izvodi se tako da se temperatura smjese održava na 30 °C; smjesa se zatim zakiseli do pH = 1 dodavanjem dovoljne količine koncentrirane klorovodične kiseline poslije čega se ekstrahira eterom. It is done under a nitrogen atmosphere in a reactor protected from room humidity. To a solution of 18.9 g (0.049 mol) of the compound of stage 4 in 180 cm3 of tetrahydrofuran cooled to -20 °C, 196 cm3 of a 1N solution of diisobutylaluminum hydride in tetrahydrofuran (0.049 x 4 mol of DIABAL) is added; the mixture is stirred at room temperature for 1 hour, then 200 ml of water is added to the mixture; this addition is exothermic and is carried out so that the temperature of the mixture is maintained at 30 °C; the mixture is then acidified to pH = 1 by adding a sufficient amount of concentrated hydrochloric acid, after which it is extracted with ether.
Eterska faza se zatim ispere vodom do neutralnosti i zatim se suši na natrij sulfatu; poslije filtriranja i isparavanja etera, dobiveno ulje se dispergira u dovoljnoj količini heksana ohlađenog na 5 °C; cijedi se i suši se nagrađena čvrsta supstancija. The ether phase is then washed with water until neutral and then dried over sodium sulfate; after filtering and evaporating the ether, the obtained oil is dispersed in a sufficient amount of hexane cooled to 5 °C; the resulting solid substance is strained and dried.
tt: 105 - 108 °C (heksan) - prinos = 87 %. mp: 105 - 108 °C (hexane) - yield = 87 %.
Analiza za C20H19CIOS M = 342,87 Analysis for C20H19CIOS M = 342.87
C H Cl S C H Cl S
% izračunato 70,06 5,59 10,34 9,35 % calculated 70.06 5.59 10.34 9.35
% nađeno 69,91 5,78 10,52 9,30 % found 69.91 5.78 10.52 9.30
Stadij 6: Stage 6:
2E-((kloro-4-fenil)-4-dimetil-2,2-2H-benzotiapiran-3 -il)-3 -propen-2-al (Shema IV - formula 2). 2E-((chloro-4-phenyl)-4-dimethyl-2,2-2H-benzothiapyran-3-yl)-3-propen-2-al (Scheme IV - formula 2).
Radi se u reaktoru zaštićenom od sobne vlage; smjesa 14,63 g (0,0427 mola) spoja stadija 5, 22,26 g (0,0427 x 6 mola) mangan dioksida i 300 cm3 diklorometana se miješa na sobnoj temperaturi tijekom 48 sati; smjesa se zatim filtrira, diklorometan ispari iz filtrata, čvrsti ostatak se dispergira u dovoljnoj količini diizopropiletera, smjesa se cijedi i suši. It is done in a reactor protected from room humidity; a mixture of 14.63 g (0.0427 mol) of the compound of stage 5, 22.26 g (0.0427 x 6 mol) of manganese dioxide and 300 cm 3 of dichloromethane is stirred at room temperature for 48 hours; the mixture is then filtered, dichloromethane evaporates from the filtrate, the solid residue is dispersed in a sufficient amount of diisopropylether, the mixture is filtered and dried.
tt: 132 - 134 °C (CH3CO2C2H5) - Prinos = 82 %. Analiza za C20H17CIOS M = 340,86 mp: 132 - 134 °C (CH3CO2C2H5) - Yield = 82 %. Analysis for C20H17CIOS M = 340.86
C H Cl S C H Cl S
% izračunato 70,47 5,03 10,40 9,41 % calculated 70.47 5.03 10.40 9.41
% nađeno 70,27 4,98 10,51 9,85 % found 70.27 4.98 10.51 9.85
NMR (CDCl3): 1,5 (s, 6H); 5,75 - 6,25 (9, IH); 6,75 - 7,5 (m, 9H); 9,25 - 9,5 (d, IH). NMR (CDCl 3 ): 1.5 (s, 6H); 5.75 - 6.25 (9, IH); 6.75 - 7.5 (m, 9H); 9.25 - 9.5 (d, IH).
Stadij 7: Stage 7:
(+,-)-6E-((kloro-4-fenil)~dimetil-2,2-2H-benzotiapiran-3-il)-7-hidroksi-5-okso-3-hepten-6-metilat (Shema I - formula 4). (+,-)-6E-((chloro-4-phenyl)~dimethyl-2,2-2H-benzothiapyran-3-yl)-7-hydroxy-5-oxo-3-heptene-6-methylate (Scheme I - formula 4).
Dobiveno je od spoja stadija 6 prema postupku stadija 4 primjera 1. It was obtained from the compound of stage 6 according to the procedure of stage 4 of example 1.
tt: 86 - 88 °C (CH3OH) - Prinos 94 %. mp: 86 - 88 °C (CH3OH) - Yield 94 %.
IC: IR:
Vc=o: 1740 i 1700 cm-1 Vc=o: 1740 and 1700 cm-1
NMR (CDCl3): 1,5 (s, 6H); 2,25 - 2,75 8m, 3H); 3,3 (s, 2H); 3,75 (s, 3H); 4,25 - 4,5 (m, IH); 5 - 5,55 (dd, IH); 5,75 - 6,25 (d, IH); 6,5 - 7,5 (m, 8H). NMR (CDCl 3 ): 1.5 (s, 6H); 2.25 - 2.75 8m, 3H); 3.3 (s, 2H); 3.75 (s, 3H); 4.25 - 4.5 (m, IH); 5 - 5.55 (dd, IH); 5.75 - 6.25 (d, IH); 6.5 - 7.5 (m, 8H).
