NO780101L - NEW DITIENYLALKYLAMINES AND PROCEDURES FOR THEIR PREPARATION - Google Patents
NEW DITIENYLALKYLAMINES AND PROCEDURES FOR THEIR PREPARATIONInfo
- Publication number
- NO780101L NO780101L NO780101A NO780101A NO780101L NO 780101 L NO780101 L NO 780101L NO 780101 A NO780101 A NO 780101A NO 780101 A NO780101 A NO 780101A NO 780101 L NO780101 L NO 780101L
- Authority
- NO
- Norway
- Prior art keywords
- group
- residue
- compound
- compounds
- alkyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 52
- 238000006243 chemical reaction Methods 0.000 claims description 16
- -1 piperazino group Chemical group 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 11
- 125000001931 aliphatic group Chemical group 0.000 claims description 11
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052740 iodine Inorganic materials 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 239000011541 reaction mixture Substances 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 229910052744 lithium Inorganic materials 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 8
- 239000011630 iodine Substances 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 7
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 150000001412 amines Chemical class 0.000 claims description 7
- 150000002170 ethers Chemical class 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 239000011877 solvent mixture Substances 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 229930195734 saturated hydrocarbon Natural products 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 150000007514 bases Chemical class 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 229940126601 medicinal product Drugs 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- 150000002894 organic compounds Chemical class 0.000 claims 1
- 239000008024 pharmaceutical diluent Substances 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 52
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000002253 acid Substances 0.000 description 15
- 239000000126 substance Substances 0.000 description 12
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 8
- 150000004996 alkyl benzenes Chemical class 0.000 description 7
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 7
- 229930195733 hydrocarbon Natural products 0.000 description 7
- 150000002430 hydrocarbons Chemical class 0.000 description 7
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- ROIMNSWDOJCBFR-UHFFFAOYSA-N 2-iodothiophene Chemical compound IC1=CC=CS1 ROIMNSWDOJCBFR-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 239000004215 Carbon black (E152) Substances 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 150000001983 dialkylethers Chemical class 0.000 description 5
- SNHOZPMHMQQMNI-UHFFFAOYSA-N lithium;2h-thiophen-2-ide Chemical compound [Li+].C=1C=[C-]SC=1 SNHOZPMHMQQMNI-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000011976 maleic acid Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- TUCRZHGAIRVWTI-UHFFFAOYSA-N 2-bromothiophene Chemical compound BrC1=CC=CS1 TUCRZHGAIRVWTI-UHFFFAOYSA-N 0.000 description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000007306 turnover Effects 0.000 description 3
- QEGNUYASOUJEHD-UHFFFAOYSA-N 1,1-dimethylcyclohexane Chemical compound CC1(C)CCCCC1 QEGNUYASOUJEHD-UHFFFAOYSA-N 0.000 description 2
- FWWOWPGPERBCNJ-UHFFFAOYSA-N 2-hydroxy-4-(2-hydroxyethoxy)-4-oxobutanoic acid Chemical compound OCCOC(=O)CC(O)C(O)=O FWWOWPGPERBCNJ-UHFFFAOYSA-N 0.000 description 2
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 description 2
- XCMISAPCWHTVNG-UHFFFAOYSA-N 3-bromothiophene Chemical compound BrC=1C=CSC=1 XCMISAPCWHTVNG-UHFFFAOYSA-N 0.000 description 2
- JAYBQRKXEFDRER-UHFFFAOYSA-N 4-(2-amino-1-hydroxypropyl)phenol Chemical compound CC(N)C(O)C1=CC=C(O)C=C1 JAYBQRKXEFDRER-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- 150000005215 alkyl ethers Chemical class 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000001273 butane Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethylcyclohexane Chemical compound CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methylcyclopentane Chemical compound CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 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 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 239000000052 vinegar Substances 0.000 description 2
- 235000021419 vinegar Nutrition 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- PZIBVWUXWNYTNL-UHFFFAOYSA-N 1-(3-methoxyphenyl)piperazine Chemical compound COC1=CC=CC(N2CCNCC2)=C1 PZIBVWUXWNYTNL-UHFFFAOYSA-N 0.000 description 1
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- WLXGQMVCYPUOLM-UHFFFAOYSA-N 1-hydroxyethanesulfonic acid Chemical compound CC(O)S(O)(=O)=O WLXGQMVCYPUOLM-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound 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 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
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- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
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- 150000007522 mineralic acids Chemical class 0.000 description 1
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- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
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- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
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- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
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- 229940072033 potash Drugs 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000001120 potassium sulphate Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000011555 saturated liquid Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 150000003388 sodium compounds Chemical class 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
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- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 150000003628 tricarboxylic acids Chemical class 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- NLVXSWCKKBEXTG-UHFFFAOYSA-N vinylsulfonic acid Chemical compound OS(=O)(=O)C=C NLVXSWCKKBEXTG-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Nye dithienylalkylaminer. og fremgangsmåte til deres fremstilling.New dithienylalkylamines. and method of their preparation.
Description
Forbindelser med den generelle formel: Compounds with the general formula:
hvori R,. R„ og Rchver betyr et hydrogenatom eller en metyl- where R,. R„ and Rchver mean a hydrogen atom or a methyl
1 ^o1 ^o
gruppe, Rj betyr et hydrogenatom eller en hydroksylgruppe, R^betyr et hydrogen-, klor- eller fluoratom eller en trifluorraetyl-gruppe eller en alkylgruppe med 1-6 karbonatomer eller en alkoksygruppe med 1-6 karbonatomer og broleddet >A-B- tilkommer strukturen 5C(0H)-CH2- eller -CsCH- er kjent. De bevirker spesielt en for-bedring av hjernegjennombladningen. group, Rj means a hydrogen atom or a hydroxyl group, R^ means a hydrogen, chlorine or fluorine atom or a trifluoroethyl group or an alkyl group with 1-6 carbon atoms or an alkoxy group with 1-6 carbon atoms and the bridge link >A-B- adds to the structure 5C (OH)-CH2- or -CsCH- are known. They particularly cause an improvement in brain perfusion.
Por fremstillingen av disse forbindelser er det angitt en fremgangsmåte som består i at en forbindelse amed den generelle formel: For the preparation of these compounds, a method has been specified which consists in a compound with the general formula:
hvori Y betyr klor eller brom'eller en alkoksygruppe eller en thienylrest omsettes med en thienylmetallforbindelse (thienyl-litium, thienylgrignardforbindelse) og eventuelt overføres forbindelse med den generelle formel, hvori =A-B- betyr gruppen sCCOHJ-CHg- etter kjente metoder med vannavspaltende midler i in which Y means chlorine or bromine'or an alkoxy group or a thienyl residue is reacted with a thienyl metal compound (thienyl-lithium, thienylgrignard compound) and optionally a compound with the general formula is transferred, in which =A-B- means the group sCCOHJ-CHg- according to known methods with water-releasing agents in
de tilsvarende umettede forbindelse (=A-B- : =C=CH-) og -^eventuelt overføres de dannede basiske forbindelser etter kjente metoder i deres salter (tysk patent 1.921.453). the corresponding unsaturated compound (=A-B- : =C=CH-) and -^possibly the formed basic compounds are transferred according to known methods in their salts (German patent 1,921,453).
I henhold til denne fremgangsmåte kan det imidlertid eksempelvis ikke fremstilles forbindelser hvor fenylresten av denne innledningsvis angitte formel er substituert med en hydroksy-gruppe og hvis amindel avleder seg fra strukturelt andre aminer.. According to this method, however, compounds cannot be prepared, for example, where the phenyl residue of this initially stated formula is substituted with a hydroxy group and whose amine part is derived from structurally other amines.
