NO135962B - - Google Patents
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- Publication number
- NO135962B NO135962B NO4800/73A NO480073A NO135962B NO 135962 B NO135962 B NO 135962B NO 4800/73 A NO4800/73 A NO 4800/73A NO 480073 A NO480073 A NO 480073A NO 135962 B NO135962 B NO 135962B
- Authority
- NO
- Norway
- Prior art keywords
- compounds
- methyl
- salts
- piperazino
- ethyl
- Prior art date
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- -1 1,2-ethylene Chemical group 0.000 claims description 42
- 150000001875 compounds Chemical class 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 35
- 239000002253 acid Substances 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 150000003856 quaternary ammonium compounds Chemical class 0.000 claims description 9
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 7
- 239000011707 mineral Substances 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Chemical group 0.000 claims description 4
- 239000000460 chlorine Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 210000004369 blood Anatomy 0.000 claims description 3
- 239000008280 blood Substances 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- SDDKIZNHOCEXTF-UHFFFAOYSA-N methyl carbamimidothioate Chemical compound CSC(N)=N SDDKIZNHOCEXTF-UHFFFAOYSA-N 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- 239000000203 mixture Substances 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000009835 boiling Methods 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 10
- NNBBQNFHCVVQHZ-UHFFFAOYSA-N methyl carbamimidothioate;sulfuric acid Chemical compound CSC(N)=N.OS(O)(=O)=O NNBBQNFHCVVQHZ-UHFFFAOYSA-N 0.000 description 10
- 238000001816 cooling Methods 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 239000012280 lithium aluminium hydride Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 150000007513 acids Chemical class 0.000 description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 7
- 239000003085 diluting agent Substances 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-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
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- 229960004198 guanidine Drugs 0.000 description 5
- 150000002357 guanidines Chemical class 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 5
- UQQANGXEKGPJNV-UHFFFAOYSA-N 2-[2-(4-methylpiperazin-1-yl)ethyl]guanidine Chemical compound CN1CCN(CCN=C(N)N)CC1 UQQANGXEKGPJNV-UHFFFAOYSA-N 0.000 description 4
- DXJCNWSIUQCGKT-UHFFFAOYSA-N 2-[2-(4-methylpiperazin-1-yl)ethyl]guanidine sulfuric acid Chemical compound S(=O)(=O)(O)O.CN1CCN(CC1)CCNC(=N)N DXJCNWSIUQCGKT-UHFFFAOYSA-N 0.000 description 4
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000000155 melt Substances 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- GOWUDHPKGOIDIX-UHFFFAOYSA-N 2-(4-methyl-1-piperazinyl)ethanamine Chemical compound CN1CCN(CCN)CC1 GOWUDHPKGOIDIX-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 125000001453 quaternary ammonium group Chemical group 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 description 2
- SHUQIGHJQMJUHB-UHFFFAOYSA-N 2-(4-ethylpiperazin-1-yl)ethanamine Chemical compound CCN1CCN(CCN)CC1 SHUQIGHJQMJUHB-UHFFFAOYSA-N 0.000 description 2
- XCUQQNRWWCWVOP-UHFFFAOYSA-N 2-(4-methylpiperazin-1-yl)acetonitrile Chemical compound CN1CCN(CC#N)CC1 XCUQQNRWWCWVOP-UHFFFAOYSA-N 0.000 description 2
- FVSHDOWSASNQDC-UHFFFAOYSA-N 2-[2-(4-butylpiperazin-1-yl)ethyl]guanidine Chemical compound C(CCC)N1CCN(CC1)CCNC(=N)N FVSHDOWSASNQDC-UHFFFAOYSA-N 0.000 description 2
- UHIQVPRCDRTUKV-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)piperazin-1-yl]ethanamine Chemical compound C1CN(CCN)CCN1C1=CC=C(Cl)C=C1 UHIQVPRCDRTUKV-UHFFFAOYSA-N 0.000 description 2
- SJSOFNCYXJUNBT-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC(OC)=C1OC SJSOFNCYXJUNBT-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical class [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- RXYMIJUILCHWEJ-UHFFFAOYSA-N C(CC)N1CCN(CC1)CCNC(=N)N Chemical compound C(CC)N1CCN(CC1)CCNC(=N)N RXYMIJUILCHWEJ-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- UCQFSGCWHRTMGG-UHFFFAOYSA-N pyrazole-1-carboximidamide Chemical class NC(=N)N1C=CC=N1 UCQFSGCWHRTMGG-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 238000001953 recrystallisation Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 229910021653 sulphate ion Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- YIAGRWLFJWTYTD-KNVOCYPGSA-N (3r,5s)-3,5-dimethylpiperazine-1-carbaldehyde Chemical compound C[C@H]1CN(C=O)C[C@@H](C)N1 YIAGRWLFJWTYTD-KNVOCYPGSA-N 0.000 description 1
- CLPZHEDSMNQBPP-KNVOCYPGSA-N (3s,5r)-1,3,5-trimethylpiperazine Chemical compound C[C@H]1CN(C)C[C@@H](C)N1 CLPZHEDSMNQBPP-KNVOCYPGSA-N 0.000 description 1
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- BZCOSCNPHJNQBP-UPHRSURJSA-N (z)-2,3-dihydroxybut-2-enedioic acid Chemical compound OC(=O)C(\O)=C(\O)C(O)=O BZCOSCNPHJNQBP-UPHRSURJSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- PXFJLKKZSWWVRX-UHFFFAOYSA-N 1-(3,4-dichlorophenyl)piperazine Chemical compound C1=C(Cl)C(Cl)=CC=C1N1CCNCC1 PXFJLKKZSWWVRX-UHFFFAOYSA-N 0.000 description 1
- MSSDTZLYNMFTKN-UHFFFAOYSA-N 1-Piperazinecarboxaldehyde Chemical compound O=CN1CCNCC1 MSSDTZLYNMFTKN-UHFFFAOYSA-N 0.000 description 1
- WGCYRFWNGRMRJA-UHFFFAOYSA-N 1-ethylpiperazine Chemical compound CCN1CCNCC1 WGCYRFWNGRMRJA-UHFFFAOYSA-N 0.000 description 1
- FXHRAKUEZPSMLJ-UHFFFAOYSA-N 1-methyl-1,4-diazepane Chemical compound CN1CCCNCC1 FXHRAKUEZPSMLJ-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- HUOKGKBTYCFARR-UHFFFAOYSA-N 2-(4-ethylpiperazin-1-yl)acetonitrile Chemical compound CCN1CCN(CC#N)CC1 HUOKGKBTYCFARR-UHFFFAOYSA-N 0.000 description 1
- YADBDPBUDXPYRK-UHFFFAOYSA-N 2-(4-methylpiperazin-1-yl)ethanamine;trihydrochloride Chemical compound Cl.Cl.Cl.CN1CCN(CCN)CC1 YADBDPBUDXPYRK-UHFFFAOYSA-N 0.000 description 1
- JQIZYQKCPLKROQ-UHFFFAOYSA-N 2-(4-phenylpiperazin-1-yl)ethanamine Chemical compound C1CN(CCN)CCN1C1=CC=CC=C1 JQIZYQKCPLKROQ-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- FNPZJYQEZIZCDL-DTORHVGOSA-N 2-[(2s,6r)-2,4,6-trimethylpiperazin-1-yl]acetonitrile Chemical compound C[C@H]1CN(C)C[C@@H](C)N1CC#N FNPZJYQEZIZCDL-DTORHVGOSA-N 0.000 description 1
- DWQQHGZHPQXSPI-UHFFFAOYSA-N 2-[2-(4-ethylpiperazin-1-yl)ethyl]guanidine sulfuric acid Chemical compound S(=O)(=O)(O)O.C(C)N1CCN(CC1)CCNC(=N)N DWQQHGZHPQXSPI-UHFFFAOYSA-N 0.000 description 1
- WCHRITKZYUPTIQ-UHFFFAOYSA-N 2-[2-(4-heptylpiperazin-1-yl)ethyl]guanidine Chemical compound C(CCCCCC)N1CCN(CC1)CCNC(=N)N WCHRITKZYUPTIQ-UHFFFAOYSA-N 0.000 description 1