Stadij 8: Stage 8:
(±)-6E-eritro-((-kloro-4-fenil)-4-dimetil-2,2-2H-benzotiapiran-3 -il)-7-dihidroksi-3,5-hepten-6-metilat. (±)-6E-erythro-((-chloro-4-phenyl)-4-dimethyl-2,2-2H-benzothiapyran-3-yl)-7-dihydroxy-3,5-heptene-6-methylate.
(Shema I-formula 1). (Scheme I-formula 1).
Dobiveno je polazeći od spoja stadija 7 prema postupku stadija 5 primjera 1. It was obtained starting from the compound of stage 7 according to the procedure of stage 5 of example 1.
tt: 115 - 117 °C (diizopropileter) - Prinos 58 % Analiza za C25H27CIO4S M = 458,99 mp: 115 - 117 °C (diisopropylether) - Yield 58 % Analysis for C25H27CIO4S M = 458.99
C H Cl S C H Cl S
% izračunato 65,42 5,93 7,72 6,98 % calculated 65.42 5.93 7.72 6.98
% nađeno 65,52 6,02 7,80 7,09 % found 65.52 6.02 7.80 7.09
IC: IR:
Vc=o: 1720 cm-1 Vc=o: 1720 cm-1
VOH: 3400 cm-1 VOH: 3400 cm-1
NMR (CDCl3): NMR (CDCl3):
1,5 (s, 6H); 2,5 (d, 2H); 3 - 3,75 (m, 2H); 3,75 (s, 3H); 4 - 4,5 (m, 2H); 5 - 5,5 (dd,IH); 5,75 - 6,25 (d, IH); 6,5 - 7,5 (m, 8H). 1.5 (s, 6H); 2.5 (d, 2H); 3 - 3.75 (m, 2H); 3.75 (s, 3H); 4 - 4.5 (m, 2H); 5 - 5.5 (dd, IH); 5.75 - 6.25 (d, IH); 6.5 - 7.5 (m, 8H).
Primjer 4. Example 4.
(+,-)-eritro-((-fluoro-4-fenil)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3)-7-dihidroksi-3,5-heptan etilat (+,-)-erythro-((-fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5-heptane ethylate
(spoj br. 4 - formule 1: X = 0, R1-R2 = (CH2)4-, R3 = 4'F, R4 = R5 = R6 = R7 = R8 = R9 – R10 = H, R11 = OC2H5). (compound no. 4 - formula 1: X = 0, R1-R2 = (CH2)4-, R3 = 4'F, R4 = R5 = R6 = R7 = R8 = R9 – R10 = H, R11 = OC2H5).
Stadij 1: Stage 1:
3E-((fluoro-4-fenil)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3)-3 propen-2-al, di-metilacetal (Shema V-formula 10). 3E-((Fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-3-propen-2-al, dimethylacetal (Scheme V-Formula 10).
Radi se pod atmosferom dušika, u reaktoru zaštićenom do vlage. It is done under a nitrogen atmosphere, in a reactor protected against moisture.
Smjesa 16,75 g (0,05 mola) 3E-((fluoro-4-fenil)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3)-propen-2-ala dobivenog od spiro(2H-benzopiran-1-2,1'-ciklopentanon-4) prema postupcima stadija 1,2 i 3 primjera 1 i 2,25 g Amberlyst 15 smole, u 625 cm3 metil ortoformiata se miješa tijekom 7 sati na sobnoj temperaturi. Doda se novih 2,25 g Amberlyst smole i smjesa se miješa na sobnoj temperaturi tijekom 12 sati. Ponoviti ovaj tretman četiri puta, poslije čega se smjesa filtrira i upari se višak metil ortoformiata; izolira se bijela čvrsta supstancija koja se dispergira u heksanu; smjesa se cijedi i suši. A mixture of 16.75 g (0.05 mol) of 3E-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-propen-2-al obtained from spiro(2H-benzopyran-1-2,1'-cyclopentanone-4) according to the procedures of stages 1,2 and 3 of example 1 and 2.25 g of Amberlyst 15 resin, in 625 cm3 of methyl orthoformate are stirred for 7 hours at room temperature. A further 2.25 g of Amberlyst resin was added and the mixture was stirred at room temperature for 12 hours. Repeat this treatment four times, after which the mixture is filtered and the excess methyl orthoformate is evaporated; a white solid is isolated which is dispersed in hexane; the mixture is strained and dried.
tt: 112 - 114 °C - Prinos = 16,3 g = 88 %. mp: 112 - 114 °C - Yield = 16.3 g = 88 %.
NMR (CDCl3): NMR (CDCl3):
2,1 - 2,2 (m, 8H); 3,07 (s, 6H); 6,05 (d, IH, J = 5 Hz); 5,3 (dd, IH J = 5 Hz i 16 Hz); 6,05 (d, IH J = 16 Hz); 6,3 - 7,2 (m, 8H). 2.1 - 2.2 (m, 8H); 3.07 (s, 6H); 6.05 (d, IH, J = 5 Hz); 5.3 (dd, IH J = 5 Hz and 16 Hz); 6.05 (d, IH J = 16 Hz); 6.3 - 7.2 (m, 8H).
Stadij 2: Stage 2:
((fluoro-4-fenil)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3)-3-propanol dimetilacetal (Shema V - formula 11). ((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-3-propanol dimethyl acetal (Scheme V - formula 11).