Videre er forbindelser med følgende formler:Furthermore, there are compounds with the following formulas:
kjent. I de nettopp angitte formler betyr R og R. hydrogen eller en metylgruppe og begge rester R2betyr -C^-^-alkylgrupper eller en rest R2betyr hydrogen og den andre rest R2betyr en benzyl-gruppe eller hele gruppen -NR2R2danner en pyrrolidinogruppe, en piperidinogruppe, en morfolinogruppe eller en homopiperidino-gruppe. Som hovedvirkning angis for disse■forbindelser en spas-molytisk virkning (Chimie Thérapeutique 1973>s. 22-31)• Oppfinnelsen vedrører blant annet nye forbindelser med den generelle formel known. In the formulas just stated, R and R. mean hydrogen or a methyl group and both residues R2 means -C^-^-alkyl groups or one residue R2 means hydrogen and the other residue R2 means a benzyl group or the whole group -NR2R2 forms a pyrrolidino group, a piperidino group, a morpholino group or a homopiperidino group. The main effect of these■compounds is stated to be a spasmolytic effect (Chimie Thérapeutique 1973>p. 22-31)• The invention relates, among other things, to new compounds with the general formula
hvor =A-B- enten har strukturen =C(OH)-CH2- eller strukturen =C=CH-S i-.Alk betyr en rettlinjet eller forgrenet C^-C^-alkylen-gruppe og Y betyr en C^-Cy-cykloalkylrest, en benzylrest, en metylenoksybensylrest, en en- eller to- eller tre- ganger med C^-C^-alkyl- eller C-^-Cjij-alkoksygruppe substituert benzylrest eller en rettlinjet eller forgrenet C^-Cg-alkylrest som også kan være substituert med en aminogruppe, en Di-C^-C^-alkylamino- where =A-B- either has the structure =C(OH)-CH2- or the structure =C=CH-S i-.Alk means a straight or branched C^-C^-alkylene group and Y means a C^-Cy- cycloalkyl radical, a benzyl radical, a methyleneoxybenzyl radical, a benzyl radical substituted one-, two- or three-fold with a C₁-C₁-alkyl or C₁-C₁-alkyl group or a straight or branched C₁-C₆-alkyl radical which also may be substituted with an amino group, a Di-C^-C^-alkylamino-
gruppe, en raono-C^-C^-alkylaminogruppe, en'morfolinogruppe, en piperazinogruppe eller en 4-(C^-Cij-alkyl)-piperazinogruppe eller betyr resten idet R er hydrogen eller en C-^-C^-alkylgruppe og hydroksylgruppen også kan være acylert med en C^-C^-alkanoylgruppe eller hvori gruppen -NHY betyr resten group, a ra-ono-C₁-C₁-alkylamino group, a'morpholino group, a piperazino group or a 4-(C₁-C₁-alkyl)-piperazino group or means the residue wherein R is hydrogen or a C₁-C₁-alkyl group and the hydroxyl group can also be acylated with a C₁-C₁-alkanoyl group or in which the group -NHY means the residue
og R' betyr hydrogen, en fenylrest, en fenylrest som er substituert i 1- til 2- ganger med C-^-C^-alkylgrupper, C^-C^-alkoksy-grupper eller halogenatomer, en C^-Cg-alkylrest, en C^-C^-oksy-alkylrest eller en fenyl-C-^-C^-alkylrest som i fenylringen også kan være substituert med 1-3 C^-C^-alkoksygrupper eller hvori gruppen -NHY også kan være en di-C^-C^-alkylaminorest eller resten -NH-CH(R)-CH(OH)~CgH^ (hvor R har ovennevnte betydning), hvis Alk består av 2-5 karbonatomer samt deres salter. and R' means hydrogen, a phenyl radical, a phenyl radical which is substituted in 1- to 2-fold by C-^-C^-alkyl groups, C^-C^-alkoxy groups or halogen atoms, a C^-Cg-alkyl radical , a C^-C^-oxy-alkyl radical or a phenyl-C-C^-C^-alkyl radical which in the phenyl ring can also be substituted with 1-3 C^-C^-alkoxy groups or in which the group -NHY can also be a di-C^-C^-alkylamino residue or the residue -NH-CH(R)-CH(OH)~CgH^ (where R has the above meaning), if Alk consists of 2-5 carbon atoms and their salts.
Fortrinnsvis er de to thienylrester sammenknyttetPreferably, the two thienyl residues are linked
i hver gang lik stilling med =A-B- (bis-thienyl-(3)- eller bis-thienyl-(2)-derivat). Der er imidlertid likeledes mulig at =A-B- samtidig er sammenknyttet med en thienyl-(2)- og en thienyl-(3)-rest. Resten R i strukturdelen in each time equal position with =A-B- (bis-thienyl-(3)- or bis-thienyl-(2)-derivative). However, it is also possible that =A-B- is simultaneously linked with a thienyl-(2)- and a thienyl-(3)-residue. The rest R in the structure part
er fortrinnsvis metyl eller etyl. Hydroksygruppen med fenylringen kan stå i ortho-, para- eller metastilling. Hvis disse er acylert e, kan den tilgrunn liggende alifatiske Cj-Cg-karboksylsyre være rettlinjet eller forgrenet og spesielt bestå av 2-4 C-atomer. Alkylenkjeden Alk er fortrinnsvis, rettlinjet og består fortrinnsvis av 1, 2 eller 3 karbonatomer. Y betyr fortrinnsvis resten is preferably methyl or ethyl. The hydroxy group with the phenyl ring can be in the ortho, para or meta position. If these are acylated, the underlying aliphatic Cj-Cg carboxylic acid can be linear or branched and in particular consist of 2-4 C atoms. The alkylene chain Alk is preferably straight and preferably consists of 1, 2 or 3 carbon atoms. Y preferably means the rest
idet R' har de angitte betydninger, fortrinnsvis er R' en fenylrest eller en fenylrest som er substituert med en C^-C2-alkylgruppe (eksempelvis CH^) eller en C^-C^-alkoksygruppe (OCH^) wherein R' has the indicated meanings, preferably R' is a phenyl radical or a phenyl radical which is substituted with a C₁-C₂ alkyl group (for example CH₂) or a C₁-C₂ alkoxy group (OCH₂)
(fortrinnsvis i o-stilling). Hvis R' betyr en fenyl-C^-C^-alkylrest, dreier det seg spesielt ora benzyl- eller fenyletylre3ten (eventuelt substituert med 1 eller 2 metoksygrupper). (preferably in o position). If R' means a phenyl-C 1 -C 4 -alkyl radical, it is particularly the benzyl or phenylethyl radical (optionally substituted with 1 or 2 methoxy groups).
Forbindelsen ifølge oppfinnelsen med formel I er farmakodynamisk virksomme, spesielt ved hjerte- og kretsløps-sykdommer. De bevirker spesielt en økning av den perifere og cerebrale gjennomblødning : og har i denne henseende eksempelvis betraktelig sterkere virksom, spesielt med hensyn til den perifere gjennomblødning enn de kjente forbindelser fra tysk patent 1.921.453. Eventuelt foregår også en utvidelse av koronarkarene og en økning av hjertekraften. The compound according to the invention with formula I is pharmacodynamically active, especially in heart and circulatory diseases. They especially cause an increase in peripheral and cerebral blood flow: and in this respect, for example, are considerably more effective, especially with regard to peripheral blood flow, than the known compounds from German patent 1,921,453. Possibly, an expansion of the coronary vessels and an increase in heart power also take place.
Fremstillingen av forbindelsene med den generelle formel I foregår, idet en forbindelse med den generelle formel The preparation of the compounds of the general formula I takes place, as a compound of the general formula
hvori Alk betyr en rettlinjet eller forgrenet C1-C^-alkylengruppe og X betyr klor, brom eller jod kondenseres med et amin med den generelle formel in which Alk means a straight or branched C1-C4 alkylene group and X means chlorine, bromine or iodine is condensed with an amine of the general formula
idet Y har den allerede angitte betydning og eventuelt overføres with Y having the already stated meaning and possibly being transferred
forbindelse med den generelle formel I, hvori =A-B- er lik =C(OH)-CH2- etter kjente metoder med vannavspaltende midler i de tilsvarende umettede forbindelser (=A-B- er lik =C=CH-) og acyleres ved hjalp av en alifatisk C2-Cg-k&rboksylsyre og fra de dannende basiske forbindelser fremstilles eventuelt saltene. compound with the general formula I, in which =A-B- is equal to =C(OH)-CH2- according to known methods with water-releasing agents in the corresponding unsaturated compounds (=A-B- is equal to =C=CH-) and is acylated with the help of a aliphatic C2-C8-carboxylic acid and from the forming basic compounds the salts are optionally prepared.