- DXAWNHNLQUWIHF-UHFFFAOYSA-N 2-[2-(4-pentylpiperazin-1-yl)ethyl]guanidine Chemical compound C(CCCC)N1CCN(CC1)CCNC(=N)N DXAWNHNLQUWIHF-UHFFFAOYSA-N 0.000 description 1
- BIEWCVDTVLCCJG-UHFFFAOYSA-N 2-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]guanidine Chemical compound ClC1=CC=C(C=C1)N1CCN(CC1)CCNC(=N)N BIEWCVDTVLCCJG-UHFFFAOYSA-N 0.000 description 1
- XFPUVZZHWRXYBA-UHFFFAOYSA-N 2-[2-[4-(4-methylphenyl)piperazin-1-yl]ethyl]guanidine Chemical compound CC1=CC=C(C=C1)N1CCN(CC1)CCNC(=N)N XFPUVZZHWRXYBA-UHFFFAOYSA-N 0.000 description 1
- BKTZIZAWQMGVPX-UHFFFAOYSA-N 2-[3-(4-methylpiperazin-1-yl)propyl]guanidine Chemical compound CN1CCN(CCCNC(N)=N)CC1 BKTZIZAWQMGVPX-UHFFFAOYSA-N 0.000 description 1
- FRQMJZZUNJTQCS-UHFFFAOYSA-N 2-[4-(3,4-dichlorophenyl)piperazin-1-yl]ethanamine Chemical compound C1CN(CCN)CCN1C1=CC=C(Cl)C(Cl)=C1 FRQMJZZUNJTQCS-UHFFFAOYSA-N 0.000 description 1
- CJJGYUNFHMWIAR-UHFFFAOYSA-N 2-[4-(4-methylphenyl)piperazin-1-yl]ethanamine Chemical compound C1=CC(C)=CC=C1N1CCN(CCN)CC1 CJJGYUNFHMWIAR-UHFFFAOYSA-N 0.000 description 1
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 1
- UOBYKYZJUGYBDK-UHFFFAOYSA-N 2-naphthoic acid Chemical compound C1=CC=CC2=CC(C(=O)O)=CC=C21 UOBYKYZJUGYBDK-UHFFFAOYSA-N 0.000 description 1
- PKRSYEPBQPFNRB-UHFFFAOYSA-N 2-phenoxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1OC1=CC=CC=C1 PKRSYEPBQPFNRB-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
- IWPZKOJSYQZABD-UHFFFAOYSA-N 3,4,5-trimethoxybenzoic acid Natural products COC1=CC(OC)=CC(C(O)=O)=C1 IWPZKOJSYQZABD-UHFFFAOYSA-N 0.000 description 1
- GAZRNXIMWKZADY-UHFFFAOYSA-N 3,5-dimethylpyrazole-1-carboximidamide Chemical compound CC=1C=C(C)N(C(N)=N)N=1 GAZRNXIMWKZADY-UHFFFAOYSA-N 0.000 description 1
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- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
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- 206010067598 Neurogenic hypertension Diseases 0.000 description 1
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
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- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
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- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
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- GANNOFFDYMSBSZ-UHFFFAOYSA-N [AlH3].[Mg] Chemical compound [AlH3].[Mg] GANNOFFDYMSBSZ-UHFFFAOYSA-N 0.000 description 1
- SSBRSHIQIANGKS-UHFFFAOYSA-N [amino(hydroxy)methylidene]azanium;hydrogen sulfate Chemical compound NC(N)=O.OS(O)(=O)=O SSBRSHIQIANGKS-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
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- 150000003855 acyl compounds Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
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- 230000029936 alkylation Effects 0.000 description 1
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- 125000005263 alkylenediamine group Chemical group 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
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- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical class N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
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- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
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- 230000003276 anti-hypertensive effect Effects 0.000 description 1
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- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
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- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
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- 229960004365 benzoic acid Drugs 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
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- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
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- 239000001569 carbon dioxide Substances 0.000 description 1
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- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
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- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
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- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
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- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
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- 238000001035 drying Methods 0.000 description 1
- 238000000909 electrodialysis Methods 0.000 description 1
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- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
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- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- IPXPQJFDBZXVDF-UHFFFAOYSA-N ethyl carbamimidothioate;sulfuric acid Chemical compound OS(O)(=O)=O.CCSC(N)=N IPXPQJFDBZXVDF-UHFFFAOYSA-N 0.000 description 1
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- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
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- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical group COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
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- DBFAKALHTSOYSG-UHFFFAOYSA-N n-cyanobenzamide Chemical compound N#CNC(=O)C1=CC=CC=C1 DBFAKALHTSOYSG-UHFFFAOYSA-N 0.000 description 1
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- UNEIHNMKASENIG-UHFFFAOYSA-N para-chlorophenylpiperazine Chemical compound C1=CC(Cl)=CC=C1N1CCNCC1 UNEIHNMKASENIG-UHFFFAOYSA-N 0.000 description 1
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- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
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- 150000003222 pyridines Chemical class 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000005956 quaternization reaction Methods 0.000 description 1
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- 206010038464 renal hypertension Diseases 0.000 description 1
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- 239000012609 strong anion exchange resin Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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- 238000005292 vacuum distillation Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Fremgangsmåte til fremstilling av nye diazaforbindelser med blodtrykksenkende virkning. Process for the production of new diaza compounds with blood pressure-lowering action.