Na normalnom tlaku vodika i sobnoj temperaturi 3,8 g (0,01 mola) spoja stadija 1 otopljenog u 100 m3 THF, u prisustvu 0,5 g paladija se dispergiraju na ugljik. Kad se teorijska količina vodika adsorbira, smjesa se filtrira i upari se THF; dobiveno ulje sporo kristalizira tako da se dobivena čvrsta supstancija dispergira, zatim u heksanu cijedi i suši. At normal hydrogen pressure and room temperature, 3.8 g (0.01 mol) of the compound of stage 1 dissolved in 100 m3 of THF, in the presence of 0.5 g of palladium are dispersed on carbon. When the theoretical amount of hydrogen is adsorbed, the mixture is filtered and the THF is evaporated; the obtained oil crystallizes slowly so that the obtained solid substance is dispersed, then strained in hexane and dried.
tt: 83 - 85 °C Prinos: 3,2 g = 84 %. mp: 83 - 85 °C Yield: 3.2 g = 84 %.
(CCM: silicij dioksidni gel: AcOEt-heksan: 1-9:1 mrlja) (CCM: silica gel: AcOEt-hexane: 1-9:1 stain)
NMR (CDCl3): 1,9 - 2,5 (m, 12H); 3,2 (s, 6H); 4,15 (t, IH J = 5 Hz); 6,3 - 7,25 (m, 8H). NMR (CDCl 3 ): 1.9 - 2.5 (m, 12H); 3.2 (s, 6H); 4.15 (t, IH J = 5 Hz); 6.3 - 7.25 (m, 8H).
Stadij 3: Stage 3:
((Fluoro-4-fenil)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3)-3 propanal. (Shema V - formula 2). ((Fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-3 propanal. (Scheme V - formula 2).
Na sobnoj temperaturi tijekom 96 sati miješa se smjesa 2 g (0,0052 mola) spoja stadija 2 i 2 g Amberlyst 15 smole; smola se odfiltrira, filtrat se upari do suhog, smola se stavi u 40 cm3 metilen klorida, ispire se vodom i suši na natrij sulfatu, filtrat se upari do suhog tako da se dobiva 0,9 g ulja. A mixture of 2 g (0.0052 mol) of the stage 2 compound and 2 g of Amberlyst 15 resin is mixed at room temperature for 96 hours; the resin is filtered off, the filtrate is evaporated to dryness, the resin is placed in 40 cm3 of methylene chloride, washed with water and dried over sodium sulfate, the filtrate is evaporated to dryness so that 0.9 g of oil is obtained.
tt: 118 - 120 °C (diizopropileter) mp: 118 - 120 °C (diisopropylether)
IC: IR:
Vc=o: 1720 cm-1 Vc=o: 1720 cm-1
NMR (CDCl3): 1-2,5 (m, 10H); 6,2 - 7,2 (m, 8H); 9,55 (s, IH). NMR (CDCl 3 ): 1-2.5 (m, 10H); 6.2 - 7.2 (m, 8H); 9.55 (s, IH).
Analiza za C22H21FO2 M = 336,39 Analysis for C22H21FO2 M = 336.39
C H F CH F
% izračunato 78,55 6,29 5,65 % calculated 78.55 6.29 5.65
% nađeno 78,33 6,04 5,57. % found 78.33 6.04 5.57.
Stadij 4: Stage 4:
(±)-fluoro-4-fenil)-4-spiro(24-benzopiran-1,2,1'-ciklopentil-3)-7-hidroksi-5-okso-3-heptan etilat (±)-fluoro-4-phenyl)-4-spiro(24-benzopyran-1,2,1'-cyclopentyl-3)-7-hydroxy-5-oxo-3-heptane ethylate
(Shema I - formula 4 - R7 = R8 = H) (Scheme I - formula 4 - R7 = R8 = H)
Dobiva se polazeći od stadija 3 i prema postupku stadija 4 primjera 1. It is obtained starting from stage 3 and according to the procedure of stage 4 of example 1.
Spoj se dobiva u obliku ulja (prinos =51 %); koristi se kao takvo u slijedećoj sintezi. The compound is obtained in the form of an oil (yield = 51%); is used as such in the following synthesis.
Stadij 5: Stage 5:
(+,-)-eritro-((fluoro-4-fenil)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3)-7-dihidroksi-3,5-heptan etilat (spoj br. 4). (+,-)-erythro-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5-heptane ethylate (compound No. 4).
Dobiva se redukcijom spoja stadija 4 prema postupku stadija 5 primjera 1. It is obtained by reduction of the compound of stage 4 according to the procedure of stage 5 of example 1.
Spoj je bijel. The joint is white.
tt: 103 - 105 °C (Diizopropileter) - Prinos 65 %. mp: 103 - 105 °C (Diisopropylether) - Yield 65 %.
Analiza za C28H33FO5 M = 468,54 Analysis for C28H33FO5 M = 468.54
C H F CH F
% izračunato 71,77 7,10 4,05 % calculated 71.77 7.10 4.05
% nađeno 71,63 7,11 3,98. % found 71.63 7.11 3.98.
NMR (CDCl3): NMR (CDCl3):
0,9 - 2,5 (m, 17H); 2,35 (d, 2H, J = 6 Hz); 3 - 3,5 (m, 2H); 3,5 - 3,9 (m, IH); 3,9-4,4(m,3H);6,2-7,2(m,8H). 0.9 - 2.5 (m, 17H); 2.35 (d, 2H, J = 6 Hz); 3 - 3.5 (m, 2H); 3.5 - 3.9 (m, IH); 3.9-4.4(m,3H); 6.2-7.2(m,8H).
Primjer 5. Example 5.