Denne kondensasjon gjennomføres eksempelvis med eller uten oppiøsningsmiddel i et temperaturoraråde mellom 0 og +150°C, fortrinnsvis mellom 20 og 100°C. Som inerte oppløsnings-resp. suspensjonsmidler egner det seg eksempelvis mettede-etere som lavere alifatiske dialkyletere, alkyletere av cykloalkanoler og alkylsubstituerte cykloalkanoler, mettede flytende hydrokarboner, mettede cykloalifatiske hydrokarboner som også kan være substituert med lavere alkylrester, cyklisker*etere_ som tetra-hydrofuran og dioxan, benzen, alkylbenzener som toluen, alifatiske mettede ketoner, alifatiske og cykloalifatiske. alkoholer. Konsentrasjonen av forbindelsen II i oppløsnings- resp. suspen-sjonsmidlet ligger eksempelvis mellom 10 og 50 %. Hensiktsmessig foregår kondensasjonen med forbindelse III i nærvær av en base respektive en halogenhydrogenakseptor som eksempelvis tertiære aminer (trietylamin), alkalikarbonater (pottaske), alkalihydrok-syder. Som halogenhydrogenakseptor kan det også anvendes selve forbindelsen III. Fordelaktig foregår kondensasjonen i støkio-metrisk forhold, imidlertid kan man også anvende et ønskelig høyt overskudd av forbindelse III. Reaksjonsvarigheten retter seg etter reaksjonstemperaturen. Ved temperaturer på 100-120°C er omsetningen eksempelvis avsluttet i løpet av 4-12 timer. This condensation is carried out, for example, with or without a solvent in a temperature range between 0 and +150°C, preferably between 20 and 100°C. As inert solution resp. suspending agents suitable for example are saturated ethers such as lower aliphatic dialkyl ethers, alkyl ethers of cycloalkanols and alkyl-substituted cycloalkanols, saturated liquid hydrocarbons, saturated cycloaliphatic hydrocarbons which can also be substituted with lower alkyl residues, cyclic ethers_ such as tetrahydrofuran and dioxane, benzene, alkylbenzenes which toluene, aliphatic saturated ketones, aliphatic and cycloaliphatic. alcohols. The concentration of compound II in solution or the suspending agent is, for example, between 10 and 50%. Conveniently, the condensation with compound III takes place in the presence of a base or a halogen hydrogen acceptor, such as, for example, tertiary amines (triethylamine), alkali carbonates (pot ash), alkali hydroxides. Compound III itself can also be used as halogen hydrogen acceptor. Advantageously, the condensation takes place in a stoichiometric ratio, however, a desirable high excess of compound III can also be used. The reaction duration depends on the reaction temperature. At temperatures of 100-120°C, for example, the turnover is completed within 4-12 hours.
Vannavspaltningen fra forbindelsen med den generelle formel I hvori =A-B- betyr =C(0H)-CH2- gjennomføres hensiktsmessig ved høyere temperaturer, eksempelvis i et températurområde fra 20-150°C. Fortrinnsvis anvendes oppløsningsmidler som f.eks. dialkyleter, dioxan, iseddik, benzen, toluen, etanol, isopropanol o.s.v. The water separation from the compound with the general formula I in which =A-B- means =C(OH)-CH2- is conveniently carried out at higher temperatures, for example in a temperature range from 20-150°C. Solvents such as e.g. dialkyl ether, dioxane, glacial acetic acid, benzene, toluene, ethanol, isopropanol, etc.
For denne vannavspaltning er det ikke nødvendig først å isolere forbindelsen med formel I, hvori =A-B- betyr gruppen =C(0H)-CH2-, men man kan eksempelvis behandle direkte den etter omsetning av forbindelse II med forbindelse III dannede reaksjonsblanding, eventuelt etter fjerning av oppløsningsmidlet med det dehydratiserende middel. Eksempelvis kan man blande reaksjonsblandingen direkte med isopropanolisk eller etanolisk saltsyre og oppvarme noen minutter til 'kokning idet dehydrati-seringen foregår. Opparbeidelsen kan foregå på vanlig måte. For this water separation, it is not necessary to first isolate the compound of formula I, in which =A-B- means the group =C(OH)-CH2-, but you can, for example, directly treat the reaction mixture formed after reacting compound II with compound III, optionally after removing the solvent with the dehydrating agent. For example, the reaction mixture can be mixed directly with isopropanolic or ethanolic hydrochloric acid and heated to boiling for a few minutes while the dehydration takes place. Processing can take place in the usual way.
Som vannavspaltende middel kommer eksempelvis i betraktning: mineralsyrer som svovelsyre eller halogenhydrogensyrer, organiske syrer som oxalsyre, maursyre, thionylklorid, ammoniumklorid, sinkklorid, tinnklorid, bortrifluorid, kalium-hydrogensulfat, fosforpentoksyd, syreklorider, rødt fosforjod i nærvær av vann. As a water-releasing agent, for example: mineral acids such as sulfuric acid or hydrohalogen acids, organic acids such as oxalic acid, formic acid, thionyl chloride, ammonium chloride, zinc chloride, stannous chloride, boron trifluoride, potassium hydrogen sulphate, phosphorus pentoxide, acid chlorides, red phosphorus iodine in the presence of water.
Fåes forbindelser med strukturdelenConnections are obtained with the structural part
så kan eventuelt hydroksygruppen ved fenyltfingen acyleres etterpå med en Cg-Cg-alkanoylgruppe. then optionally the hydroxy group at the phenyl group can be acylated afterwards with a Cg-Cg-alkanoyl group.
Acyleringen kan foregå i inerte oppløsnings- resp. suspens jonsiaidler som dioxan, dimetylformamid, benzen, toluen ved temperaturer mellom 0 til 200°C. Som acyleringsmiddel kommer i betraktning: alifatiske c2-C6-ketener samt syrehalogenider, syreanhydrider eller syreestere av alifatiske karboksylsyrer med 2-6 C-atomer eventuelt under tilsetning av et syrebindende middel som kaliumkarbonat eller natriumetylat eller et tertiært amin, eksempelvis trietylamin. Med esterene dreier det seg spesielt om slike med lavere alifatisk alkoholer. Ved acyleringen kan man også gå frem således at man først fra forbindelse I som skai omsettes med hydroksygruppen ved fenylringen fremstiller en alkaliforbin-del3e idet man omsetter den i et inert oppløsningsmiddel som dioxan, dimetylformamid, benzen eller toluen med et alkalimetall, alkalihydrider eller alkaliamider (spesielt natrium eller natrium-forbindelser) ved temperaturer mellom 0 og 150°C og deretter tilsetter det acylerende stoff. The acylation can take place in inert solutions or suspension ionic agents such as dioxane, dimethylformamide, benzene, toluene at temperatures between 0 and 200°C. As an acylating agent comes into consideration: aliphatic c2-C6 ketenes as well as acid halides, acid anhydrides or acid esters of aliphatic carboxylic acids with 2-6 C atoms, optionally with the addition of an acid binding agent such as potassium carbonate or sodium ethylate or a tertiary amine, for example triethylamine. With the esters, it is particularly about those with lower aliphatic alcohols. During the acylation, one can also proceed in such a way that one first prepares an alkali compound 3e from compound I, which is to be reacted with the hydroxy group at the phenyl ring, by reacting it in an inert solvent such as dioxane, dimethylformamide, benzene or toluene with an alkali metal, alkali hydrides or alkali amides ( especially sodium or sodium compounds) at temperatures between 0 and 150°C and then adds the acylating substance.
Istedenfor de anførte acyleringsmidler kan det også anvendes andre i kjemien vanlige kjemiske ekvivalente;1 midler (se eksempelvis også: L.F. og Mary Fieser: "Reagents for Organic Synthesis", John Wiley and Sons, Inc. Nev; York, 1967, vol. 1, Instead of the listed acylating agents, other chemical equivalents common in chemistry can also be used; 1 agents (see also for example: L.F. and Mary Fieser: "Reagents for Organic Synthesis", John Wiley and Sons, Inc. Nev; York, 1967, vol. 1 ,
s. 1303-4 og vol. 2, s. 471). Selvsagt kan i forbindelse med pp. 1303-4 and vol. 2, p. 471). Of course can in connection with
formel I tilstedeværende acylgruppe på kjent måte eksempelvis ved hydrolyse i nærvær av syrer eller basiske stoffer igjen også avspaltes ved temperaturer mellom 20 og 150°C. formula I acyl group present in a known manner, for example by hydrolysis in the presence of acids or basic substances, is also split off again at temperatures between 20 and 150°C.