Oppfinnelsen angår fremstilling av nye The invention relates to the production of new
blodtrykksenkende forbindelser med den generelle formel blood pressure-lowering compounds of the general formula
hvori R betyr en alkylrest med 1—7 karbonatomer eller fenyl, som kan være substituert med alkyl, alkoksy, hvori alkylresten inneholder 1—4 karbonatomer og/eller med fluor, klor eller brom, m, og m2 betyr betyr tallene 1 eller 2, R, og R;, betyr hydrogen, metyl eller etyl, -alkylen- betyr 1,2-etylen, 1,2-, 2,3- eller 1,3-propylen og R, betyr in which R means an alkyl residue with 1-7 carbon atoms or phenyl, which may be substituted with alkyl, alkoxy, in which the alkyl residue contains 1-4 carbon atoms and/or with fluorine, chlorine or bromine, m, and m2 means means the numbers 1 or 2, R, and R;, means hydrogen, methyl or ethyl, -alkylene- means 1,2-ethylene, 1,2-, 2,3- or 1,3-propylene and R, means
hydrogen eller betyr acylresten av en or-ganisk karbonsyre, deres kvaternære ammoniumforbindelser eller salter av disse forbindelser. hydrogen or means the acyl residue of an organic carboxylic acid, their quaternary ammonium compounds or salts of these compounds.
Som acylsubstituenter R, fra guanido-gruppen kan nevnes f. eks. slike av alkan-karbonsyrer, slik som eddiksyre, propion-eller trimetyleddiksyre, substituerte al-kankarbonsyrer, slik som trifluoreddiksyre, hydroksyeddiksyre eller cyklopentylpro-pionsyre, eller alkenkarbonsyrer, som akryl-syre. Videre kan nevnes slike av monocyklisk eller bicyklisk aromatiske karbonsyrer, som benzoesyre, hydroksybenzoesyre, ami-nobenzoesyre, 1-naftosyre eller 2-naftosyre, eller av monocykliske, heterocykliske karbonsyrer, som nikotin-, isonikotin- eller 2-furankarbonsyre. As acyl substituents R, from the guanido group can be mentioned, e.g. such as alkanecarboxylic acids, such as acetic acid, propionic or trimethylacetic acid, substituted alkanecarboxylic acids, such as trifluoroacetic acid, hydroxyacetic acid or cyclopentylpropionic acid, or alkenecarboxylic acids, such as acrylic acid. Mention may also be made of monocyclic or bicyclic aromatic carboxylic acids, such as benzoic acid, hydroxybenzoic acid, aminobenzoic acid, 1-naphthoic acid or 2-naphthoic acid, or of monocyclic, heterocyclic carboxylic acids, such as nicotinic, isonicotinic or 2-furanic acid.
Salter av de nye forbindelser er fortrinsvis terapeutiske anvendelige syreaddisjonssalter, f. eks. slike av anorganiske syrer, som saltsyre, bromhydrogensyre, svo-vel- eller fosforsyrer, eller av organiske syrer, f. eks. eddik-, propion-, glykol-, melke-, drue-, oksal-, malon-, rav-, malein-, fumar-, eple-, vin-, citron-, askorbin-citrakonhydroksymalein- eller dihydroksy-maleinsyre, eller benzoesyre, fenyleddiksy-re,4-amino-benzoesyre, 4-hydroksy-benzoesyre, antranilsyre, kanelsyre, mandelsyre, salicylsyre, 4-aminosalicylsyre, 2-fenoksy-benzoesyre eller 2-acetoksybenzoesyre, eller metansulfonsyre, etansulfonsyre, 2-hydrok-syetansulfonsyre eller p-toluolsulfonsyre. Herav kan dannes mono- eller polysalter. Salts of the new compounds are preferably therapeutically applicable acid addition salts, e.g. those of inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric or phosphoric acids, or of organic acids, e.g. acetic, propionic, glycolic, lactic, grape, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, ascorbic-citracone-hydroxymaleic or dihydroxy-maleic, or benzoic acid , phenylacetic acid, 4-amino-benzoic acid, 4-hydroxy-benzoic acid, anthranilic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxy-benzoic acid or 2-acetoxybenzoic acid, or methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid or p-toluenesulfonic acid. Mono- or poly-salts can be formed from this.
Som kvaternære ammoniumforbindelser kommer fortrinsvis slike på tale som oppstår ved omsetning med reaksjonsdyktige estere av lavere-alkanoler eller aralkanoler. Av disse tilleiringsforbindelser kan ammoniumhydroksydene fås, hvilke kan omsettes med de ovenfor anførte terapeutisk anvendelige syrer til andre kvaternære ammoniumsalter. Quaternary ammonium compounds are preferably those which arise from reaction with reactive esters of lower alkanols or aralkanols. From these addition compounds, ammonium hydroxides can be obtained, which can be reacted with the above-mentioned therapeutically applicable acids to form other quaternary ammonium salts.
