CH569707A5 - Indenylacetic acid derivs - useful as antiinflammatory agents - Google Patents
Indenylacetic acid derivs - useful as antiinflammatory agentsInfo
- Publication number
- CH569707A5 CH569707A5 CH1073875A CH1073875A CH569707A5 CH 569707 A5 CH569707 A5 CH 569707A5 CH 1073875 A CH1073875 A CH 1073875A CH 1073875 A CH1073875 A CH 1073875A CH 569707 A5 CH569707 A5 CH 569707A5
- Authority
- CH
- Switzerland
- Prior art keywords
- alkyl
- methyl
- alkoxy
- fluoro
- acid
- Prior art date
Links
- PTUSXMWNCXRKAX-UHFFFAOYSA-N 2-(1h-inden-1-yl)acetic acid Chemical compound C1=CC=C2C(CC(=O)O)C=CC2=C1 PTUSXMWNCXRKAX-UHFFFAOYSA-N 0.000 title abstract description 5
- 229940121363 anti-inflammatory agent Drugs 0.000 title 1
- 239000002260 anti-inflammatory agent Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 239000000463 material Substances 0.000 claims 1
- -1 nitro, amino Chemical group 0.000 abstract description 7
- 230000000202 analgesic effect Effects 0.000 abstract description 2
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 2
- 230000001754 anti-pyretic effect Effects 0.000 abstract description 2
- 125000003545 alkoxy group Chemical group 0.000 abstract 5
- 125000000217 alkyl group Chemical group 0.000 abstract 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 abstract 3
- 125000001188 haloalkyl group Chemical group 0.000 abstract 3
- 125000004423 acyloxy group Chemical group 0.000 abstract 2
- 125000003282 alkyl amino group Chemical group 0.000 abstract 2
- 125000004663 dialkyl amino group Chemical group 0.000 abstract 2
- 125000001475 halogen functional group Chemical group 0.000 abstract 2
- 125000004442 acylamino group Chemical group 0.000 abstract 1
- 125000004414 alkyl thio group Chemical group 0.000 abstract 1
- 125000005122 aminoalkylamino group Chemical group 0.000 abstract 1
- 125000003118 aryl group Chemical group 0.000 abstract 1
- 150000001768 cations Chemical class 0.000 abstract 1
- 125000000000 cycloalkoxy group Chemical group 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 abstract 1
- 125000001072 heteroaryl group Chemical group 0.000 abstract 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 abstract 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract 1
- 125000005191 hydroxyalkylamino group Chemical group 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- MLKXDPUZXIRXEP-UHFFFAOYSA-N 2-[6-fluoro-2-methyl-3-[(4-methylsulfinylphenyl)methylidene]-1-indenyl]acetic acid Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2C1=CC1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- HMJXQEIMQBPTHN-UHFFFAOYSA-N 5-fluoro-2-methyl-2,3-dihydroinden-1-one Chemical compound FC1=CC=C2C(=O)C(C)CC2=C1 HMJXQEIMQBPTHN-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- DMXDUJPYGUWROU-FNORWQNLSA-N (e)-2-methyl-3-(3-nitrophenyl)prop-2-enoic acid Chemical compound OC(=O)C(/C)=C/C1=CC=CC([N+]([O-])=O)=C1 DMXDUJPYGUWROU-FNORWQNLSA-N 0.000 description 2
- PSHHGHLPWFEVLB-UHFFFAOYSA-N 3-(3-aminophenyl)-2-methylpropanoic acid Chemical compound OC(=O)C(C)CC1=CC=CC(N)=C1 PSHHGHLPWFEVLB-UHFFFAOYSA-N 0.000 description 2
- ZNGQTWWSSQMYIO-UHFFFAOYSA-N 3-(3-fluorophenyl)-2-methylpropanoic acid Chemical compound OC(=O)C(C)CC1=CC=CC(F)=C1 ZNGQTWWSSQMYIO-UHFFFAOYSA-N 0.000 description 2
- JIZWNONYKZOASX-UHFFFAOYSA-N 5-fluoro-2-methyl-1-[(4-methylsulfanylphenyl)methyl]-1h-indene Chemical compound C1=CC(SC)=CC=C1CC1C2=CC=C(F)C=C2C=C1C JIZWNONYKZOASX-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 150000003935 benzaldehydes Chemical class 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- JGJLWPGRMCADHB-UHFFFAOYSA-N hypobromite Chemical compound Br[O-] JGJLWPGRMCADHB-UHFFFAOYSA-N 0.000 description 2
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- QDLKMRTVELBKFE-UHFFFAOYSA-N 1-(bromomethyl)-4-methylsulfanylbenzene Chemical compound CSC1=CC=C(CBr)C=C1 QDLKMRTVELBKFE-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- JMNVALXGIOSFGW-UHFFFAOYSA-N 2-(3h-inden-1-yl)acetic acid Chemical compound C1=CC=C2C(CC(=O)O)=CCC2=C1 JMNVALXGIOSFGW-UHFFFAOYSA-N 0.000 description 1
- IUZGJIIUDQXXBO-UHFFFAOYSA-N 3-(3H-inden-1-ylperoxy)-1H-indene Chemical compound C1C=C(C2=CC=CC=C12)OOC1=CCC2=CC=CC=C12 IUZGJIIUDQXXBO-UHFFFAOYSA-N 0.000 description 1
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 description 1
- DNLFNKPOQAMIMG-UHFFFAOYSA-N 5-fluoro-2-methyl-1-[(4-methylsulfinylphenyl)methyl]-1h-indene Chemical compound CC1=CC2=CC(F)=CC=C2C1CC1=CC=C(S(C)=O)C=C1 DNLFNKPOQAMIMG-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 238000003512 Claisen condensation reaction Methods 0.000 description 1