De forbindelser som inneholder asymmetriske karbonatomer og vanligvis fremkommer som racemater, kan på i og for seg kjent måte eksempelvis ved hjelp av en optisk aktiv syre spaltes i de optisk aktive isomere. Det er imidlertid også mulig, fra begynnelsen å anvende optisk aktive resp. også diastereomere utgangsstoffer med den generelle formel III, idet det da som sluttprodukt fåes en tilsvarende ren optisk aktiv form resp. diastereomere konfigurasjon. The compounds which contain asymmetric carbon atoms and usually appear as racemates can be split into the optically active isomers in a manner known per se, for example with the aid of an optically active acid. However, it is also possible, from the beginning, to use optically active resp. also diastereomeric starting substances with the general formula III, as the end product is then a correspondingly pure optically active form resp. diastereomeric configuration.
Hvis det anvendes aminer med formel f^N-CHClO-CHCOH)-CgH^(som også i fenylringen kan være substituert med hydroksy eller Cg-Cg-alkanoyloksy) som utgangsstoffer, kan disse foreligge i erytro- eller treo-konfigurasjon. If amines of the formula f^N-CHClO-CHCOH)-CgH^ (which can also be substituted in the phenyl ring with hydroxy or Cg-Cg-alkanoyloxy) are used as starting materials, these can be present in erythro or threo configuration.
Alt etter fremgangsmåtebetingelser og utgangsstoffer får man sluttstoffene med formel I i fri form eller i form av deres salter. Saltene av sluttstoffene kan på i og for seg kjent måte eksempelvis med alkali eller ioneutveksler igjen overføres i basene. Av sistnevnte lar det seg ved omsetning med organiske eller uorganiske syrer, spesielt slike som er egnet til dannelse av terapeutisk anvendbare salter fremstilles salter. Som slike syrer skal det eksempelvis nevnes: halogenhydrogensyrer, svovelsyre, fosforsyrer, salpetersyre, perklorsyre, organiske mono-, di- eller trikarboksylsyrer av den alifatiske, alicykliske, aro-matiske eller heterocykliske rekke som sulfonsyrer. Eksempler herfra er: maursyre, eddiksyre, propionsyre, ravsyre, glykolsyre, melkesyre, eplesyre, vinsyre, sitronsyre, askorbinsyre, maleinsyre, fumarsyre, hydroksymaleinsyre eller pyrodruesyre, fenyleddiksyre, benzosyre, p-arainobenzosyre, antranilsyre, p-hydroksybenzosyre, salicylsyre eller p-aminosalicylsyre, embonsyre, metansulfonsyre, etansulfonsyre, hydroksyetansulfonsyre, etylensulfonsyre, halogen-benzensulfonsyre, toluensulfonsyre, naftalinsulfonsyre eller sul-fanilsyre. Depending on the process conditions and starting materials, the end products with formula I are obtained in free form or in the form of their salts. The salts of the final substances can be transferred back into the bases in a manner known per se, for example with alkali or ion exchangers. Salts can be prepared from the latter by reaction with organic or inorganic acids, especially those which are suitable for the formation of therapeutically usable salts. Examples of such acids should be mentioned: halogenated acids, sulfuric acid, phosphoric acids, nitric acid, perchloric acid, organic mono-, di- or tricarboxylic acids of the aliphatic, alicyclic, aromatic or heterocyclic series such as sulphonic acids. Examples from this are: formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, fumaric acid, hydroxymaleic acid or pyruvic acid, phenylacetic acid, benzoic acid, p-arainobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid or p- aminosalicylic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid or sulfanilic acid.
Porbindelsene ifølge oppfinnelsen er egnet til fremstilling av farmasøytiske sammensetninger og tilberedninger. De farmasøytiske sammensetninger inneholder som virksomt stoff en eller flere av forbindelsene ifølge oppfinnelsen eventuelt i blanding med andre farmakologisk virksomme stoffer. Fremstilling av legemidler kan foregå under anvendelse av de kjente og vanlige farmasøytiske bæremidler og tilsetninger. Legemidlene kan anvendes enteralt, parenteralt, oralt, perlingualt eller i form av sprays. Administreringen kan foregå i form av tabletter, kapsler, piller, dragéer, suppositorier, liquida eller aerosoler. Som liquida kommer det^'eksempelvis på tale: oljeaktige eller vandige oppløsninger eller suspensjoner, emulsjoner, injiserbare vandige eller oljeaktige oppløsninger eller suspensjoner. The pore compounds according to the invention are suitable for the production of pharmaceutical compositions and preparations. The pharmaceutical compositions contain as active substance one or more of the compounds according to the invention, optionally in admixture with other pharmacologically active substances. Medicines can be manufactured using the known and common pharmaceutical carriers and additives. The drugs can be used enterally, parenterally, orally, perlingually or in the form of sprays. The administration can take place in the form of tablets, capsules, pills, dragées, suppositories, liquids or aerosols. Liquids include, for example: oily or aqueous solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions.
Utgangsforbindelsen med formel II er likeledes nye og fåes ifølge oppfinnelsen ved omsetning av thienyl-(3)- eller thienyl-(2)-litium med en forbindelse med formel The starting compound with formula II is likewise new and is obtained according to the invention by reacting thienyl-(3)- or thienyl-(2)-lithium with a compound of formula
hvori Alk betyr en rettlinjet eller forgrenet C-^-C^-alkylengruppe fortrinnsvis en rettlinjet C^-C^-alkylengruppe, Z betyr en lavere alkoksygruppe, klor, brom, jod eller en thienylrest og Hal betyr klor, brom eller jod ved lave temperaturer, fortrinnsvis under -50 C i et inert middel. Herved oppstår forbindelsen med formel II i et utbytte på eksempelvis 96 % av det teoretiske. in which Alk means a straight or branched C-^-C^-alkylene group, preferably a straight-line C^-C^-alkylene group, Z means a lower alkoxy group, chlorine, bromine, iodine or a thienyl residue and Hal means chlorine, bromine or iodine at low temperatures, preferably below -50 C in an inert medium. This results in the compound of formula II in a yield of, for example, 96% of the theoretical.
De hittil kjente analoge omsetninger, eksempelvis av The previously known analogue sales, for example by
.thienyl-(3)-litium med^-fenyletylamino-propionsyreestere (se.thienyl-(3)-lithium with ^-phenylethylamino-propionic acid esters (see
tysk patent 1.921.453) forløper derimot ikke enhetlig og den ønskede dithienyl-(3)-forbindelse kan bre isoleres i et utbytte på maksimalt 30 %. Spesielt oppstår her alltid andre thienyl-isoraerer i større mengder. Dessuten er adskillelsen og rensningen av den Ønskede dithfenyl-forbindelse fra de øvrige reaksjonsprodukter meget vanskelig og eksempelvis bare mulig ved omstendelig -og komplisert flere gangers omkrystallisering i kombinasjon med en aktivkull-behandling. German patent 1,921,453) however, does not proceed uniformly and the desired dithienyl-(3)-compound can be isolated in a maximum yield of 30%. In particular, other thienyl isomers always occur here in larger quantities. Moreover, the separation and purification of the desired dithphenyl compound from the other reaction products is very difficult and, for example, only possible by time-consuming and complicated recrystallization several times in combination with an activated charcoal treatment.
I den generelle formel IV betyr resten Z spesieltIn the general formula IV, the residue Z means in particular
en mettet alifatisk alkoksygruppe med 1-6 C-atomer, fortrinnsvis 1-4 C-atoraer som også kan være forgrenet, klor eller brom. Z kan imidlertid også være en thienyl-(2)-rest eller en thienyl-(3)-rest. a saturated aliphatic alkoxy group with 1-6 C atoms, preferably 1-4 C atoms which may also be branched, chlorine or bromine. However, Z can also be a thienyl-(2) residue or a thienyl-(3) residue.