(+,-)-6E-eritro-((fluoro-4-fenil)-4-spiro(2H-benzopiran-1-2,1 '-ciklopentil)-3 )-7-dihidroksi-3,5-hepten-6-ester natrija (spoj br. 5 - formula 1: X = 0, R1-R2 = -(CH2)4-; R3 = 4'F; R4 = R5 = R6 = R9 = R10 = H; R7 i R8 = veza; R11 = -O"Na+). (+,-)-6E-erythro-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3 )-7-dihydroxy-3,5-heptene- Sodium 6-ester (compound No. 5 - formula 1: X = 0, R1-R2 = -(CH2)4-; R3 = 4'F; R4 = R5 = R6 = R9 = R10 = H; R7 and R8 = bond; R11 = -O"Na+).
Grije se na 60 °C 2,14 g (0,0046 mola) spoja br. 4 u 30 cm3 etanola radi dobivanja bistre otopine, zatim se ova otopina ohladi do sobne temperature i doda se vodena otopina natrij karbonata dobivena otapanjem 0,18 g (0,0046 mola) natrij karbonata u perlicama u 100 cm3. Smjesa se miješa tijekom 30 min, filtrira se i upari do suhog; ostatak se suši grijanjem na 60 °C pod sniženim tlakom (0,05 mm Hg) tijekom 1 sata. 2.14 g (0.0046 mol) of compound no. is heated to 60 °C. 4 in 30 cm3 of ethanol to obtain a clear solution, then this solution is cooled to room temperature and an aqueous solution of sodium carbonate obtained by dissolving 0.18 g (0.0046 mol) of sodium carbonate in beads in 100 cm3 is added. The mixture is stirred for 30 min, filtered and evaporated to dryness; the residue is dried by heating at 60 °C under reduced pressure (0.05 mm Hg) for 1 hour.
tt: nije definirana - Prinos 2,04 g = 96 %. tt: not defined - Yield 2.04 g = 96 %.
(CCM: silicij dioksidni gel: AcOEt - heksan : 1 - 1 + 3 % AcOH : 1 mrlja) (CCM: silica gel: AcOEt - hexane : 1 - 1 + 3 % AcOH : 1 spot)
Analiza za C26H26FNaO5 M = 460,47 Analysis for C26H26FNaO5 M = 460.47
C H F Na C H F Na
% izračunato 67,82 5,69 4,13 4,99 % calculated 67.82 5.69 4.13 4.99
% nađeno 67,44 5,71 3,91 5,11. % found 67.44 5.71 3.91 5.11.
Primjer 6. Example 6.
(+,-)-6E-Eritro-((fluoro-4-fenil)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-7-dihidroksi-3,5-hepten-6-benzilat (+,-)-6E-Erythro-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-7-dihydroxy-3,5-heptene-6-benzylate
(spoj br. 6 - formula 1 : X = O, R1- R2 = -(CH2)4-, R3 = 4'F, R4-R5 = R6 = R9 = R10 = H, R7 i R8 = veza, R11 = C6H5CH2O-). (compound no. 6 - formula 1 : X = O, R1- R2 = -(CH2)4-, R3 = 4'F, R4-R5 = R6 = R9 = R10 = H, R7 and R8 = bond, R11 = C6H5CH2O-).
U otopinu 1,55 g (0,00337 mola) spoja br. 5 u 40 cm3 metil etil ketona, dodaje se 0,638 g (0,00337 mola + 10 %) benzil bromida i zatim se smjesa grije na refluksu 3 sata. In a solution of 1.55 g (0.00337 mol) of compound no. 5 in 40 cm3 of methyl ethyl ketone, 0.638 g (0.00337 mol + 10 %) of benzyl bromide is added and then the mixture is heated at reflux for 3 hours.
Dodaje se zatim novih 0,638 g benzil bromida i smjesa se grije na refluksu tijekom 8 sati. A new 0.638 g of benzyl bromide is then added and the mixture is heated at reflux for 8 hours.
Smjesa se filtrira, filtrat se upari, zatim se ostatak ulije u dovoljnu količinu etil acetata, otopina se ispire vodom, suši na natrij sulfatu, filtrira i upari do suhog. The mixture is filtered, the filtrate is evaporated, then the residue is poured into a sufficient amount of ethyl acetate, the solution is washed with water, dried over sodium sulfate, filtered and evaporated to dryness.
Kromatografira se preostalo ulje na 15 g silicij dioksidnog gela korištenjem smjese etil acetat-heksan: 30 - 70 %. The remaining oil is chromatographed on 15 g of silica gel using a mixture of ethyl acetate-hexane: 30 - 70 %.
Sakupljena frakcija II poslije uparavanja otapala daje čvrstu supstanciju koja se dispergira u diizopropileteru. Čvrsta supstancija se cijedi i suši. The collected fraction II after evaporation of the solvent gives a solid substance which is dispersed in diisopropyl ether. The solid substance is strained and dried.
tt = 81 - 83 °C - Prinos = 1,17 g = 66 %. Analiza za C33H33FO5 M = 528,59 mp = 81 - 83 °C - Yield = 1.17 g = 66 %. Analysis for C33H33FO5 M = 528.59
C H F CH F
% izračunato 74,98 6,29 3,59 % calculated 74.98 6.29 3.59
% nađeno 74,91 6,23 3,55 % found 74.91 6.23 3.55
NMR (CDCl3): 1,1 - 2,3 (m, 10H); 2,45 (d, 2H J = 6,7 Hz); 2,7 - 3,2 (M, IH (D2)); 3,3 - 3,6 (m, IH D2O)); 3,8 - 4,5 (m, 2H); 5,0 - 5,6 ( s + d, 3H); 5,9 (d, IH J = 15,7 Hz); 6,3 - 7,7 (m,13H). NMR (CDCl 3 ): 1.1 - 2.3 (m, 10H); 2.45 (d, 2H J = 6.7 Hz); 2.7 - 3.2 (M, 1H (D2)); 3.3 - 3.6 (m, 1H D2O)); 3.8 - 4.5 (m, 2H); 5.0 - 5.6 (s + d, 3H); 5.9 (d, IH J = 15.7 Hz); 6.3 - 7.7 (m, 13H).