- PGTKVMVZBBZCKQ-UHFFFAOYSA-N Fulvene Chemical compound C=C1C=CC=C1 PGTKVMVZBBZCKQ-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical group CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 238000006680 Reformatsky reaction Methods 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- QGZPJPDPGXDUSL-UHFFFAOYSA-M [Br-].CSC1=CC=C(C[Mg+])C=C1 Chemical compound [Br-].CSC1=CC=C(C[Mg+])C=C1 QGZPJPDPGXDUSL-UHFFFAOYSA-M 0.000 description 1
- 150000001243 acetic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 150000002168 ethanoic acid esters Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 238000005911 haloform reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000009863 impact test Methods 0.000 description 1
- YIAPLDFPUUJILH-UHFFFAOYSA-N indan-1-ol Chemical compound C1=CC=C2C(O)CCC2=C1 YIAPLDFPUUJILH-UHFFFAOYSA-N 0.000 description 1
- QNXSIUBBGPHDDE-UHFFFAOYSA-N indan-1-one Chemical compound C1=CC=C2C(=O)CCC2=C1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 description 1
- 150000002469 indenes Chemical class 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 150000003151 propanoic acid esters Chemical class 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000015067 sauces Nutrition 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 1
- 235000010334 sodium propionate Nutrition 0.000 description 1
- 239000004324 sodium propionate Substances 0.000 description 1
- 229960003212 sodium propionate Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- PNGLEYLFMHGIQO-UHFFFAOYSA-M sodium;3-(n-ethyl-3-methoxyanilino)-2-hydroxypropane-1-sulfonate;dihydrate Chemical compound O.O.[Na+].[O-]S(=O)(=O)CC(O)CN(CC)C1=CC=CC(OC)=C1 PNGLEYLFMHGIQO-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000010414 supernatant solution Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5407—Acyclic saturated phosphonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/56—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
- C07C209/32—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups
- C07C209/36—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst
- C07C209/365—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst by reduction with preservation of halogen-atoms in compounds containing nitro groups and halogen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/32—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with molecular oxygen
- C07C45/37—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with molecular oxygen of >C—O—functional groups to >C=O groups
- C07C45/38—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with molecular oxygen of >C—O—functional groups to >C=O groups being a primary hydroxyl group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
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Abstract
Anti-inflammatory indenylacetic acid derivatives. Compds. of formula:- (where Ar = aryl or heteroaryl; R1 = H, 1-4C alkyl, 1-4C haloalkyl; R2 = H or 1-6C alkyl; R3, R4, R5, R6 = H, halo, alkyl, acyloxy, alkoxy, nitro, amino, acylamino, alkylamino, dialkylamino, dialkylaminoalkyl, sulphamyl, alkylthio, mercapto, hydroxy, hydroxyalkyl, alkylsulphonyl, cyano, carboxyl, carbalkoxy, carbamido, haloalkyl, cycloalkyl, cycloalkoxy where all alkyl, acyloxy and alkoxy groups have 1-6C; R7 = 1-6C alkylsulphonyl, 1-6C alkylsulphonyl; R8 = H, halo 1-6C alkoxy, 1-6C haloalkyl; M = hydroxy, opt. substd. alkoxy, amino, alkylamino, dialkylamino, N-morpholino, hydroxyalkylamino, polyhydroxyalkylamino, dialkylaminoalkylamino, aminoalkylamino or a group OMe where Me is a cation, where all alkyl and alkoxy gps. are 1-6C. The compounds may be as or transisomers or a racemate or optically active form) also exhibit analgesic and antipyretic activity.
Description
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von 5-Fluor-2-methyl-1 -(4' -methylsulfinylbenzyli den)-3-indenyl-essigsiiure der Formel I
EMI1.1
Diese Verbindung weist entzündungshemmende und fiebersenkende sowie analgetische Aktivitiit auf und diese Verbindung ist zur Behandlung derartiger Krankheiten geeignet, welche sich dadurch äussern, dass sie Symptome wie z. B.
Schmerzen, Fieber oder Entziindungsprozesse zeigen. Bei der Behandlung derartiger Krankheiten kann 5-Fluor-2-methyl-1 (4'-methylsulfinylbenzyliden)-3-indenyl-essigsäure topisch, oral. rektal oder parenteral verabreicht werden, und zwar in Dosierungsbereichen, welche von etwa 0,1 mg bis 50 mg/kg Körpergewicht pro Tag erreichen und insbesondere von etwa 1 mg bis etwa 15 mg/kg Körpergewicht pro Tag.
Es sei festgestellt, dass die 5-Fluor-2-methyl-1 -(4' -me- thylsulfinylbenzyliden)-3-indenyl-essigsäure nach an sich bekannten Verfahren in die cis- bzw. trans-isomere Form umgewandelt werden kann. Das cis-Isomere ist diejenige isomere Form, in welcher die Benzylidenfunktion sich unterhalb des Phenylringes des Indenkernes befindet. Es sei somit festgestellt, dass dieses cis-Isomere sowohl chemisch stabiler ist und auch biologisch wirksamer als das entsprechende trans Isomere.