Omsetningen av thienyHitium-forbindelsen, spesieltThe turnover of the thienyHitium compound, esp
da thienyl-(3)-litium med forbindelsen IV foregår i en inert flytende oppløsningsmiddelblanding, som fortrinnsvis består av en mettet eter og et mettet hydrokarbon og/eller en ved C^-Cj"alkylrest mono- eller di-substituert benzen. Som halogen-C^-Cg-alkankarboksylsyreester kommer det eksempelvis på tale: ø-halogen-propionsyreester, -smørsyreester eller -valeriansyreester. since thienyl-(3)-lithium with the compound IV takes place in an inert liquid solvent mixture, which preferably consists of a saturated ether and a saturated hydrocarbon and/or a mono- or di-substituted benzene at the C^-Cj" alkyl residue. As halogen Examples of -C 1 -C 8 -alkanecarboxylic acid esters include: -halo-propionic acid ester, -butyric acid ester or -valeric acid ester.
Består oppløsningsmiddelblandingen av en eter og mettet hydrokarbon, så benyttes eksempelvis på en volumdel hydrokarbon 0,3 - 3, fortrinnsvis 0,8-3 volumdeler eter. Por en oppløsningsmiddelblanding av eter og mono- eller dialkylbenzen gjelder eksempelvis pr. 1 volumdel alkylbenzen 0,1 - 3, fortrinnsvis 0,2 - 1 volumdel eter. Består oppløsningsmiddelblandingen av de tre komponenter: eter, mettet hydrokarbon og alkylbenzen, da er eksempelvis blandingsforholdet av de tre komponenter eter .-hydrokarbon :benzen = 0,1-0,9:0,1-0,9:0,1-0,9- Som mettede etere kommer det spesielt på tale alifatiske symmetriske eller usymmetriske dialkyletere, idet alkylgruppene fortrinnsvis, består av 1-6 C-atorner og er eksempelvis metyl, etyl, isopj^opyl, propyl, isobutyl,eller butyl. Videre kommer det som etere eksempelvis også i betraktning C^-Cg-alkyletere av mettede cykloalkanoler og alkylsubstituerte cykloalkanoler, idet cykloalkanolringene hver gang består av 3, 4, 5 eller 6 C-atomer. Fortrinnsvis er eterene flytende i området mellom -80 og +20°C. If the solvent mixture consists of an ether and saturated hydrocarbon, then 0.3 - 3, preferably 0.8 - 3 parts by volume of ether are used, for example, per part by volume of hydrocarbon. Por a solvent mixture of ether and mono- or dialkylbenzene applies, for example, per 1 volume part alkylbenzene 0.1 - 3, preferably 0.2 - 1 volume part ether. If the solvent mixture consists of the three components: ether, saturated hydrocarbon and alkylbenzene, then for example the mixing ratio of the three components is ether .-hydrocarbon:benzene = 0.1-0.9:0.1-0.9:0.1-0 ,9- Saturated ethers are in particular aliphatic symmetrical or unsymmetrical dialkyl ethers, the alkyl groups preferably consisting of 1-6 carbon atoms and are, for example, methyl, ethyl, isopropyl, propyl, isobutyl, or butyl. Furthermore, as ethers, for example, C 1 -C 8 alkyl ethers of saturated cycloalkanols and alkyl-substituted cycloalkanols also come into consideration, the cycloalkanol rings each time consisting of 3, 4, 5 or 6 C atoms. Preferably, the ethers are liquid in the range between -80 and +20°C.
Ved de mettede hydrokarboner draer det seg om alifatiske eller cykloalifatiske hydrokarboner, som er flytende i tempe-raturområdet mellom -80 og +20°C og eksempelvis har 5 til 9, fortrinnsvis 6-7 C-atomer og også kan være forgrenet. De cykloalifatiske hydrokarboner er fortrinnsvis substituert med C^-C^-alkylrester, spesielt metyl-, etyl- eller propylrester en- eller også flere ganger (to ganger, tre ganger) idet antall ringatomer kan være 3»4, 5, 6 eller 7. De mettede alkylrester, som kommer på tale som substituenter for benzen er metyl, etyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, 1-metyl-propyl.. The saturated hydrocarbons are aliphatic or cycloaliphatic hydrocarbons, which are liquid in the temperature range between -80 and +20°C and, for example, have 5 to 9, preferably 6-7 C atoms and can also be branched. The cycloaliphatic hydrocarbons are preferably substituted with C₁-C₂ alkyl residues, especially methyl, ethyl or propyl residues once or several times (twice, three times), as the number of ring atoms can be 3, 4, 5, 6 or 7 The saturated alkyl residues that come into question as substituents for benzene are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, 1-methyl-propyl..
Eksempler for aktuelle oppløsningsmidler er: dietyleter, diisopropyleter, metylcyklopentyleter, hexan, cyklohexan, toluen, xyleSt, metylcyklohexan, metylcyklpentan, etylcyklohexan, dimetylcyklohexan. Examples of relevant solvents are: diethyl ether, diisopropyl ether, methylcyclopentyl ether, hexane, cyclohexane, toluene, xyleSt, methylcyclohexane, methylcyclopentane, ethylcyclohexane, dimethylcyclohexane.
Det er fordelaktig når forbindelsen IV, spesielt når det dreier seg om g-halogen-alkankarboksylsyreester tildoseres som sådan eller i form av en oppløsning i hydrokarbonet og/eller eter (eksempelvis diisopropyleter og/eller toluen) til det til reaksjonstemperaturen foravkjølte thienyllitium (som thienyl-(3)~litium) og deretter holdes reaksjonsblandingen ennå 1 til 4 timer på reaksjonstemperaturen. Deretter blandes eksempelvis reaksjons-oppløsningen med vann, eventuelt etter oppvarming til -20 til +20°C. Den organiske fase tørkes (MgSO^, NagSO^) og inndampes under nedsatt trykk. Den således dannede rå 1,1-bis-(thienyl- It is advantageous when the compound IV, especially when it is a g-halo-alkanecarboxylic acid ester, is added as such or in the form of a solution in the hydrocarbon and/or ether (for example diisopropyl ether and/or toluene) to the thienyllithium precooled to the reaction temperature (as thienyl -(3)~lithium) and then the reaction mixture is kept for a further 1 to 4 hours at the reaction temperature. Then, for example, the reaction solution is mixed with water, optionally after heating to -20 to +20°C. The organic phase is dried (MgSO^, NagSO^) and evaporated under reduced pressure. The crude 1,1-bis-(thienyl-
(3 eller 2)}-3-Iialogenalkanol kan anvendes uten videre rensning for omsetningen med aminet NHgY. Thienyllitium-forbindelsene, eksempelvis thienyl-(3 eller 2)-litium fremstilles vanligvis hver gang på forhånd av 3-brom- eller 2-brom-thiofen eller 3-jod- resp. 2-jod-thiofen i eteren og en C^^-C^-alkyllitium- eller aryllitium-forbindelse i eter-hydrokarbon-blanding, idet som eter og hydrokarbonet (innbefattende alkylbensenene) kommer det på tale de allerede nevnte (som eter, spesielt dialkyleter). Alkylresten av alkyllitium-forbindelsen kan være rettlinjet eller forgrenet. Eksempler er: butyllitium, sek.-butyllitium, tert.-butyHitium, metyllitium, etyllitium, fenyllitium, naftyllitium. (3 or 2)}-3-Ialogenalkanol can be used without further purification for the reaction with the amine NHgY. The thienyllithium compounds, for example thienyl-(3 or 2)-lithium, are usually prepared each time in advance from 3-bromo- or 2-bromo-thiophene or 3-iodo- resp. 2-iodo-thiophene in the ether and a C^-C^-alkyllithium or aryllithium compound in an ether-hydrocarbon mixture, the ether and the hydrocarbon (including the alkylbenzenes) being those already mentioned (as ether, especially dialkyl ether). The alkyl residue of the alkyllithium compound can be straight or branched. Examples are: butyllithium, sec.-butyllithium, tert.-butyllithium, methyllithium, ethyllithium, phenyllithium, naphthyllithium.