De nye guanidinforbindelser er karakterisert ved antihypertensive egenskaper og kan derfor anvendes som middel mot høyt blodtrykk, spesielt mot neurogen, re-nal eller essensiell hypertoni. Dertil for-årsaker de en stigning av den perifere blod-sirkulasjon og kan derfor også anvendes til behandling av perifere karsykdommer, f. eks. Reynauds sykdom. De farmakolo-giske virkninger som fremkalles av de nye forbindelser varer forholdsvis lenge, og de nye forbindelser utmerker seg også ved en bemerkelsesverdig lav giftighet. The new guanidine compounds are characterized by antihypertensive properties and can therefore be used as a remedy for high blood pressure, especially for neurogenic, renal or essential hypertension. In addition, they cause an increase in the peripheral blood circulation and can therefore also be used to treat peripheral vascular diseases, e.g. Reynaud's disease. The pharmacological effects induced by the new compounds last relatively long, and the new compounds are also distinguished by a remarkably low toxicity.
Videre kan de nye guanidiner også tjene som mellomprodukter for fremstilling av andre verdifulle forbindelser. Furthermore, the new guanidines can also serve as intermediates for the production of other valuable compounds.
Oppfinnelsen angår spesielt fremstil-lingen av forbindelser med formel 1, hvori R betyr alkyl med 1—4 karbonatomer eller fenyl, R„ R., og R:, betyr hydrogen og de øvrige symboler har den angitte betydning ganske spesielt 2-(4-metyl-piperazino)-etyl-guanidin og deres terapeutisk anvendelige syreaddisjonssalter. The invention relates in particular to the preparation of compounds of formula 1, in which R means alkyl with 1-4 carbon atoms or phenyl, R„ R., and R:, means hydrogen and the other symbols have the indicated meaning quite especially 2-(4- methyl-piperazino)-ethyl-guanidine and their therapeutically useful acid addition salts.
Eksempler på de sistnevnte særlig virksomme forbindelser med formel 1 ses av følgende tabell: Examples of the latter particularly effective compounds with formula 1 can be seen in the following table:
De nye guanidiner, deres salter, acyl-forbinclelser og/eller kvaternære ammoniumforbindelser skal anvendes som lege-midler i form av farmasøytiske preparater. The new guanidines, their salts, acyl compounds and/or quaternary ammonium compounds are to be used as drugs in the form of pharmaceutical preparations.
De nye forbindelser kan fås ved at man omsetter N-R-aza-alkylenimino-alkyla-mino med formelen The new compounds can be obtained by reacting N-R-aza-alkylenimino-alkylamino with the formula
hvori R, m„ m,., R.., R3 og -alkylen- har den ovenfor angitte betydning eller salter av disse med forbindelser med formel in which R, m„ m,., R.., R3 and -alkylene- have the above meaning or salts thereof with compounds of the formula
eller deres salter, hvori R, har den ovenfor angitte betydning, X betyr en avspaltbar rest, slik som en alkylmerkaptoalkoksy-eller 1-pyrazolrest, Y er hydrogen, eller X og Y sammen med CN-dobbeltbindingen danner en CN-tredobbeltbinding, og, om ønskes, acylerer erholdte forbindelser med reaksjonsdyktige derivater av organiske or their salts, in which R has the meaning given above, X means a cleavable residue, such as an alkylmercaptoalkyloxy or 1-pyrazole residue, Y is hydrogen, or X and Y together with the CN double bond form a CN triple bond, and, if desired, acylate the obtained compounds with reactive organic derivatives
karbonsyrer, og/eller omdanner til kvaternære ammoniumforbindelser og/eller over-fører erholdte salter til de frie forbindelser eller erholdte frie forbindelser til salter. carboxylic acids, and/or converts to quaternary ammonium compounds and/or transfers obtained salts to the free compounds or obtained free compounds to salts.
Forbindelser med formel III er f. eks. S-alkylisotiourinstoffer, f. eks. S-metyl-eller S-etylisotiourinstoffer, O-alkyl-isourinstoffer, f. eks. O-metyl- eller O-etyliso-urinstoffer, cyanamid eller l-guanyl-3,5-dimetylpyrazol. Som N-substituenter kommer acylrester, f. eks. av lavere-alkankar-bonsyrer eller en monocyklisk aromatisk karbonsyre, f. eks. eddik-, propion-, ben-zoe-, eller 3,4,5-trimetoksy-benzoesyre på tale. 1-guanyl-pyrazoler er fortrinsvis også substituert i kjernen, f. eks. med lavere-al-kylgrupper. De nevnte forbindelser kan og-så foreligge i form av syreaddisjonssalter, fortrinsvis mineralsyreaddisj onssalter. Compounds of formula III are e.g. S-alkylisothioureas, e.g. S-methyl or S-ethylisothioureas, O-alkylisoureas, e.g. O-methyl or O-ethyliso-ureas, cyanamide or l-guanyl-3,5-dimethylpyrazole. As N-substituents, acyl residues, e.g. of lower alkane carboxylic acids or a monocyclic aromatic carboxylic acid, e.g. acetic, propionic, benzoic or 3,4,5-trimethoxy-benzoic acid in question. 1-guanyl-pyrazoles are preferably also substituted in the nucleus, e.g. with lower alkyl groups. The aforementioned compounds can also be present in the form of acid addition salts, preferably mineral acid addition salts.
En særlig foretrukket forbindelse av denne gruppe er S-metyl-isotiourinstoff og dens mineralsyre-addisj onssalter, særlig S-metyl-isotiourinstoffsulfat, fordi den ved reaksjonen ifølge fremgangsmåten gir flyk-tige merkaptaner som biprodukter som lett lar seg fjerne fra reaksjonsblandingen. A particularly preferred compound of this group is S-methyl-isothiourea and its mineral acid addition salts, especially S-methyl-isothiourea sulphate, because in the reaction according to the method it gives volatile mercaptans as by-products which can be easily removed from the reaction mixture.