Des weiteren sei festgestellt, dass das in der oben angefiihrten 5 -Fluor-2-methyl-1 -(4' -methylsulfinylbenzyliden)- 3-indenylessigsäure enthaltene Schwefelatom ein asymmetrisches Zentrum darstellt und dass die Verbindung mittels Verfahren, die wohi bekannt sind, in Form einer (+) und in Form einer (-) Form erhalten werden kann.
Es sei dariiber hinaus festgestellt, dass diese Verbindung polymorph ist und mehr als eine kristalline Struktur aufweist, womit es gegeben ist, dass diese Verbindung je nach ihrem Herstellungsverfahren in festem Zustand verschiedene Schmelzpunkte aufweisen kann.
Bisher wurden andere 1 -Benzyliden-3 4ndenylessigsiuren hergestellt, und zwar indem man substituierte Benzaldehyde mit substituierten Essigsiiureestern in einer Claisen-Reaktion kondensierte; ein anderes Herstellungsverfahren fir derartige Verbindungen beruhte darauf, dass man einen a -halogenierten Propionsäureester mit einem substituierten Benzaldehyd in einer Reformatsky-Reaktion umsetzte. Der erhaltene unge slttigte Ester wurde reduziert und hydrolysiert, wobei sich einess-Arylpropionsäure ergab, welche einem Ringschluss unterworfen wurde, worauf man ein Indanon erhielt.
Die aliphatische Säure-Seitenkette wurde mittels einer Reformatsky- oder einer Wittig-Reaktion eingefiihrt und sodann wurde der 1 -Substituent in die resultierende Indenylessigsiure oder deren Ester durch Umsetzung des jeweiligen Säure- derivates mit einem aromatischen Aldehyd oder Keton der erwiinschten Formel und anschliessendes Dehydratisieren eingefiigt, um die erwiinschte Indenylessigslure zu erhalten.
Ziel der Erfindung ist also ein neues Verfahren zur Herstellung von 5-Fluor-2-methyl-l -(4' -methylsulfinylbenzyli- den)-3-indenyl-essigsäure, das dadurch gekennzeichnet ist, dass man eine Verbindung der Formeln
EMI1.2
in uelchen n = Null oder 1 ist, mit einem Alkalimetallhypohalogenit behandelt.
Nachfolgend werden bevorzugte Ausfiihrungsformen zur Herstellung von im erfindungsgemiissen Verfahren einsetzbaren Ausgangsverbindungen sowie des erfindungsgemässen Verfahrens beschrieben:
Die Kondensation einer Verbindung der Formel II
EMI2.1
in welcher X Wasserstoff bedeutet und n = 1 ist, mit Chloraceton unter üblichen Bedingungen ergibt das Indenyl(2propanon). Dieses Propanon geht eine tibliche Haloformreaktion unter Behandlung mit Natriumhypochlorit, Hypobromit oder Hypojodit ein, und zwar in einem Lösungsmittel wie z. B.
Dioxan, Tetrahydrofuran oder Dimethylsulfoxyd, wobei die erwünschte Indenylessigsäure gemäss des folgenden Formelschemas gebildet wird:
EMI2.2
Die folgenden Beispiele sollen Ausfuhrungsformen des vorliegenden erfindungsgemässen Verfahrens niter erläutern.
Beispiel 1
Schritt A
Herstellung von a -Methyl -3 -nitrozimtsiure
Eine Mischung von 150 g (1 Mol) 3-Nitrobenzaldehyd, 200 g Propionsiureanhydrid und 96 g (1 Mol) Natriumpropionat werden bei 1700 C während 5 Stunden mit gelegentlichem Rfihren belassen. Das Produkt wird abgekiihlt und in 1 Liter Wasser eingegossen und durch portionsweise Zugabe von Natriumcarbonat unter Rühren stark alkalisch gemacht.
Die dunkle Flussigkeit wird mit Aktivkohle gekocht bis eine abzentrifugierte Probe eine farblose aberstehende Lösung ergibt, sodann wird filtriert und mit Chlorwasserstoff siure angesiuert. Der erhaltene Niederschlag an a-Methyl-3 nitrozimtslure wird gesammelt, getrocknet und aus Ethanol umkristallisiert.
Schritt B
Herstellung von a -Methyl-3 -aminohydrozimtsHure
Das Produkt aus Schritt A wird in 2500 ml absolutem Äthanol gelöst und bei Raumtemperatur unter einem Druck von 2,8 Atmosphären Wasserstoff reduziert, wobei ein Katalysator von Palladium auf Aktivkohle angewandt wird, und die Reduktion wird so lange fortgefiihrt, bis ein Aquivalent von 4 Molen Wasserstoff absorbiert ist. Nach Entfernung des Katalysators wird das Athanol unter vermindertem Druck abgedampft, wonach die Aminosiure kristallisiert.