Konsentrasjonen av alkyl- resp. aryHitium-forbindelsen i det eventuelle oppløsningsmiddel ligger eksempelvis mellom 5 og 30 vektprosent. Konsentrasjonen av brom-thiofen eller jod-thiofen i det eventuelle oppløsningsmiddel ligger eksempelvis mellom 10 og 100 vektprosent. The concentration of alkyl or The aryHitium compound in the possible solvent is, for example, between 5 and 30 percent by weight. The concentration of bromine-thiophene or iodo-thiophene in the possible solvent is, for example, between 10 and 100 percent by weight.
Vanligvis går man frem således, at man tildoserer brom- eller jod-thiofenet som sådant eller i form av en oppløsning i eteren eller flytende alifatisk hydrokarbon eller alkylbenzenet til litiumalkyl eller litiumarylet, som er oppløst resp. suspen-dert i en av de nevnte etere eller en blanding av eter og alifatisk hydrokarbon (forhold 1-1,5 : 1) eller eter og alkylbenzen (forhold 0,2-0,5 : D (konsentrasjon av litiumforbindelsen mellom 5 og 30 vektprosent) og er avkjølt til temperaturer under -70°C, således at temperaturen ikke øker over -70°C. Reaksjonskomponentene med'• fo&ntel IV tilsettes da eksempelvis i form av en 10 - 100 prosentig oppløsning (vektprosent) i en som allerede angitt dialkyleter eller alkylbenzen likeledes således at temperaturen ikke øker over -70°C. Usually one proceeds in such a way that the bromine or iodothiophene is dosed as such or in the form of a solution in the ether or liquid aliphatic hydrocarbon or the alkylbenzene to the lithium alkyl or the lithium aryl, which is dissolved or suspended in one of the mentioned ethers or a mixture of ether and aliphatic hydrocarbon (ratio 1-1.5 : 1) or ether and alkylbenzene (ratio 0.2-0.5 : D (concentration of the lithium compound between 5 and 30 percent by weight) and is cooled to temperatures below -70°C, so that the temperature does not rise above -70°C. The reaction components with'• fo&ntel IV are then added, for example, in the form of a 10 - 100 percent solution (percentage by weight) in one as already stated dialkyl ether or alkylbenzene likewise so that the temperature does not rise above -70°C.
I en foretrukket utførelsesform av fremgangsmåten ifølge oppfinnelsen gjennomføres reaksjonen i en oppløsnings-middelblanding av toluen og diisopropyleter og etter hydrolyse av reaksjonsblandingen underkastes den organiske fase for en fraksjonert vakuumdestillering, idet oventil uttas den mest lettkokende del av blandingen, som eksempelvis diisopropyleter, thiofen, butylbromid o.l. samt en del av det anvendte toluen og som sumpresiduum utvinnes en oppløsning av l,l-bis-^thienyl-(3) og/eller -thienyl-(2)j -oj-halogen-alkanol i toluen som direkte anvendes i neste trinn av fremgangsmåten. In a preferred embodiment of the method according to the invention, the reaction is carried out in a solvent mixture of toluene and diisopropyl ether and, after hydrolysis of the reaction mixture, the organic phase is subjected to a fractional vacuum distillation, the most easily boiling part of the mixture being taken out above, such as diisopropyl ether, thiophene, butyl bromide beer. as well as part of the toluene used and as sum residue a solution of l,l-bis-^thienyl-(3) and/or -thienyl-(2)j-oj-halo-alkanol in toluene is recovered which is directly used in the next step of the procedure.
Reaksjonsdeltagerne kan eksempelvis anvendes i følgende molforhold: thienyl-litium: forbindelse IV = 2,0-4,0 : 1. The reaction participants can, for example, be used in the following molar ratio: thienyl-lithium: compound IV = 2.0-4.0 : 1.
Refererer man til litiumalkyl og brom- eller jod-thiofen så kommer det eksempelvis fØLgende molforhol på tale: alkyllitium-forbindelse:brom- eller jod-thiofen:forbindelse IV = 2,5-5,0 : 2,0:>4,0 : 1, spesielt 2,0-5,0 : 2,0-4,0 : 1. If one refers to lithium alkyl and bromo- or iodo-thiophene, the following molar ratio is used, for example: alkyllithium compound: bromo- or iodo-thiophene: compound IV = 2.5-5.0 : 2.0:>4.0 : 1, especially 2.0-5.0 : 2.0-4.0 : 1.
Reaksjonstemperaturen bør eksempelvis ikke overstige ~50°C, fordelaktig er gjennomføringen av reaksjonen eksempelvis ved temperaturer mellom -65 og -75°C. Fortrinnsvis overholdes en temperatur under -7.o°C, eksempelvis mellom -80 og -70°C. The reaction temperature should not, for example, exceed ~50°C, it is advantageous to carry out the reaction, for example, at temperatures between -65 and -75°C. A temperature below -7°C is preferably observed, for example between -80 and -70°C.
Det dannede 1,1-bis-fthienyl-(3 og/eller 2))-w-halogen-alkanol med formel II kan deretter omsettes direkte uten videre rensning med forbindelse III. Denne omsetning kan foregå med eller uten oppløsnings- resp. suspensjonsmiddel. Som inert oppløsnings-eller suspensjonsmiddel egner det seg eksempelvis samme middel som kommer på tale for reaksjonen av thienyl-litium med forbindelse IV eksempelvis diisopropyleter, toluen og lignende. Dessuten kan det eksempelvis også anvendes andre alkyl- og dialkylben<g>ener, dialkyletere, alifatiske ketoner og alifatiske og cykloalifatiske alkoholer. Det er også mulig å omsette direkte reaksjonsblandinger hvori forbindelsen med formel II fremkommer med forbindelse III. Da det i en slik reaksjonsblanding dessuten er tilstede det ved reaksjonen dannede alkylhalogenid, er det eventuelt nødvendig å anvende et tilsvarende overskudd av forbindelse III. The formed 1,1-bis-phthienyl-(3 and/or 2))-w-halo-alkanol of formula II can then be reacted directly without further purification with compound III. This turnover can take place with or without dissolution or suspending agent. As an inert dissolving or suspending agent, the same agent used for the reaction of thienyl lithium with compound IV is suitable, for example diisopropyl ether, toluene and the like. In addition, for example, other alkyl and dialkylbenzenes, dialkyl ethers, aliphatic ketones and aliphatic and cycloaliphatic alcohols can also be used. It is also possible to directly react reaction mixtures in which the compound of formula II appears with compound III. As the alkyl halide formed by the reaction is also present in such a reaction mixture, it is possibly necessary to use a corresponding excess of compound III.
De under anvendelse av ifølge oppfinnelsen fremstilte mellomforbindelser II fremstilte følgeprodukter er praktisk talt isomerfrie og fåes etter en gangs omkrystallisering i tilfreds-stillende renhet. The secondary products produced using the intermediate compounds II prepared according to the invention are practically isomer-free and are obtained after a single recrystallization in satisfactory purity.
Eksempel 1 . Example 1.
(l,l-dithienyl-(3)-l-hydroksy-propyl-(3)3-ll-hydroksy-l-(p-hydroksy-fenyl)-propyl-(2)) -amin 25 g (0,15 mol) p-hydroksy-norefedrin, 22,5 ml tri-etylamln og 45,5 g (0,15 mol) l,l-dithienyl-(3)-3-brom-propanol-(l) oppvarmes i 80 ml dioxan under omrøring i 8 timer ved 100°C. Derpå inndampes blandingen best mulig på rotasjonsfordamper, residuet blandes med 150 ml vann og utrystes tre ganger med hver gang 100 ml dietyleter. De forenede eteriske ekstrakter tørkes med magnesium-sulfat. Etter noen timer ved 0°C krystalliserer det ut et svakt farget stoff, som omkrystalliseres fra aceton. Man får 15 g farge-løst krystallinsk stoff. (1,1-dithienyl-(3)-1-hydroxy-propyl-(3)3-11-hydroxy-1-(p-hydroxy-phenyl)-propyl-(2))-amine 25 g (0.15 mol) p-hydroxy-norephedrine, 22.5 ml of triethylamine and 45.5 g (0.15 mol) of 1,1-dithienyl-(3)-3-bromo-propanol-(1) are heated in 80 ml of dioxane with stirring for 8 hours at 100°C. The mixture is then evaporated as best as possible on a rotary evaporator, the residue is mixed with 150 ml of water and shaken three times with 100 ml of diethyl ether each time. The combined ethereal extracts are dried with magnesium sulfate. After a few hours at 0°C, a weakly colored substance crystallizes out, which is recrystallized from acetone. 15 g of colorless crystalline substance is obtained.