Primjer 7. Example 7.
(+,-)-6E-eritro-((fluoro-4-fenil)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3)-7-dihidroksi-3,5 -N-metil-hepten-6-amid (+,-)-6E-erythro-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5-N- methyl-hepten-6-amide
(spoj br. 7 Formule 1: X = O; R1 - R2 = -(CH2)4-, R3 = 4T, R4 = R5 = R6 = R9 = R10 =H, R7 i R8 = veza, R11 = CH3NH-). (compound No. 7 of Formula 1: X = O; R1 - R2 = -(CH2)4-, R3 = 4T, R4 = R5 = R6 = R9 = R10 =H, R7 and R8 = bond, R11 = CH3NH-) .
Otopina 0,67 g (0,00165 mola) spoja br. 1 u 25 cm3 otopine metilamina u 33 % etanola se miješa tijekom 24 sata na sobnoj temperaturi. Otapalo se upari i ostatak se dispergira u 8 cm3 etil acetata, cijedi se i suši. A solution of 0.67 g (0.00165 mol) of compound no. 1 in 25 cm3 of methylamine solution in 33% ethanol is stirred for 24 hours at room temperature. The solvent is evaporated and the residue is dispersed in 8 cm3 of ethyl acetate, filtered and dried.
tt: 150 - 152 °C - Prinos = 0,52 g = 70 %. mp: 150 - 152 °C - Yield = 0.52 g = 70 %.
Analiza za C27H30FNO4 M = 451,54 Analysis for C27H30FNO4 M = 451.54
C H N F C H N F
% izračunato 71,66 6,90 3,10 4,20 % % calculated 71.66 6.90 3.10 4.20 %
nađeno 71,47 6,76 2,93 4,08. found 71.47 6.76 2.93 4.08.
Primjer 8. Example 8.
(+,-)-trans-(1E-((fluoro-4-fenil)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3)-2-etanil)-6-hidroksi-4-tetrahidro-3,4,5,6-2H-piranon-2 (Spoj br. 8 - formula 1: X = O, R1 - R2 = -(CH2)4-, R3 = 4T, R4 = R5 = R6 = R10 = H, R7 i R8 = veza, R9 i R11 = veza). (+,-)-trans-(1E-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-2-ethanyl)-6-hydroxy- 4-tetrahydro-3,4,5,6-2H-pyranone-2 (Compound No. 8 - formula 1: X = O, R1 - R2 = -(CH2)4-, R3 = 4T, R4 = R5 = R6 = R10 = H, R7 and R8 = bond, R9 and R11 = bond).
Radi se izolirano od vlage. It is insulated from moisture.
Grije se na refluksu tijekom 3 sata, smjesa 6 g (0,0135 mola) spoj br. 4 i 1,94 g (0,0135 mola) kloro-2-etil dietil amina u 120 cm R7 i R8 acetona. Upari se aceton i ostatak se ulije u dovoljnu količinu etil acetata. Otopina se pere u vodi do pH 7 i zatim se suši na natrij sulfatu. Filtrira se i upari se etil acetat. It is heated at reflux for 3 hours, a mixture of 6 g (0.0135 mol) compound no. 4 and 1.94 g (0.0135 mol) of chloro-2-ethyl diethyl amine in 120 cm of R7 and R8 acetone. Acetone is evaporated and the residue is poured into a sufficient amount of ethyl acetate. The solution is washed in water to pH 7 and then dried over sodium sulfate. Filter and evaporate the ethyl acetate.
Dobiva se čvrsta supstancija koja se direktno prekristalizira iz 120 cm R7 i R8 etil acetata. tt: 188 - 191 °C - Prinos = 4,27 g - 79 %. Analiza za A solid substance is obtained which is directly recrystallized from 120 cm R7 and R8 of ethyl acetate. mp: 188 - 191 °C - Yield = 4.27 g - 79 %. Analysis for
C26H25FO4 M = 420,49 C26H25FO4 M = 420.49
C H F CH F
% izračunato 74,27 5,99 4,52 % % calculated 74.27 5.99 4.52 %
nađeno 74,07 6,04 4,49 found 74.07 6.04 4.49
NMR (DMSOd6) -200 Mhz: 1,45 - 2,20 (m, 10H); 2,34 (dd, 1 J - 16 Hz i 3,45 Hz); 3,93 - 4,10 (m, IH); 4,85 - 5,0 (m, IH); 5,11 (d, IH J = 3,3 Hz); 4,42 (dd, IH J = 16,3 Hz i 6,7 Hz); 6,02 (d, IH J = 16,3 Hz); 6,42 - 6,54 (m IH); 6,72 - 6,83 (m, 2H); 7,07 - 7,34 (m, 5H). NMR (DMSOd 6 ) -200 MHz: 1.45 - 2.20 (m, 10H); 2.34 (dd, 1 J - 16 Hz and 3.45 Hz); 3.93 - 4.10 (m, IH); 4.85 - 5.0 (m, IH); 5.11 (d, IH J = 3.3 Hz); 4.42 (dd, IH J = 16.3 Hz and 6.7 Hz); 6.02 (d, IH J = 16.3 Hz); 6.42 - 6.54 (m IH); 6.72 - 6.83 (m, 2H); 7.07 - 7.34 (m, 5H).
Primjer 9. Example 9.