Schritt C
Herstellung von α-Methyl-3-fluor-hydrozimtsäure
179 g (1 Mol) von a-Methyl-3-aminohydrozimtsiure werden in 2 1 4normaler Chlorwasserstoffsiure suspendiert und sodann wird auf 50 C gekiihlt. Es schliesst sich nun die Diazotierung unter Riihren an und sie wird mit einer L5- sung von 88 g Natriumnitrit in 250 ml Wasser ausgefiihrt, wobei das Reagens in einem derartigen Mass zugesetzt wird, dass jede Temperaturerhöhung vermieden wird. Zu der kla- ren Lösung von -5 C Temperatur werden 350 ml Hexafluor phosphorsaure zugegeben, und zwar in einem Zuge, und gleichzeitig etwas Trockeneis, um die Temperatur auf dem gewünschten Niveau zu halten.
Der Niederschlag an Diazoniumhexafluorphosphat wird in einem Filter gesammelt und gut mit Wasser gewaschen und im Vakuum bei Raumtemperatur getrocknet. Das Salz wird in Portionen von 20 bis 30 g in 200 ml Xylol bei 125 C pyrolysiert, bis die Gasentwicklung aufhört. Die gekühlte Mischung wird sodann mit Natriumbicarbonatlösung extrahiert, um die a-Methyl-3-fluor hydrozimtsäure von neutralen Nebenprodukten abzutren nen, und der Extrakt wird mit Aktivkohle entfirbt. Aus dem farblosen Filtrat wird die niedrigschmelzende angestrebte Sauce durch Ansäuern bei 0 C und Kratzen der Gefiisswande, bis der anfänglich align Niederschlag kristallisiert, gewonnen.
Schritt D
Herstellung von 5-Fluor-2-methylindanon
Das Produkt aus Schritt C wird mit einem lOfachen seines Gewichtes an Polyphosphorsäure bei 80 bis 90" C während 2 Stunden erhitzt. Die Fliissigkeit wird sodann in 1 Liter Eiswasser eingegossen und während 1/2 Stunde geruhrt und sodann mit drei Portionen von je 100 ml anther extrahiert.
Die vereinigten Extrakte werden mit Wasser und Natrium bicarbonatlösung gewaschen bis die Atherphase neutral ist und sodann wird der Extrakt iiber Natriumsulfat getrocknet und konzentriert, wobei 5-Fluor-2-methylindanon als gelbliches ijl zurtickbleibt.
Schritt E
Herstellung von 5-Fluor-2-methyl -1 -(4'-methylthio- benzyl)-1 -indanol
Eine Lösung von 4-Methylthiobenzyl-magnesiumbromid wird aus 45,8 g 4-Methylthiobenzylbromid (0,2 Mol) in 500 ml anther hergestellt. Diese Lösung wird tropfenweise zu einer intensiv geruhrten Lösung von 32,8 g (0,2 Mol) von 5-Fluor-2-methylindanon in 1 Liter wasserfreiem ither bei 0 C zugesetzt, wobei die Zusatzgeschwindigkeit eine derartige ist, dass der Gilman Test auf freies Grignardreagens niemals positiv ist.
Schliesslich wird die kalte Mischung in 500 ml einer gesättigten wässrigen Ammoniumchloridlösung abgelöscht, die Atherphase wird abgetrennt und so lang mit Wasser gewaschen, bis sie frei von Ammoniumchlorid ist; sodann wird diese Phase tiber Magnesiumsulfat getrocknet und beim Konzentrieren unter vermindertem Druck erhält man das Indanol als Ruckstand.
Schritt F
Herstellung von 5-Fluor-2-methyl-1 -(4' -methyl- thiobenzyl) -inden
Das Produkt aus Schritt E wird in einer Mischung von 600 ml wasserfreiem anther und 60 ml wasserfreiem Pyridin aufgenommen. Unter Rühren und Feuchtigkeitsausschluss wird die Lösung auf -10" C gekühlt und tropfenweise mit 31 g Thionylchlorid behandelt. Sobald die Reaktion voll shindig ist, lisst man die Mischung unter Rtihren sofort auf Raumtemperatur erwirmen und giesst sie sodann in 1 Liter Wasser ein. Nach innigem Vermischen wird die Atherphase abgetrennt. mit Wasser gewaschen, tiber Magnesiumsulfat getrocknet und konzentriert.
Der Riickstand wird aus Hexan umkristallisiert.
Schritt G
Herstellung von 5-Fluor-2-methyl-1 -(4' -methyl- sulfinylbenzyliden) -3 -indenylessigsiure
Eine Lösung von 7,61 g (0,1 Mol) kristalliner Glycolsiure in 120 ml Pyridin wird durch Zugabe einer 40%igen Lösung von Benzyltrimethylammoniumhydroxyd (Triton B) in Pyridin (ca. 42 ml) neutralisiert. Sodann wird 1 ml Triton B im Überschuss zugegeben und schliesslich werden 50 ml Benzol hinzugefügt. Die Lösung befindet sich in einem Reaktions gefiss, das mit einer Fraktionierkolonne und einem Stickstoffeinlass ausgestattet ist, und die erhaltene Lösung wird mit reinem Stickstoff sorgflätig von Luft befreit und schliesslich werden 33,04 g (0,1 Mol) an 5-Fluor-2-methyl-1-(4'-me- thylthiobenzyl)-inden zugegeben.