Reaksjonen med S-alkyl-isotiourinstoffer utføres fortrinsvis i nærvær av for-tynningsmidler hvis valg foregår med hen-blikk på oppløseligheten for reaksjonskom-ponentene. Som fortynnings- eller oppløs-ningsmiddel kommer f. eks. vann eller med vann blandbare organiske oppløsningsmid-ler på tale, f. eks. alkanoler, slik som metanol, etanol, propanol, i-propanol eller tert. butanol, eter, slik som dioksan eller tettrahydrofuran, ketoner, slik som aceton eller metyl-etylketon, lavere alkankarbon-syrer, slik som eddiksyre, eller formamider, slik som formamid eller dimetyl-formamid, eller deres vandige blandinger. Reaksjonen kan utføres ved romtemperatur eller, om nødvendig, ved forhøyet temperatur, f. eks. ved koketemperatur for oppløsnings- eller fortynningsmiddelet verd normalt eller for-høyet trykk eller i nærvær av en inert gass, f. eks. nitrogen. The reaction with S-alkyl isothioureas is preferably carried out in the presence of diluents, the choice of which takes place with regard to the solubility of the reaction components. As a diluent or solvent, e.g. water or water-miscible organic solvents in speech, e.g. alkanols, such as methanol, ethanol, propanol, i-propanol or tert. butanol, ether, such as dioxane or tetrahydrofuran, ketones, such as acetone or methyl ethyl ketone, lower alkane carboxylic acids, such as acetic acid, or formamides, such as formamide or dimethylformamide, or their aqueous mixtures. The reaction can be carried out at room temperature or, if necessary, at an elevated temperature, e.g. at the boiling temperature of the solvent or diluent at normal or elevated pressure or in the presence of an inert gas, e.g. nitrogen.
Fremstillingsmetoden egner seg spesielt til fremstilling av mineralsyre-addisj onssalter av forbindelser med formel I, hvori R betyr alkyl med 1—4 karbonatomer, R„ R. og R„ betyr hydrogen og m„ m, og -alkylen- hadde den angitte betydning, idet man omsetter tilsvarende aminer med formelen The production method is particularly suitable for the production of mineral acid addition salts of compounds of formula I, in which R means alkyl with 1-4 carbon atoms, R„ R. and R„ mean hydrogen and m„ m, and -alkylene- had the indicated meaning, by reacting corresponding amines with the formula
med et mineralsyre-addisjonssalt av et S-alkylisotiourinstoff, spesielt med S-metyl-isotiourinstoffsulfat, fortrinsvis ved for-høyet temperatur. På analog måte utføres også omsetningen med O-laverealkyliso-urinstoffer. with a mineral acid addition salt of an S-alkylisothiourea, in particular with S-methyl isothiourea sulfate, preferably at an elevated temperature. In an analogous way, the reaction is also carried out with O-lower alkyliso-ureas.
Reaksjonen med cyanamider utføres f. eks. således at man oppvarmer en blanding av N-R-aza-alkylenimino-alkylamin, særlig et salt av dette, f. eks. et addisjonssalt med en mineralsyre, slik som saltsyre, bromhydrogensyre eller svovelsyre, og cy-namidet oppløser den erholdte smelte i et oppløsningsmiddel, f. eks. en lavere-alkan-karbonsyre, slik som eddiksyre, og isolerer reaksjonsproduktet på i og for seg kjent måte. Ovenstående omsetning kan imidler-tid også foretas i nærvær av et oppløs-nings- eller fortynningsmiddel, f. eks. en lavere alkanol, slik som etanol, eller en konsentrert vandig syre, slik som saltsyre, idet syre-addisjonssaltet av utgangsproduktet også kan dannes intermediært. Reaksjonen kan forløpe eksotermt, om nød-vendig, oppvarmer man til temperaturer mellom omtrent 80 og 200° C, eventuelt i nærvær av en inert gass, f. eks. nitrogen. The reaction with cyanamides is carried out, e.g. so that one heats a mixture of N-R-aza-alkylenimino-alkylamine, in particular a salt thereof, e.g. an addition salt with a mineral acid, such as hydrochloric acid, hydrobromic acid or sulfuric acid, and the cynamide dissolves the resulting melt in a solvent, e.g. a lower alkane carboxylic acid, such as acetic acid, and isolates the reaction product in a manner known per se. The above reaction can, however, also be carried out in the presence of a solvent or diluent, e.g. a lower alkanol, such as ethanol, or a concentrated aqueous acid, such as hydrochloric acid, the acid addition salt of the starting product can also be formed intermediately. The reaction can proceed exothermically, if necessary, heating to temperatures between approximately 80 and 200° C, possibly in the presence of an inert gas, e.g. nitrogen.
Omsetningen av N-R-aza-alkylenimino-alkylamin med en 1-guanyl-pyrazol foregår i nærvær eller fravær av et fortynningsmiddel, f. eks. ved oppvarming av blandingen til smeltepunktet eller ved nærvær av et oppløsningsmiddel til dets kokepunkt. Fordelaktig utelukker man nærvær av karbondioksyd ved anvendelse av en inert gass . The reaction of N-R-aza-alkylenimino-alkylamine with a 1-guanyl-pyrazole takes place in the presence or absence of a diluent, e.g. by heating the mixture to its melting point or by the presence of a solvent to its boiling point. Advantageously, the presence of carbon dioxide is excluded by using an inert gas.
De ovenfor anførte utgangsstoffer er kjent eller kan, i tilfelle de er nye, fremstilles etter i og for seg kjente fremgangs-måter. S-laverealkyl-isotiourinstoffer eller O-laverealkyl-isourinstoffer kan f. eks. fås ved alkylering av tiourinstoffer som inneholder minst et hydrogenatom eller urin-stoffer med laverealkyl-halogenider, slik som metyl- eller etylklorid, -bromid eller -jodid, eller di-laverealkylsulfater, slik som dimetyl- eller dietylsulfat. The starting materials listed above are known or, in the event that they are new, can be produced according to procedures known per se. S-lower alkyl isothioureas or O-lower alkyl isoureas can e.g. obtained by alkylation of thioureas containing at least one hydrogen atom or ureas with lower alkyl halides, such as methyl or ethyl chloride, -bromide or -iodide, or di-lower alkyl sulfates, such as dimethyl or diethyl sulfate.