Smeltepunkt: 174-175°C.Melting point: 174-175°C.
HydrogenmaleatHydrogen maleate
Por fremstilling av dette salt oppslemmes 5,0 g av basen i 30 ml eddikester. Etter tilsetning av 1,5 g maleinsyre oppstår en klar oppløsning, som blandes til nettopp begynnende uklarhet med dietyleter. Etter 12 timers henstand frasuger man krystallisatet, vasker etter med eddikester og tørker: 4,0 hydrogenmaleat . For the preparation of this salt, 5.0 g of the base is suspended in 30 ml of vinegar. After the addition of 1.5 g of maleic acid, a clear solution is formed, which is mixed with diethyl ether until just starting to become cloudy. After 12 hours' rest, the crystallisate is suctioned off, washed with vinegar and dried: 4.0 hydrogen maleate.
Smeltepunkt: 108-109°C.Melting point: 108-109°C.
Fremstilling av det tilsvarende utgangsstoff l,l-dithienyl-(3)-3-brorn-propanol- (1): I en 1,5 1 fire-halset kolbe med dryppetrakt, tørke-rør, rører, termometer og nitrogentilførsel avkjøles under N2Preparation of the corresponding starting material l,l-dithienyl-(3)-3-brorn-propanol-(1): In a 1.5 l four-necked flask with dropping funnel, drying tube, stirrer, thermometer and nitrogen supply, cool under N2
300 ml absolutt diisopropyleter med et kjølebad metanol/tørris. Under avkjølingen tilsetter man en 15 prosentig oppløsning av . 335,2 ml N-butyllitium i hexan (0,55 niol) og avkjøler til -75°C. Deretter tildrypper man i løpet av 90 minutter en oppløsning av 81>5g 3-brom-thiofen (0,5 mol) i 100 ml absolutt diisopropyleter således at temperaturen på~70°C ikke overstiges. Deretter lar man det etterreagere en time ved -70 C til -75 C. Deretter til-dryppes i løpet av 90 minutter en oppløsning av 36,2 g ^-brompro-pionsyreetylester (0,2 mol) i 60 ml absolutt diisopropyleter således at temperaturen på -70°C ikke overskrides. Man lar det da etterreagere i ytterligere 4 timer. Kjølebadet fjernes deretter og reaksjonsblandingen blandes med 160 ml HgO. Temperaturen 300 ml of absolute diisopropyl ether with a methanol/dry ice cooling bath. During cooling, a 15 percent solution of . 335.2 ml of N-butyllithium in hexane (0.55 niol) and cool to -75°C. A solution of 81>5g of 3-bromothiophene (0.5 mol) in 100 ml of absolute diisopropyl ether is then added dropwise over the course of 90 minutes so that the temperature of ~70°C is not exceeded. It is then allowed to react for one hour at -70 C to -75 C. Then, over the course of 90 minutes, a solution of 36.2 g of β-bromopropionic acid ethyl ester (0.2 mol) in 60 ml of absolute diisopropyl ether is added dropwise so that the temperature of -70°C is not exceeded. It is then left to react for a further 4 hours. The cooling bath is then removed and the reaction mixture is mixed with 160 ml of HgO. The temperature
øker til - 2, 0°C. Det omrøres ennu noen tid inntil temperaturen er steget til over 0°C, deretter adskilles den organiske fase, tørkes med MgSO^, filtreres og alle lettkokende stoffer avdestil-leres under vakuum i rotasjonsfordamper. Som residuum får man en lys olje. Utbytte: 54 g (96 % av det teoretiske referert til brom-propionsyreester). increases to - 2, 0°C. It is stirred for some more time until the temperature has risen to above 0°C, then the organic phase is separated, dried with MgSO 4 , filtered and all low-boiling substances are distilled off under vacuum in a rotary evaporator. A light oil is obtained as a residue. Yield: 54 g (96% of theoretical referred to bromopropionic acid ester).
På samme måte f<t>ies l,l-dithienyl-(3)_4-brom-butanol-(1) og l,l-dithienyl-(3)-5-brom-pentanol-(l) i form av lys olje.. In the same way, 1,1-dithienyl-(3)_4-bromo-butanol-(1) and 1,1-dithienyl-(3)-5-bromo-pentanol-(1) are obtained in the form of light oil..
Eksempel 2 Example 2
1,1-dithieny1-(3)-1-hydroksy-4-(4-feny1-piperazino)-butan 1,1-dithieny1-(3)-1-hydroxy-4-(4-phenyl1-piperazino)-butane
Oppløsningen av 16,2 g (0,1 mol) 4-fenylpiperazin, The solution of 16.2 g (0.1 mol) of 4-phenylpiperazine,
14 ml trietylamin og 31,7 g (0,1 mol) 1,1-dithieny1-(3)-l-hydroksy-4-brombutan i 80 ml diisopropyleter hensettes 3 dager ved værelsetempe^atur. Det krystallinske produkt frasuge3, vaskes med eter, tørkes, oppslemmes i vann, frasuges, vaskes med vann, tørkes. Råutbyttet utgjør 24,4 g, 6l,3 %, 8 g (0,02 mol) av råbasen oppløses i 50 ml aceton. Etter tilsetning av en acetonoppløsning som inneholder 2,32 g (0,02 mol) maleinsyre, oppvarming og filtrering, tilset-jes eter til begynnende uklarhet. Etter kort tid krystalliserer stoffet. Dette frasuges, vaskes med aceton/eter 1:1 og tørkes. 14 ml of triethylamine and 31.7 g (0.1 mol) of 1,1-dithienyl-(3)-1-hydroxy-4-bromobutane in 80 ml of diisopropyl ether are left for 3 days at room temperature. The crystalline product is filtered off with suction3, washed with ether, dried, slurried in water, filtered off with suction, washed with water, dried. The crude yield is 24.4 g, 61.3%, 8 g (0.02 mol) of the crude base is dissolved in 50 ml of acetone. After addition of an acetone solution containing 2.32 g (0.02 mol) of maleic acid, heating and filtration, ether is added until initial cloudiness. After a short time, the substance crystallizes. This is suctioned off, washed with acetone/ether 1:1 and dried.
Utbytte 8,3 g (8l %), maleatets smeltepunkt 110-111°C. Yield 8.3 g (8l %), melting point of the maleate 110-111°C.
Eksempel 3 Example 3
1,1-dithieny1-(3)-l-hydroksy-4-(4-(3-metoksyfeny1)-piperazinq)-butan 1,1-dithienyl-(3)-1-hydroxy-4-(4-(3-methoxyphenyl)-piperazinq)-butane
Denne forbindelse fåes analogt eksempel 2 under anvendelse av 0,1 mol 4-(3-metoksy-fenyl)-piperazin. Maleatets smeltepunkt l49-150oc (Utbytte 94 %). This compound is obtained analogously to example 2 using 0.1 mol of 4-(3-methoxy-phenyl)-piperazine. The maleate's melting point l49-150oc (Yield 94%).
Eksempel 4Example 4
1,1-dithienyl-(3)-l-hydroksy-5-dimetylamino-pentan1,1-dithienyl-(3)-1-hydroxy-5-dimethylamino-pentane
Oppløsningen av 33 g (0,72 mol) dimetylamin i 100 ml benzen og 33,1 g (0,1 mol) 1,1-dithienyl-(3)-l-hydroksy-5-brom-pentan hensettes i lukket reaksjonskar i 10 dager ved værelse-temperatur. The solution of 33 g (0.72 mol) dimethylamine in 100 ml benzene and 33.1 g (0.1 mol) 1,1-dithienyl-(3)-1-hydroxy-5-bromo-pentane is placed in a closed reaction vessel in 10 days at room temperature.
Deretter frasuges krystallgrøtsn og tørkes. Etter inndampning av oppløsningen og tilsetning av eter til residuet utfelles krystallinsk produkt. Dette frasuges, tørkes, forenes med det først dannede produkt og oppslemmes deretter i vann, frasuges , vaskes med vann og tørkes. The crystal porridge is then suctioned off and dried. After evaporation of the solution and addition of ether to the residue, crystalline product precipitates. This is suctioned off, dried, combined with the first formed product and then suspended in water, suctioned off, washed with water and dried.