Während man das Spülen mit Stickstoff aufrechterhilt, wird die Mischung so weit er wirmt, dass eine sehr langsame Destillation auftritt. Das Heteroazeotrop, das Benzol, Wasser und Pyridin enthält, kondensiert und scheidet sich in Phasen; das Erhitzen wird so lang aufrecht erhalten, bis kein Wasser mehr erscheint.
Sodann wird das Benzol abgetrennt.
etrennt.
Die obige Lösung wird sodann auf Raumtemperatur abkiihlen gelassen, der Stickstoffzustrom wird unterbrochen und die Lösung wird unter Luftzutritt gerührt. Die Bildung von 3-Indenyl-peroxyd ftihrt sowohl zur Dehydrierung zu Fulven als auch zur Oxydation des Thioithers zu Sulfoxyd.
Die Exponierung wird so lange fortschreiten gelassen, bis eine Testprobe unter Stickstoffatmosphire kein restliches Peroxyd mehr zeigt, wenn man den Jodstirketest anwendet. Das Pyridin wird sodann unter Vakuum entfernt und der Rtickstand wird mit 200 ml/einnormaler Essigsäure behandelt, wodurch rohe 5-Fluor-2-methyl-1 -(4'-methylsulfinylbenzyli- den) -3 -indenylessigsiure als Niederschlag gebildet wird, welche sodann durch Umkristallisierung gereinigt wird. Das gereinigte Produkt weist einen Schmelzpunkt von 184 bis 186"C auf.
Beispiel 2
Schritt A
Herstellung von 5-Fluor-2-methyl-1 -(4' -methyl- sulfinylbenzyl)-inden
Zu einer Lösung von 0,1 Mol von 1-(4'-Methylthiobenzyl)-2-methyl-5-fluorinden in 100 ml Benzol werden tropfenweise unter Rühren 1086 g (0,1 Mol) von tert.-Butylhypochlorit zugesetzt. Wenn die anfinglich gelbe Färbung verschwunden ist, werden die Ldsungsmittel unter vermindertem Druck entfernt und der Sulfoxydriickstand wird direkt im nächsten Reaktionsschritt weiterverwendet.
Schritt B
Herstellung von 5-Fluor-2-methyl-1 -(4' -methyl- sulfinylbenzyliden) -3 -indenylessigsäure
Es wird das in Beispiel 1 Schritt G angegebene Verfahren angewandt, jedoch ersetzt man die dortige Thiokomponente durch das Sulfoxyd, welches aus Beispiel 2 Schritt A erhalten worden ist, und behält im iibrigen die Arbeitsweise aus Beispiel 1 Schritt G bei. Auf diese Weise wird 5-Fluor 2 -methyl -1 -(4' -methylsulfinylbenzyliden) -3 -indenylessig siure hergestellt, und das Produkt weist einen Schmelzpunkt von 184 bis 186"Cauf.
Beispiel 3
Schritt A
Herstellung von 5-Fluor-2-methyl-1-(4'-methyl sulfinylbenzyl) -3 -(2' -propanon) -inden
Die Kondensation von Chloraceton mit dem Produkt aus Beispiel 2 Schritt A in Gegenwart einer Base führt zum er wünschten Idenylpropanon.
Schritt B
Herstellung von 5-Fluor-2-methyl-1 -(4' -methyl- sulfinylbenzyliden) -3 -indenylessigsiure.
11,9 g (0,033 Mol) des Methylketons aus Schritt A werden in 100 ml Dioxah aufgenommen und mit einem 10 %igen Überschuss einer Hypochloritlösung, die 2,0 g Natriumhydroxyd enthalt, während 1 Stunde bei 35 C behandelt.
Das ilberschtlssige Oxydationsmittel wird mit 10 %iger Na triumbisulfitlösung zerstört und die freie 3-Indenylessig sgure wird bei pH 2 mit Salzäure ausgefiillt. Umkristallisieren aus einem Lösungsmittelsystem, welches aus Essigsäureäthylester und Petrolliffier besteht, ergibt die Sure, welche einen Schmelzpunkt von 184 bis 186 C aufweist.
The present invention relates to a process for the preparation of 5-fluoro-2-methyl-1 - (4'-methylsulfinylbenzyli den) -3-indenyl-acetic acid of the formula I.
EMI1.1
This compound has anti-inflammatory and antipyretic as well as analgesic activity and this compound is suitable for the treatment of such diseases which manifest themselves in that they cause symptoms such as e.g. B.
Show pain, fever or inflammation. In the treatment of such diseases, 5-fluoro-2-methyl-1 (4'-methylsulfinylbenzylidene) -3-indenyl-acetic acid can be used topically, orally. can be administered rectally or parenterally, specifically in dosage ranges which reach from about 0.1 mg to 50 mg / kg body weight per day and in particular from about 1 mg to about 15 mg / kg body weight per day.
It should be noted that the 5-fluoro-2-methyl-1 - (4'-methylsulfinylbenzylidene) -3-indenylacetic acid can be converted into the cis- or trans-isomeric form by processes known per se. The cis isomer is the isomeric form in which the benzylidene function is located below the phenyl ring of the indene nucleus. It should thus be noted that this cis isomer is both chemically more stable and also more biologically effective than the corresponding trans isomer.