(+,-)-trans-hidroksi-4-tetrahidro-3,4,5,6-(((-fluoro-4-fenil)-4-spiro (2H-benzopiran-1- 2,1'-ciklopropil)-3)- 2-etil)-6- piranon-2 (Spoj br. 9 - formula 1 : X = O, R1 - R2 = -(CH2)4-, R3 = 4T, R4 = R5 = R6 = R7 = R8 =R10 = H, R9 i R11 = veza). (+,-)-trans-hydroxy-4-tetrahydro-3,4,5,6-(((-fluoro-4-phenyl)-4-spiro (2H-benzopyran-1-2,1'-cyclopropyl) -3)- 2-ethyl)-6- pyranone-2 (Compound No. 9 - formula 1 : X = O, R1 - R2 = -(CH2)4-, R3 = 4T, R4 = R5 = R6 = R7 = R8 =R10 = H, R9 and R11 = bond).
Hidrogenizira se na normalnom tlaku i sobnoj temperaturi 1,72 g (0,00409 mola) spoja br. 9 u 70 cm R4 = R5 = R6 THF u prisustvu 0,1 g paladija dispergiranog na ugljiku. Kada je adsorbirana teorijska količina vodika, smjesa se filtrira, filtrat se upari i dobiveni ostatak se dispergira u diizopropileteru. Tako dobivena čvrsta supstancija se cijedi i suši. 1.72 g (0.00409 mol) of compound no. is hydrogenated at normal pressure and room temperature. 9 in 70 cm of R4 = R5 = R6 THF in the presence of 0.1 g of palladium dispersed on carbon. When the theoretical amount of hydrogen has been adsorbed, the mixture is filtered, the filtrate is evaporated and the resulting residue is dispersed in diisopropyl ether. The solid substance thus obtained is strained and dried.
tt: 156 - 157 °C (diizopropileter) - Prinos = 0,7 g = 41 %. mp: 156 - 157 °C (diisopropylether) - Yield = 0.7 g = 41 %.
Analiza za C26H27FO4 M = 422,50 Analysis for C26H27FO4 M = 422.50
C H F CH F
% izračunato 73,91 6,44 4,50 % calculated 73.91 6.44 4.50
% nađeno 73,83 6,32 4,40 % found 73.83 6.32 4.40
NMR (DMSOd6) - 200 Mhz: 1,38 - 2,21 (m, 14H); 2,39 (dd, IH J = 17,2 Hz i 2,8 Hz); 2,57 (dd, IH J = 17,2 i 4,6 Hz); 3,96 - 4,11 (m, IH); 4,25 - 4,46 (m, IH); 5,04 (d, IH J = 3,2 Hz); 6,31 - 6,41 (m, IH); 6,69 - 6,85 (m, 2H); 7,02 - 7,34 (m, 5H). NMR (DMSOd 6 ) - 200 MHz: 1.38 - 2.21 (m, 14H); 2.39 (dd, IH J = 17.2 Hz and 2.8 Hz); 2.57 (dd, IH J = 17.2 and 4.6 Hz); 3.96 - 4.11 (m, IH); 4.25 - 4.46 (m, IH); 5.04 (d, IH J = 3.2 Hz); 6.31 - 6.41 (m, 1H); 6.69 - 6.85 (m, 2H); 7.02 - 7.34 (m, 5H).
Primjer 10. Example 10.
(+,-)-eritro-((fluoro-4-fenil)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3)-7-dihidroksi-3,5-hetan ester natrija (+,-)-erythro-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3)-7-dihydroxy-3,5-hethane sodium ester
(spoj br. 10 - formula 1; X = O, R1 - R2 = -(CH2)4-, R3 = 4T, R4 = R5 = R6 = R7 = R8 =R10 = H, R9 i R11 = -ONa+). (compound no. 10 - formula 1; X = O, R1 - R2 = -(CH2)4-, R3 = 4T, R4 = R5 = R6 = R7 = R8 = R10 = H, R9 and R11 = -ONa+).
Miješa se na sobnoj temperaturi smjesa 0,22 g (0,00052 mola) spoja br. 9 i 0,52 cm3 (0,00052 mola - 5 %) 1 N vodene otopine natrij karbonata u 25 cm3 etanola. Etanol se upari i ostatak se dispergira u eteru, cijedi se i suši tako dobivena čvrsta supstancija. (CCM: silicijdioksidni gel: AcOEt - heksan: 1 -1 + 3 % AcOH : 1 mrlja). A mixture of 0.22 g (0.00052 mol) of compound no. 9 and 0.52 cm3 (0.00052 mol - 5 %) of a 1 N aqueous solution of sodium carbonate in 25 cm3 of ethanol. Ethanol is evaporated and the residue is dispersed in ether, the resulting solid is filtered and dried. (CCM: silica gel: AcOEt - hexane: 1 -1 + 3 % AcOH : 1 spot).
tt: nije definirana - Prinos = 0,12 g = 50 %. tt: not defined - Yield = 0.12 g = 50 %.
Analiza za C26H28FNaO5 M = 462,48 Analysis for C26H28FNaO5 M = 462.48
C H F Na C H F Na
% izračunato 67,52 6,10 4,11 4,97 % calculated 67.52 6.10 4.11 4.97
% nađeno 67,30 5,92 3,90 5,00 % found 67.30 5.92 3.90 5.00
Primjer 11. Example 11.