N-R-aza-alkylenimino-alkylamin-utgangsstoffene med formel II får man f. eks. ved reaksjon av et N-R-aza-alkylen-imin som svarer til den nevnte formel med en reaksjonsdyktig forestret cyan-alkanol, f. eks. et cyan-alkylhalogenid, hvori halo-gen står f. eks. for klor eller brom, eller med et alkenyl-cyanid, hvori dobbeltbindingen er aktivert med cyangruppen. I de erholdte (N-R-aza-alkylenimino-alkyl) - cyanider overføres således cyangruppen ved reaksjon til metylenaminogruppen, f. eks. ved katalytisk hydrering, som behandling med hydrogen, i nærvær av en kata-lysator som inneholder et metall fra den 8. gruppe i det periodiske system, f. eks. pal-ladiumsort eller Raney-nikkel, eller for-troinsvis ved behandling med et dilettme-tallhydrid, slik som litium-, natrium- eller magnesium-aluminiumhydrid, eller med aluminiumhydrid eller aluminiumborhyd-rid, om nødvendig, i nærvær av en akti-vator, slik som aluminiumklorid. The N-R-aza-alkylenimino-alkylamine starting materials with formula II are obtained, e.g. by reaction of an N-R-aza-alkylene-imine corresponding to the aforementioned formula with a reactive esterified cyano-alkanol, e.g. a cyano-alkyl halide, in which halogen stands for e.g. for chlorine or bromine, or with an alkenyl cyanide, in which the double bond is activated with the cyano group. In the obtained (N-R-aza-alkylenimino-alkyl)-cyanides, the cyano group is thus transferred by reaction to the methyleneamino group, e.g. by catalytic hydrogenation, such as treatment with hydrogen, in the presence of a catalyst containing a metal from the 8th group of the periodic table, e.g. palladium black or Raney nickel, or probably by treatment with a dilett metal hydride, such as lithium, sodium or magnesium aluminum hydride, or with aluminum hydride or aluminum borohydride, if necessary, in the presence of an activator , such as aluminum chloride.
Videre kan man også få N-R-aza-alkylenimino-laverealkylaminer ved at man f. eks. omsetter forbindelser med formelen Furthermore, N-R-aza-alkylenimino-lower alkylamines can also be obtained by e.g. react compounds with the formula
hvori 2, R.,, Ra, m, og m., har den ovennevnte betydning og hvert av symbolene X betyr en reaksjonsdyktig forestret hydroksyl-gruppe, eller et salt av dette, med et alky-lendiamin, hvori alkylen har den til å begynne med angitte betydning og, om ønskes, overfører den erholdte fri forbindelse til et salt. De ovennevnte reaksjonsdyktige forestrete hydroksylgrupper er f. eks. halo-genatomer, slik som klor eller brom, eller arylsulfonyloksygrupper, slik som p-toluol-sulfonyloksy. Reaksjonen utføres på i og for seg kjent måte, f. eks. i nærvær av et inert fortynningsmiddel og, som ønskes, et syrebindende middel. Særlig viktige utgangsprodukter fra den nevnte forbindelsesgruppe, nemlig slike med formel wherein 2, R.,, Ra, m, and m., have the above meaning and each of the symbols X means a reactive esterified hydroxyl group, or a salt thereof, with an alkylenediamine, wherein the alkyl has the begin with the indicated meaning and, if desired, transfer the obtained free compound to a salt. The above-mentioned reactive esterified hydroxyl groups are e.g. halogen atoms, such as chlorine or bromine, or arylsulfonyloxy groups, such as p-toluenesulfonyloxy. The reaction is carried out in a manner known per se, e.g. in the presence of an inert diluent and, if desired, an acid scavenger. Particularly important output products from the aforementioned group of compounds, namely those with formula
hvori hvert av symbolene m, og m,. betyr tallene 1 eller 2, og deres salter. wherein each of the symbols m, and m,. means the numbers 1 or 2, and their salts.
I de erholdte (N-R-aza-alkylenimino)-alkyl-guanidiner kan, om ønskes, guani-dinogruppen acyleres på i og for seg kjent måte, f. eks. ved behandling av guanidin-forbindeisen med et reaksjonsdyktig funk-sjonelt derivat av en karbonsyre, f. eks. et halogenid, slik som klorid, eller et anhyd-rid. Herved kan man omsette reaksjons-komponenten i nærvær av inerte fortyn-ningsmidler, f. eks. hydrokarboner, slik som pentan, heksan, benzol, touol eller xylol, eller tertiære organiske baser, f. eks. fly-tende pyridiner, slik som pyridin eller kolli-din, eller i fravær av slike, f. eks. ved opp-hetning med acyleringsmiddelet, f. eks. sddiksyreanhydrid, alene, i åpent eller lukket kar under trykk. In the obtained (N-R-aza-alkylenimino)-alkyl-guanidines, if desired, the guanidino group can be acylated in a manner known per se, e.g. by treating the guanidine compound with a reactive functional derivative of a carboxylic acid, e.g. a halide, such as chloride, or an anhydride. In this way, the reaction component can be reacted in the presence of inert diluents, e.g. hydrocarbons, such as pentane, hexane, benzene, toluene or xylol, or tertiary organic bases, e.g. volatile pyridines, such as pyridine or collidine, or in the absence of such, e.g. by heating with the acylating agent, e.g. acetic anhydride, alone, in an open or closed vessel under pressure.
De nye guanidinforbindelser fås enten som frie forbindelser eller i form av deres salter. Et salt kan på i og for seg kjent måte, f. eks. ved behandling med et sterkt alkalisk middel slik som vandig alkalime-tallhydroksyd, f. eks. litim-, natrium- eller kaliumhydroksyd, eller med sterke anion-utvekslerharpikser, slik som kvaternære ammonium-utvekslingsharpikser, overføres til de frie forbindelser. Av de frie baser kan det fremstilles terapeutisk anvendelige addisjonssalter med egnete f. eks. de til å begynne med nevnte anorganiske eller organiske syrer. Omsetningen med syrer foregår fortrinsvis i egnete fortynnings-midler, f. eks. laverealkanoler, slik som metanol, etanol, n-propanol eller i-propanol, etere, slik som dietyleter eller dioksan, estere, slik som eddiksyreetylester eller blandinger av disse. Herved kan det fås basiske, nøytrale, sure eller blandete salter. The new guanidine compounds are available either as free compounds or in the form of their salts. A salt can in a manner known per se, e.g. by treatment with a strong alkaline agent such as aqueous alkali metal hydroxide, e.g. lithium, sodium or potassium hydroxide, or with strong anion exchange resins, such as quaternary ammonium exchange resins, are transferred to the free compounds. From the free bases, therapeutically applicable addition salts can be prepared with suitable, e.g. the initially mentioned inorganic or organic acids. The reaction with acids takes place preferably in suitable diluents, e.g. lower alkanols, such as methanol, ethanol, n-propanol or i-propanol, ethers, such as diethyl ether or dioxane, esters, such as ethyl acetate or mixtures thereof. In this way, basic, neutral, acidic or mixed salts can be obtained.