Furthermore, it should be noted that the sulfur atom contained in the above-mentioned 5-fluoro-2-methyl-1 - (4'-methylsulfinylbenzylidene) -3-indenylacetic acid represents an asymmetric center and that the compound can be converted into an asymmetric center by means of processes which are well known Form of (+) and form of (-) form can be obtained.
In addition, it should be noted that this compound is polymorphic and has more than one crystalline structure, which means that this compound can have different melting points in the solid state depending on its method of preparation.
So far, other 1-benzylidene-34denyl acetic acids have been prepared by condensing substituted benzaldehydes with substituted acetic acid esters in a Claisen reaction; Another preparation process for such compounds was based on the reaction of an α-halogenated propionic acid ester with a substituted benzaldehyde in a Reformatsky reaction. The obtained unsaturated ester was reduced and hydrolyzed to give an ß-arylpropionic acid, which was cyclized to give an indanone.
The aliphatic acid side chain was introduced by means of a Reformatsky or a Wittig reaction and then the 1 -substituent was incorporated into the resulting indenylacetic acid or its ester by reacting the respective acid derivative with an aromatic aldehyde or ketone of the desired formula and subsequent dehydration to obtain the desired indenyl acetic acid.
The aim of the invention is therefore a new process for the preparation of 5-fluoro-2-methyl-1- (4'-methylsulfinylbenzylidene) -3-indenyl-acetic acid, which is characterized in that a compound of the formulas is used
EMI1.2
in uelchen n = zero or 1, treated with an alkali metal hypohalite.
Preferred embodiments for the production of starting compounds which can be used in the process according to the invention and the process according to the invention are described below:
The condensation of a compound of formula II
EMI2.1
in which X is hydrogen and n = 1, with chloroacetone under conventional conditions gives the indenyl (2propanone). This propanone enters into a common haloform reaction under treatment with sodium hypochlorite, hypobromite or hypojodite, in a solvent such as. B.
Dioxane, tetrahydrofuran or dimethyl sulfoxide, whereby the desired indenyl acetic acid is formed according to the following equation:
EMI2.2
The following examples are intended to explain embodiments of the present process according to the invention.
example 1
Step A.
Production of α-methyl -3-nitrocinnamic acid
A mixture of 150 g (1 mol) 3-nitrobenzaldehyde, 200 g propionic anhydride and 96 g (1 mol) sodium propionate are left at 1700 ° C. for 5 hours with occasional stirring. The product is cooled and poured into 1 liter of water and made strongly alkaline by adding sodium carbonate in portions while stirring.
The dark liquid is boiled with activated charcoal until a centrifuged sample results in a colorless supernatant solution, then it is filtered and acidified with hydrochloric acid. The resulting precipitate of α-methyl-3-nitrocinnamic acid is collected, dried and recrystallized from ethanol.
Step B.
Production of α-methyl-3-aminohydrocinnamic acid
The product from step A is dissolved in 2500 ml of absolute ethanol and reduced at room temperature under a pressure of 2.8 atmospheres of hydrogen using a catalyst of palladium on charcoal, and the reduction is continued until an equivalent of 4 moles Hydrogen is absorbed. After removing the catalyst, the ethanol is evaporated off under reduced pressure, after which the amino acid crystallizes.
Step c
Preparation of α-methyl-3-fluoro-hydrocinnamic acid
179 g (1 mol) of α-methyl-3-aminohydrocinnamic acid are suspended in 2 liters of normal hydrochloric acid and the mixture is then cooled to 50.degree. The diazotization then follows, with stirring, and it is carried out with a solution of 88 g of sodium nitrite in 250 ml of water, the reagent being added in such an amount that any increase in temperature is avoided. 350 ml of hexafluorophosphoric acid are added to the clear solution at a temperature of -5 C, in one go, and a little dry ice at the same time to keep the temperature at the desired level.
The precipitate of diazonium hexafluorophosphate is collected in a filter and washed well with water and dried in vacuo at room temperature. The salt is pyrolyzed in portions of 20 to 30 g in 200 ml of xylene at 125 ° C. until the evolution of gas ceases. The cooled mixture is then extracted with sodium bicarbonate solution to separate the α-methyl-3-fluoro hydrocinnamic acid from neutral by-products, and the extract is decolorized with activated charcoal. The desired low-melting sauce is obtained from the colorless filtrate by acidification at 0 ° C. and scratching the walls of the vessel until the precipitate initially crystallizes.
Step D.
Production of 5-fluoro-2-methylindanone
The product from step C is heated with ten times its weight of polyphosphoric acid at 80 to 90 ° C for 2 hours. The liquid is then poured into 1 liter of ice water and stirred for 1/2 hour and then with three portions of 100 ml each extracted.
The combined extracts are washed with water and sodium bicarbonate solution until the ether phase is neutral, and the extract is then dried over sodium sulfate and concentrated, 5-fluoro-2-methylindanone remaining as a yellowish oil.
Steps
Preparation of 5-fluoro-2-methyl -1 - (4'-methylthiobenzyl) -1-indanol
A solution of 4-methylthiobenzyl magnesium bromide is prepared from 45.8 g of 4-methylthiobenzyl bromide (0.2 mol) in 500 ml of anther. This solution is added dropwise to a vigorously stirred solution of 32.8 g (0.2 mol) of 5-fluoro-2-methylindanone in 1 liter of anhydrous ither at 0 C, the rate of addition being such that the Gilman test on free Grignard reagent is never positive.