(+,-)-eritro-((fluoro-4-fenil)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil-3)-7-dihidroksi-3,5-heptan etilat (spoj br. 4) (+,-)-erythro-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl-3)-7-dihydroxy-3,5-heptane ethylate (compound no 4)
Hidrogenizira se pri normalnom tlaku 1,4 g (0,003 mola) spoja br. 1 otopljenog u 100 cm3 THF i u prisustvu 0,6 g paladija dispergiranog na ugljiku. Nakon što se adsorbira teorijska količina vodika, smjesa se filtrira, filtrat se upari do suhog i ostatak tako dobiven se disperira u heksanu, cijedi se i suši. 1.4 g (0.003 mol) of compound no. is hydrogenated at normal pressure. 1 dissolved in 100 cm3 of THF and in the presence of 0.6 g of palladium dispersed on carbon. After the theoretical amount of hydrogen has been adsorbed, the mixture is filtered, the filtrate is evaporated to dryness and the residue thus obtained is dispersed in hexane, filtered and dried.
tt: 103 - 105 °C (diizopropileter) - Prinos = 1 g = 71 %. mp: 103 - 105 °C (diisopropylether) - Yield = 1 g = 71 %.
Primjer 12. Example 12.
(+,-)-trans-((lE-((fluoro-4-fenil)-4-spiro(2H-benzopiran-1-2,1'-ciklopentil)-3-2-etenil)-6-dirnetil-2,2-dioheksan-1,3-il-4)etil aceta (spoj br. 11 - formula 1: X + O, R1 - R2 = -(CH2)4-, R3 = 4T, R4 = R5 = R6 = H, R7 i R8 = veza, R9 - R10 = (CH3)2C-, R11 = OC2H5). (+,-)-trans-((1E-((fluoro-4-phenyl)-4-spiro(2H-benzopyran-1-2,1'-cyclopentyl)-3-2-ethenyl)-6-dirnethyl- 2,2-diohexane-1,3-yl-4)ethyl acetate (compound No. 11 - formula 1: X + O, R1 - R2 = -(CH2)4-, R3 = 4T, R4 = R5 = R6 = H, R7 and R8 = bond, R9 - R10 = (CH3)2C-, R11 = OC2H5).
Miješa se na sobnoj temperaturi smjesa 2 g (0,0043 mola) spoja br. 1, 0,7 g metoksi-2 propena i 8 mg paratoluensulfonske kiseline monohidrata u 25 cm3 DMF tijekom 48 sati. Doda se 125 cm3 etera i ispire se zasićenom vodenom otopinom natrij bikarbonata i zatim vodom. Suši se organska faza na natrij sulfatu, filtrira i suši do suhog. Dobiva se ulje koje kristalizira iz heksana, cijedi se, suši i kromatografira na 20 g silicij dioksidnog gela korištenjem smjese heksan-etil acetat: 1 -1 kao otapalo i eluant. A mixture of 2 g (0.0043 mol) of compound no. 1, 0.7 g of methoxy-2-propene and 8 mg of paratoluenesulfonic acid monohydrate in 25 cm3 of DMF for 48 hours. Add 125 cm3 of ether and wash with saturated aqueous sodium bicarbonate solution and then with water. The organic phase is dried over sodium sulfate, filtered and dried to dryness. An oil is obtained which crystallizes from hexane, is filtered, dried and chromatographed on 20 g of silica gel using a mixture of hexane-ethyl acetate: 1-1 as solvent and eluent.
tt: 103 - 105 °C - Prinos = 0,95 g = 44 %. mp: 103 - 105 °C - Yield = 0.95 g = 44 %.
Analiza za C31H35FO5 M = 506,61 Analysis for C31H35FO5 M = 506.61
C H F CH F
% izračunato 73,50 6,96 3,75 % calculated 73.50 6.96 3.75
% nađeno 73,64 6,98 3,73 % found 73.64 6.98 3.73
NMR (CDCl3) NMR (CDCl3)
0,9 - 2,5 (m, 16H); 3,9 - 4,5 (m, 2H); 4,05 (q, 2H); 5,15 (dd, IH); 5,95 (d, IH); 6,2 -7,25 (m, 8H). 0.9 - 2.5 (m, 16H); 3.9 - 4.5 (m, 2H); 4.05 (q, 2H); 5.15 (dd, IH); 5.95 (d, IH); 6.2-7.25 (m, 8H).
U primjerima spojeva izuma koji slijede korištene kratice imaju slijedeća značenja: Me = metil, Et = etil, Pr - prpol, Bz = benzil, Pen = pentil, Tbu = tetriobutil, iPr = izopropil, Phe = fenil, Pyr = pirolidino. In the following examples of the compounds of the invention, the abbreviations used have the following meanings: Me = methyl, Et = ethyl, Pr - prpol, Bz = benzyl, Pen = pentyl, Tbu = tetriobutyl, iPr = isopropyl, Phe = phenyl, Pyr = pyrrolidino.
Primjer 13. Example 13.
Korištenjem postupka prema primjerima 1-12 dobiveni su spojevi (tabela u daljnjem tekstu), formule 1 u kojoj X = O, R1 i R2 grade lanac -(CH2)n-, R7 i R8 grade zajedno jednostavnu vezu, R9 i R10 svaki označava atom vodika: By using the procedure according to examples 1-12, compounds (table below) were obtained, formula 1 in which X = O, R1 and R2 build a chain -(CH2)n-, R7 and R8 together build a single bond, R9 and R10 each represent hydrogen atom:
[image] [image]
Primjer 14. Example 14.
Korištenjem postupka odgovarajućih primjera 1-12, dobiveni su spojevi (dani u tabeli u daljnjem tekstu) formule 1 u kojoj X - O, R4 = R5 = R9 = R10 = H i R7 i R8 grade vezu: Using the procedure of the corresponding examples 1-12, compounds (given in the table below) of formula 1 were obtained in which X - O, R4 = R5 = R9 = R10 = H and R7 and R8 form a bond:
[image] [image]
Primjer 15. Example 15.