De nye guanidinforbindelser eller salter av disse kan også overføres til kvaternære ammoniumforbindelser, f. eks. ved omsetning med reaksjonsdyktige estere av laverealkanoler eller aralkanoler, slik som laverealkyl- eller aralkylhalogenider, f. eks. metyl-, etyl-, n -eller i-propyl- eller benzyl-klorid-, bromid eller -jodid, di-laveralkyl-sulfater, slik som dimetyl- eller dietylsulfat, eller laverealkylestere av alkan- eller arylsulfonsyrer, slik som metan-, etan- eller p-toluolsulfonsyre-metyl- eller -etylester. The new guanidine compounds or salts thereof can also be transferred to quaternary ammonium compounds, e.g. by reaction with reactive esters of lower alkanols or aralkanols, such as lower alkyl or aralkyl halides, e.g. methyl, ethyl, n -or i -propyl or benzyl chloride, bromide or iodide, di-lower alkyl sulphates, such as dimethyl or diethyl sulphate, or lower alkyl esters of alkane or aryl sulphonic acids, such as methane-, ethane or p-toluenesulfonic acid methyl or ethyl ester.
Kvaterniseringen utfører man hen-siktsmessig i nærvær av fortynningsmid-ler, f. eks. i laverealkanoler, slik som metanol, etanol, n-propanol, i-propanol eller tert. butanol, laverealkanoner, slik som aceton eller metyl-etylketon, eller organiske syreamider, slik som formamid eller dimetyl-formamid. The quaternization is expediently carried out in the presence of diluents, e.g. in lower alkanols, such as methanol, ethanol, n-propanol, i-propanol or tert. butanol, lower alkanones, such as acetone or methyl ethyl ketone, or organic acid amides, such as formamide or dimethylformamide.
Erholdte kvaternære ammoniumforbindelser kan man overføre til de tilsvarende ammoniumhydroksyder, f. eks. ved Obtained quaternary ammonium compounds can be transferred to the corresponding ammonium hydroxides, e.g. by
reaksjon av ammoniumsaltene med en reaction of the ammonium salts with a
ioneutveksler, ammoniumhalogenidene med med fuktig sølvoksyd, ammoniumsulfatene ion exchanger, the ammonium halides with moist silver oxide, the ammonium sulphates
med bariumhydroksyd eller ved elektro-dialyse. Fra de erholdte kvaternære ammoniumhydroksyder kan da fremstilles terapeutisk anvendelige ammoniumsalter med de til å begynne med nevnte syrer. with barium hydroxide or by electrodialysis. From the quaternary ammonium hydroxides obtained, therapeutically usable ammonium salts can then be prepared with the initially mentioned acids.
Fortrinsvis anvendes slike utgangsma-terialer som gir de til å begynne med nevnte foretrukne forbindelser. Such starting materials are preferably used which give the initially mentioned preferred compounds.
Oppfinnelsen beskrives nærmere i de følgende eksempler. Temperaturen er angitt i Celsiusgrader. The invention is described in more detail in the following examples. The temperature is indicated in degrees Celsius.
Eksempel 1 Example 1
En blanding av 3 g 2-(4-metyl-piperazino)-etylamin, 2,92 g S-metyl-isotiourinstoff-sulfat og 5 cm<3> vann lar man koke i 4 timer med tilbakeløpskjøler. Etter inndampning krystalliserer man resten fra vandig etanol og får således 2-(4-metyl-piperazino)-etyl-guanidin med formelen A mixture of 3 g of 2-(4-methyl-piperazino)-ethylamine, 2.92 g of S-methyl-isothiourea sulfate and 5 cm<3> of water is allowed to boil for 4 hours with a reflux condenser. After evaporation, the residue is crystallized from aqueous ethanol, thus obtaining 2-(4-methyl-piperazino)-ethyl-guanidine with the formula
som sulfat med smeltepunkt 191—200° C (dekomponering)). as sulfate with melting point 191-200° C (decomposition)).
For fremstilling av andre terapeutisk anvendelige syreaddisjonssalter av 2-(4-metyl-piperazino) -etyl-guanidin oppløser man sulfatet i en minimal vannmengde, lar oppløsningen strømme gjennom en søyle med en sterk kvaternær ammoniumutveks-lerharpiks (hydroksyl-ioner), behandler den erholdte frie base med saltsyre og får hydrokloridet av 2-(4-metyl-piperazino)-etyl-guanidin. For the preparation of other therapeutically useful acid addition salts of 2-(4-methyl-piperazino)-ethyl-guanidine, one dissolves the sulfate in a minimal amount of water, allows the solution to flow through a column with a strong quaternary ammonium exchange resin (hydroxyl ions), treats it obtained free base with hydrochloric acid and obtains the hydrochloride of 2-(4-methyl-piperazino)-ethyl-guanidine.