Finally, the cold mixture is quenched in 500 ml of a saturated aqueous ammonium chloride solution, the ether phase is separated off and washed with water until it is free of ammonium chloride; this phase is then dried over magnesium sulphate and, on concentration under reduced pressure, the indanol is obtained as a residue.
Step F.
Production of 5-fluoro-2-methyl-1 - (4 '-methyl-thiobenzyl) -indene
The product from step E is taken up in a mixture of 600 ml of anhydrous anther and 60 ml of anhydrous pyridine. While stirring and excluding moisture, the solution is cooled to -10 ° C. and treated dropwise with 31 g of thionyl chloride. As soon as the reaction is complete, the mixture is immediately warmed to room temperature with stirring and then poured into 1 liter of water Mixing, the ether phase is separated off, washed with water, dried over magnesium sulfate and concentrated.
The residue is recrystallized from hexane.
Step G
Preparation of 5-fluoro-2-methyl-1 - (4'-methylsulfinylbenzylidene) -3-indenyl acetic acid
A solution of 7.61 g (0.1 mol) of crystalline glycolic acid in 120 ml of pyridine is neutralized by adding a 40% solution of benzyltrimethylammonium hydroxide (Triton B) in pyridine (approx. 42 ml). Then 1 ml of Triton B is added in excess and finally 50 ml of benzene are added. The solution is located in a reaction vessel which is equipped with a fractionation column and a nitrogen inlet, and the resulting solution is carefully freed from air with pure nitrogen and finally 33.04 g (0.1 mol) of 5-fluoro-2 -methyl-1- (4'-methylthiobenzyl) -indene added.
While maintaining the nitrogen purge, the mixture becomes heated to the point where a very slow distillation occurs. The heteroazeotrope, which contains benzene, water and pyridine, condenses and separates into phases; the heating is maintained until no more water appears.
The benzene is then separated off.
separated.
The above solution is then allowed to cool to room temperature, the nitrogen flow is interrupted and the solution is stirred with admission of air. The formation of 3-indenyl peroxide leads both to dehydration to fulvene and to oxidation of the thioether to sulfoxide.
The exposure is allowed to proceed until a test sample under a nitrogen atmosphere shows no more residual peroxide when using the iodine impact test. The pyridine is then removed under vacuum and the residue is treated with 200 ml / one normal acetic acid, whereby crude 5-fluoro-2-methyl-1 - (4'-methylsulfinylbenzylidene) -3 -indenyl acetic acid is formed as a precipitate, which then is purified by recrystallization. The purified product has a melting point of 184 to 186 "C.
Example 2
Step A.
Preparation of 5-fluoro-2-methyl-1 - (4 '-methylsulfinylbenzyl) -indene
To a solution of 0.1 mol of 1- (4'-methylthiobenzyl) -2-methyl-5-fluoroindene in 100 ml of benzene, 1086 g (0.1 mol) of tert-butyl hypochlorite are added dropwise with stirring. When the initially yellow color has disappeared, the solvents are removed under reduced pressure and the sulphoxide residue is used directly in the next reaction step.
Step B.
Preparation of 5-fluoro-2-methyl-1 - (4'-methylsulfinylbenzylidene) -3-indenyl acetic acid
The procedure given in Example 1, Step G is used, but the thio component there is replaced by the sulfoxide obtained from Example 2, Step A, and the procedure from Example 1, Step G, is otherwise retained. In this way, 5-fluoro-2 -methyl -1 - (4'-methylsulfinylbenzylidene) -3 -indenyl acetic acid is prepared and the product has a melting point of 184-186 "C.
Example 3
Step A.
Preparation of 5-fluoro-2-methyl-1- (4'-methyl sulfinylbenzyl) -3 - (2 '-propanone) -indene
The condensation of chloroacetone with the product from Example 2, step A in the presence of a base leads to the desired idenylpropanone.
Step B.
Preparation of 5-fluoro-2-methyl-1 - (4'-methylsulfinylbenzylidene) -3-indenyl acetic acid.
11.9 g (0.033 mol) of the methyl ketone from step A are taken up in 100 ml of dioxah and treated with a 10% excess of a hypochlorite solution containing 2.0 g of sodium hydroxide at 35 ° C. for 1 hour.
The excess oxidizing agent is destroyed with 10% sodium bisulfite solution and the free 3-indenyl acetic acid is precipitated with hydrochloric acid at pH 2. Recrystallization from a solvent system consisting of ethyl acetate and Petrol diffuse gives the acid, which has a melting point of 184 to 186 ° C.