Korištenjem postupka odgovarajućih primjera 1-12 doboveni su spojevi (dani u tabeli u daljnjem tekstu) formule 1 a kojoj R4 = R6 = R10 = H, a R7 i R8, odnosno R9 i R11 grade zajedno jednu jednostavnu vezu: By using the procedure of the corresponding examples 1-12, the compounds (given in the table below) of formula 1 were obtained, in which R4 = R6 = R10 = H, and R7 and R8, that is, R9 and R11 together form one simple bond:
[image] [image]
Primjer 16. Example 16.
Koristeći postupke odgovarajućih primjera 1 - 12, dobiveni su spojevi (tabela u daljnjem tekstu) formule 1 u kojoj X = CH2 ili S, R4 = R6 = R9 = R10 = H, R7 i R8 grade jednostavnu vezu: Using the procedures of the corresponding examples 1 - 12, compounds (table below) of formula 1 were obtained in which X = CH2 or S, R4 = R6 = R9 = R10 = H, R7 and R8 form a simple bond:
[image] [image]
Korištenjem postupaka stadija odgovarajućih intermedijernih primjera 1-4 dobiveni su intermedijerni spojevi sakupljeni u neograničavajućim primjerima koji slijede. Using the step procedures of the corresponding intermediate examples 1-4, the intermediate compounds collected in the following non-limiting examples were obtained.
Primjer 17. Example 17.
Intermedijerni spojevi opće formule 4 u kojoj X = O, R1 i R2 grade lanac -(CH2)m R7 i R8 grade zajedno jednu vezu, R9 označava atom vodika: Intermediate compounds of the general formula 4 in which X = O, R1 and R2 form a chain -(CH2)m R7 and R8 form one bond together, R9 denotes a hydrogen atom:
[image] [image]
Primjer 18. Example 18.
Intermedijerni spojevi opće formule 4 u kojoj X = O, R4 = R5 = R6 = R9, = i R7 i R8 grade jednu vezu: Intermediate compounds of the general formula 4 in which X = O, R4 = R5 = R6 = R9, = and R7 and R8 form one bond:
[image] [image]
Primjer 19. Example 19.
Intermedijerni spojevi opće formule 4 u kojoj X=CH2 ili S, R4=R6=R9=H, R7 i R8 grade jednu vezu i R11 = metoksi. Intermediate compounds of general formula 4 in which X=CH2 or S, R4=R6=R9=H, R7 and R8 form one bond and R11 = methoxy.
[image] [image]
Primjer 20 Example 20
Intermedijerni spojevi opće formule 2 u kojoj X=O, R1 i R2 grade jedan lanac -CH2)n-, i R7 i R8 grade jednu vezu Intermediate compounds of general formula 2 in which X=O, R1 and R2 form one chain -CH2)n-, and R7 and R8 form one bond
[image] [image]
Primjer 21. Example 21.
Intermedijerni spojevi opće formule 2 u kojoj X=CH2, O ili S, R4=R6=H i R7 i R8 grade zajedno jednu vezu. Intermediate compounds of the general formula 2 in which X=CH2, O or S, R4=R6=H and R7 and R8 together form one bond.
[image] [image]
Primjer 22. Example 22.
Intermedijerni spojevi opće formule 6 u kojoj X=CH2ili S, R4=R6=H. Intermediate compounds of the general formula 6 in which X=CH2 or S, R4=R6=H.
[image] [image]
Primjer 23. Example 23.
Intermedijerni spojevi opće formule 5 u kojoj X=O i R1 i R2 grade tetrametilenski lanac -(CH2)4- Intermediate compounds of the general formula 5 in which X=O and R1 and R2 form a tetramethylene chain -(CH2)4-
[image] [image]
Primjer 24. Example 24.
Intermedijerni spojevi opće formule 5 u kojoj R4=R6=H. Intermediate compounds of the general formula 5 in which R4=R6=H.
[image] [image]
Primjer 25 Example 25
Intermedijerni spojevi opće formule 9 u kojoj X=S, a R4=R5=H. Intermediate compounds of the general formula 9 in which X=S and R4=R5=H.
[image] [image]
Primjer26. Example 26.
[image] [image]
ANALITIČKI PODACI ANALYTICAL DATA
[image] [image] [image] [image]
* računato s pola molekule vode * calculated with half a molecule of water
Rč: računato Rč: calculated
Tr: teorijski Tr: theoretical
** računato s 1/3 molekule vode ** calculated with 1/3 water molecule
*** računato s 1/4molekule vode *** calculated with 1/4 water molecule
Claims (7)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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FR8900790A FR2642065B1 (en) | 1989-01-24 | 1989-01-24 | DERIVATIVES OF ALCOHANIC BENZOCYCLOALCENYL DIHYDROXY ACIDS, PROCESS FOR THEIR PREPARATION AND MEDICAMENTS CONTAINING THEM |
YU12490A YU48227B (en) | 1989-01-24 | 1990-01-24 | PROCEDURE FOR THE PREPARATION OF BENZOCYCLOCHENYL DERIVATIVES OF ALKANOIC ACIDS AND THE PHARMACEUTICAL PRODUCTS CONTAINING THEM |
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HRP-124/90A HRP920760A2 (en) | 1989-01-24 | 1992-10-01 | Process for the preparation of benzocycloalkenyl dihydroxy alkane acid derivatives and medicaments containing them |
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HR (1) | HRP920760A2 (en) |
SI (1) | SI9010124A (en) |
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1990
- 1990-01-24 SI SI9010124A patent/SI9010124A/en unknown
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1992
- 1992-10-01 HR HRP-124/90A patent/HRP920760A2/en not_active Application Discontinuation
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