Råutbyttet utgjør 23,3 g (78 50. Smeltepunkt 129-130°C.The crude yield amounts to 23.3 g (78 50. Melting point 129-130°C.
10 g base (0,0338 mol) oppslemmes i 30 ml aceton. Etter tilsetning av 4 g maleinsyre oppstår en klar oppløsning. Det tilsettes eter til begynnende uklarhet, hvorpå det etter 3 dager krystalliserer stoffet. 10 g of base (0.0338 mol) are suspended in 30 ml of acetone. After adding 4 g of maleic acid, a clear solution is formed. Ether is added to the initial cloudiness, after which the substance crystallizes after 3 days.
Etter frasugning, vasking med aceton/eter 1:1 og tørkning, fåes 11,5 g (82 % stoff) av maleatet av smeltepunkt 79-80°C. After extraction, washing with acetone/ether 1:1 and drying, 11.5 g (82% substance) of the maleate of melting point 79-80°C are obtained.
Eksempel 5Example 5
Fremstilling av ytterligere (l,l-(dithienyl-(3)-l-hydroksy-propyl-(3)] -aminer med formel Preparation of additional (1,1-(dithienyl-(3)-1-hydroxy-propyl-(3)]-amines of formula
De i tabell 1 oppførte forbindelser fremstilles etter følgende arbeidsmåte: 0,1 mol 1,1-dithienyl-(3)-3-brom-propanol-(l), 0,11 mol trietylamin og 0,1 mol primært eller sekundært amin (se spalte 2 i tabell 1) oppvarmes i 60 ml diisopropyleter ca. 12-15 timer under omrøring og tilbakeløp. Etter avkjøling frasuges krystallisatet, vaskes med diisopropyleter og tørkes. Der etter oppslemmes i vann, frasuges, vaskes med vann, tørkes, omkrystalliseres og analogt eksempel 1 fremstilles eventuelt malein-syresaltet. The compounds listed in Table 1 are prepared according to the following procedure: 0.1 mol 1,1-dithienyl-(3)-3-bromo-propanol-(1), 0.11 mol triethylamine and 0.1 mol primary or secondary amine ( see column 2 in table 1) is heated in 60 ml of diisopropyl ether approx. 12-15 hours under stirring and reflux. After cooling, the crystallisate is suctioned off, washed with diisopropyl ether and dried. It is then slurried in water, sucked off, washed with water, dried, recrystallized and, analogously to example 1, the maleic acid salt is optionally prepared.
Eksempel 6 (l,l-dithienyl-(3)-l-propenyl-(3)]-(1-hydroksy-l-(p-hydroksy-fenyl)-propyl-(2)j-amin. 25 g (0,15 mol) p-hydroksy-norefedrin, 22,5 ml tri-etylarain og 45,5 g (0,15 mol) 1,1-dithienyl-(3)-3-brom-propanol-(1) oppvarmes i 80 ml dioxan under omrøring i 8 timer ved 100°C. Deretter inndampes blandingen i rotasjonsfordamper best mulig og det sirupøse residuet digereres to ganger med hver gang 250 ml dietyleter. De forenede eteriske oppløsninger surgjøres med isopropanolisk HC1 hvorpå det utfelles et høyviskøst produkt. Etter oppløsningsmidlets avhelling opptar man residuet i 100 ml etanol, oppvarmer 10 minutter under tilbakeløptil kokning og inndamper oppløsningen på rotasjonsfordamper. Residuet oppløses i 100 ml varm aceton, hvorfra stoffet etter avkjøling langsomt utkrystalliserer. Etter omkrystallisering fra isopropanol får man forbindelsen som hydroklorid i form av fargeløse krystaller. Hydro-kloridets smeltepunkt: 138-l40°C. Utbytte: 10,2 g. Example 6 (1,1-dithienyl-(3)-1-propenyl-(3)]-(1-hydroxy-1-(p-hydroxy-phenyl)-propyl-(2)j-amine. 25 g (0 .15 mol) p-hydroxy-norephedrine, 22.5 ml of triethylaraine and 45.5 g (0.15 mol) of 1,1-dithienyl-(3)-3-bromo-propanol-(1) are heated in 80 ml of dioxane with stirring for 8 hours at 100°C. The mixture is then evaporated in a rotary evaporator as best as possible and the syrupy residue is digested twice with 250 ml of diethyl ether each time. The combined ethereal solutions are acidified with isopropanolic HC1 whereupon a highly viscous product is precipitated. After the solvent's decanting, take up the residue in 100 ml of ethanol, heat for 10 minutes under reflux to boiling and evaporate the solution on a rotary evaporator. The residue is dissolved in 100 ml of hot acetone, from which the substance slowly crystallizes after cooling. After recrystallization from isopropanol, the compound is obtained as hydrochloride in the form of colorless crystals Melting point of the hydrochloride: 138-140° C. Yield: 10.2 g.
Eksempel 7Example 7
Fremstilling av 1,1-dithienyl-(3)-alken-(l)-yl-aminer med formel Preparation of 1,1-dithienyl-(3)-alken-(1)-yl-amines of formula
De i tabell 2 oppførte forbindelser fremstilles etter følgende arbeidsmåte: The compounds listed in Table 2 are produced according to the following method:
0,1 mol av aminet med formel0.1 mol of the amine of formula
oppløses i 50 ml metanol og blandes med en 10 prosentig overskudd dissolve in 50 ml of methanol and mix with a 10 percent excess
av den for saltdannelsen nødvendig mengde isopropanolisk saltsyre, hvis konsentrasjon burde utgjøre 5-7 mol/liter. Reaksjonsblandingen oppvarmes ca. 20-30 minutter under tilbakeløp. Etter av-kjøling utkrystalliserer forbindelsen ofte. Skulle dette i enkelte tilfeller ikke være tilfelle, så blandes oppløsningen med så meget eter inntil det opptrer en blivende uklarhet, reaksjons-produktet utskiller seg deretter for det meste krystallinsk form. of the amount of isopropanolic hydrochloric acid required for salt formation, the concentration of which should be 5-7 mol/litre. The reaction mixture is heated approx. 20-30 minutes under reflux. After cooling, the compound often crystallizes. Should this not be the case in some cases, the solution is mixed with as much ether as possible until a permanent turbidity appears, the reaction product then separates out mostly in crystalline form.
Oppløsningsmiddel til orakrystallisering er fortrinnsvis metanol, etanol og isopropanol. Solvent for oracrystallization is preferably methanol, ethanol and isopropanol.
Claims (12)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1120/77A GB1579541A (en) | 1977-01-12 | 1977-01-12 | Process for the production of (1,1 - dithien - (3)-yl - 1 - hydroxy - (3) - propyl) - (1-phenyl - 1 - hydroxy - (2) - propyl)-amine and (1,1 - dithien - (3) - yl-(1) - propen - (3) - yl) - (1 - phenyl-1 - hydroxy - (2) - propyl)- amine |
| GB1121/77A GB1597591A (en) | 1977-01-12 | 1977-01-12 | Dithienyl alkylamines and alkenylamines and a process for their production |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO780101L true NO780101L (en) | 1978-07-13 |
Family
ID=26236487
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO780101A NO780101L (en) | 1977-01-12 | 1978-01-11 | NEW DITIENYLALKYLAMINES AND PROCEDURES FOR THEIR PREPARATION |
| NO823010A NO823010L (en) | 1977-01-12 | 1982-09-06 | 1,1-DITIENYL- (3) -1-HYDROXY-ALKYLHALOGENIDES. |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO823010A NO823010L (en) | 1977-01-12 | 1982-09-06 | 1,1-DITIENYL- (3) -1-HYDROXY-ALKYLHALOGENIDES. |
Country Status (1)
| Country | Link |
|---|---|
| NO (2) | NO780101L (en) |
-
1978
- 1978-01-11 NO NO780101A patent/NO780101L/en unknown
-
1982
- 1982-09-06 NO NO823010A patent/NO823010L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO823010L (en) | 1978-07-13 |
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