Claims (1)
Applications Claiming Priority (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US87821069A | 1969-11-19 | 1969-11-19 | |
US88232769A | 1969-12-04 | 1969-12-04 | |
US3397470A | 1970-05-01 | 1970-05-01 | |
US3389070A | 1970-05-01 | 1970-05-01 | |
US3397170A | 1970-05-01 | 1970-05-01 | |
US3397670A | 1970-05-01 | 1970-05-01 | |
US3389270A | 1970-05-01 | 1970-05-01 | |
US3397570A | 1970-05-01 | 1970-05-01 | |
US3397270A | 1970-05-01 | 1970-05-01 | |
US3389370A | 1970-05-01 | 1970-05-01 | |
US3397370A | 1970-05-01 | 1970-05-01 |
Publications (1)
Publication Number | Publication Date |
---|---|
CH569707A5 true CH569707A5 (en) | 1975-11-28 |
Family
ID=27582501
Family Applications (13)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CH1656370D CH583691A5 (en) | 1969-11-19 | 1970-07-13 | |
CH1074675A CH575387A5 (en) | 1969-11-19 | 1970-11-09 | |
CH1074775A CH587809A5 (en) | 1969-11-19 | 1975-08-18 | |
CH1073875A CH569707A5 (en) | 1969-11-19 | 1975-08-18 | Indenylacetic acid derivs - useful as antiinflammatory agents |
CH1074175A CH569710A5 (en) | 1969-11-19 | 1975-08-18 | |
CH1073975A CH569708A5 (en) | 1969-11-19 | 1975-08-18 | |
CH1074275A CH569711A5 (en) | 1969-11-19 | 1975-08-18 | |
CH1074575A CH570370A5 (en) | 1969-11-19 | 1975-08-18 | |
CH1074075A CH569709A5 (en) | 1969-11-19 | 1975-08-18 | |
CH1074375A CH576436A5 (en) | 1969-11-19 | 1975-08-18 | |
CH1074475A CH587238A5 (en) | 1969-11-19 | 1975-08-18 | |
CH619876A CH586671A5 (en) | 1969-11-19 | 1976-05-18 | |
CH1565176A CH596160A5 (en) | 1969-11-19 | 1976-12-13 |
Family Applications Before (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CH1656370D CH583691A5 (en) | 1969-11-19 | 1970-07-13 | |
CH1074675A CH575387A5 (en) | 1969-11-19 | 1970-11-09 | |
CH1074775A CH587809A5 (en) | 1969-11-19 | 1975-08-18 |
Family Applications After (9)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CH1074175A CH569710A5 (en) | 1969-11-19 | 1975-08-18 | |
CH1073975A CH569708A5 (en) | 1969-11-19 | 1975-08-18 | |
CH1074275A CH569711A5 (en) | 1969-11-19 | 1975-08-18 | |
CH1074575A CH570370A5 (en) | 1969-11-19 | 1975-08-18 | |
CH1074075A CH569709A5 (en) | 1969-11-19 | 1975-08-18 | |
CH1074375A CH576436A5 (en) | 1969-11-19 | 1975-08-18 | |
CH1074475A CH587238A5 (en) | 1969-11-19 | 1975-08-18 | |
CH619876A CH586671A5 (en) | 1969-11-19 | 1976-05-18 | |
CH1565176A CH596160A5 (en) | 1969-11-19 | 1976-12-13 |
Country Status (3)
Country | Link |
---|---|
JP (1) | JPS5727107B1 (en) |
AR (1) | AR193345A1 (en) |
CH (13) | CH583691A5 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPWO2005054181A1 (en) * | 2003-12-01 | 2007-12-06 | 株式会社リバース・プロテオミクス研究所 | Novel target protein of anticancer drug and corresponding new anticancer drug (Spnal) |
-
1970
- 1970-07-13 CH CH1656370D patent/CH583691A5/xx not_active IP Right Cessation
- 1970-11-06 AR AR23226070A patent/AR193345A1/en active
- 1970-11-09 CH CH1074675A patent/CH575387A5/xx not_active IP Right Cessation
- 1970-11-19 JP JP10151170A patent/JPS5727107B1/ja active Pending
-
1975
- 1975-08-18 CH CH1074775A patent/CH587809A5/xx not_active IP Right Cessation
- 1975-08-18 CH CH1073875A patent/CH569707A5/en not_active IP Right Cessation
- 1975-08-18 CH CH1074175A patent/CH569710A5/xx not_active IP Right Cessation
- 1975-08-18 CH CH1073975A patent/CH569708A5/xx not_active IP Right Cessation
- 1975-08-18 CH CH1074275A patent/CH569711A5/xx not_active IP Right Cessation
- 1975-08-18 CH CH1074575A patent/CH570370A5/xx not_active IP Right Cessation
- 1975-08-18 CH CH1074075A patent/CH569709A5/xx not_active IP Right Cessation
- 1975-08-18 CH CH1074375A patent/CH576436A5/xx not_active IP Right Cessation
- 1975-08-18 CH CH1074475A patent/CH587238A5/xx not_active IP Right Cessation
-
1976
- 1976-05-18 CH CH619876A patent/CH586671A5/xx not_active IP Right Cessation
- 1976-12-13 CH CH1565176A patent/CH596160A5/xx not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
CH569711A5 (en) | 1975-11-28 |
CH569708A5 (en) | 1975-11-28 |
JPS5727107B1 (en) | 1982-06-08 |
CH570370A5 (en) | 1975-12-15 |
CH596160A5 (en) | 1978-02-28 |
CH575387A5 (en) | 1976-05-14 |
CH586671A5 (en) | 1977-04-15 |
CH583691A5 (en) | 1977-01-14 |
CH569710A5 (en) | 1975-11-28 |
CH587809A5 (en) | 1977-05-13 |
CH569709A5 (en) | 1975-11-28 |
AR193345A1 (en) | 1973-04-23 |
CH576436A5 (en) | 1976-06-15 |
CH587238A5 (en) | 1977-04-29 |
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