Utgangspunktet kan fås som følger: En oppløsning av 133 g 1-metyl-piperazin i 100 cm' etanol tildryppes under om-røring 50,4 g kloracetonitril, blandingen holdes 2 timer ved stadig omrøring ved kokning og får stå natten over. Deretter inndamper man under forminsket trykk, tilsetter resten under avkjøling 270 cm" 30 pst.-ig vandig natronlut og ekstraherer med dietyleter. Ekstrakten tørkes over fast natriumhydroksyd, oppløsningsmiddelet avdampes og resten fraksjoneres i vakuum. Man får (4-metyl-piperazino)-acetonitril med kokepunkt v< 120—125° C og smeltepunkt 53—56° C. The starting point can be obtained as follows: A solution of 133 g of 1-methyl-piperazine in 100 cm3 of ethanol is added dropwise with stirring to 50.4 g of chloroacetonitrile, the mixture is kept for 2 hours with constant stirring while boiling and allowed to stand overnight. It is then evaporated under reduced pressure, the residue is added while cooling to 270 cm" of 30% aqueous sodium hydroxide solution and extracted with diethyl ether. The extract is dried over solid sodium hydroxide, the solvent is evaporated and the residue is fractionated in vacuo. You get (4-methyl-piperazino)- acetonitrile with boiling point v< 120-125° C and melting point 53-56° C.
En suspensjon av 19 g litium-aluminiumhydrid i 1000 cm3 vannfri eter tilsettes under omrøring og utvendig kjøling en blanding av 50 g (4-metyl-piperazino)-acetonitril og 400 cm' vannfri eter, reaksjonsblandingen holdes 6 timer med til-bakeløpskjøler med kokning og får stå natten over. Deretter tilsetter man i rekkeføl-ge 17 cm' vann, 20 cm' 20 pst.-ig vandig natronlut og 53 cm' vann, filtrerer, inndamper filtratet og destillerer resten i vakuum. Man får 2-(4-metyl-piperazino)T etylamin med kokepunkt „, 90—92° C. A suspension of 19 g of lithium-aluminum hydride in 1000 cm3 of anhydrous ether is added with stirring and external cooling to a mixture of 50 g of (4-methyl-piperazino)-acetonitrile and 400 cm' of anhydrous ether, the reaction mixture is maintained for 6 hours with a reflux condenser with boiling and let stand overnight. 17 cm' of water, 20 cm' of 20% aqueous sodium hydroxide solution and 53 cm' of water are then added in sequence, filtered, the filtrate evaporated and the residue distilled in vacuum. 2-(4-Methyl-piperazino)T ethylamine with a boiling point of 90-92° C is obtained.
På analog måte kan man fremstille andre 2- (4-lavere-alkyl-piperazino) -etyl-guanidiner og deres salter, fortrinsvis terapeutisk anvendelige mineralsyreaddisj onssalter, slik som sulfater, f. eks. 2-(4-n-propyl-piperazino) -etyl-guanidin, 2- (4-i-propyl-piperazino)-etyl-guanidin, . 2-(4-n-butyl-piperazino) -etyl-guanidin, 2- (4-i-butyl-piperazino) -etyl-guanidin, 2- (4-sek. butyl-piperazino) -etyl-guanidin, 2-(4-tert. butyl-piperazino) -etyl-guanidin, 2- (4-n-pentyl-piperazino) -etyl-guanidin, 2- (4-n-heksyl-piperazino) -etyl-guanidin eller 2-(4-n-heptyl-piperazino)-etyl-guanidin. Other 2-(4-lower-alkyl-piperazino)-ethyl-guanidines and their salts, preferably therapeutically useful mineral acid addition salts, such as sulphates, e.g. 2-(4-n-propyl-piperazino)-ethyl-guanidine, 2-(4-i-propyl-piperazino)-ethyl-guanidine, . 2-(4-n-butyl-piperazino)-ethyl-guanidine, 2-(4-i-butyl-piperazino)-ethyl-guanidine, 2-(4-sec. butyl-piperazino)-ethyl-guanidine, 2- (4-tert.butyl-piperazino)-ethyl-guanidine, 2-(4-n-pentyl-piperazino)-ethyl-guanidine, 2-(4-n-hexyl-piperazino)-ethyl-guanidine or 2-(4 -n-heptyl-piperazino)-ethyl-guanidine.
Eksempel 2 Example 2
En blanding av 3,14 g 2-(4-etyl-piperazino)-etylamin, 2,78 g S-metyl-isotiourinstoff-sulfat og 5 cm<3> vann holder man 4 timer ved kokning, inndamper reaksjonsblandingen under forminsket trykk og krystalliserer det erholdte 2-(4-etyl-piperazino)-etyl-guanidin-sulfat fra en blanding av etanol og dietyleter, smeltepunkt 201— 203° C. Den frie forbindelse har formelen A mixture of 3.14 g of 2-(4-ethyl-piperazino)-ethylamine, 2.78 g of S-methyl-isothiourea sulfate and 5 cm<3> of water is boiled for 4 hours, the reaction mixture is evaporated under reduced pressure and crystallizes the obtained 2-(4-ethyl-piperazino)-ethyl-guanidine-sulphate from a mixture of ethanol and diethyl ether, melting point 201-203° C. The free compound has the formula
For fremstilling av utgangsmaterialet lar man i nærvær av 37,1 g natriumkarbonat 13,2 kloracetonitril innvirke på 13,2 g 1-etyl-piperazin i 150 cm3 toluol. 17 g av det erholdte (4-etyl-piperazino)-acetonitril med kokepunkt,., 117—118° C reduserer man med 6,33 g litium-aluminiumhydrid i dietyleter og får således det ønskede 2-(4-etyl-piperazino)-etylamin med kokepunkt ,:i 97—98° C analogt med .den frem-igangsmåte som er angitt i eksempel 1. To prepare the starting material, in the presence of 37.1 g of sodium carbonate, 13.2 g of chloroacetonitrile is allowed to act on 13.2 g of 1-ethyl-piperazine in 150 cm 3 of toluene. 17 g of the obtained (4-ethyl-piperazino)-acetonitrile with a boiling point of 117-118° C is reduced with 6.33 g of lithium aluminum hydride in diethyl ether, thus obtaining the desired 2-(4-ethyl-piperazino) -ethylamine with a boiling point of 97-98° C analogously to the procedure indicated in example 1.
Eksempel 3 Example 3
En blanding av 3 g 3-(4-metyl-piper-|azino)-propylamin, 2,66 g S-metyl-isotio-! urinstoff-sulfat og 5 cm" vann lar man koke 4 timer med tilbakeløpskjøler, inndamper A mixture of 3 g of 3-(4-methyl-piper-|azino)-propylamine, 2.66 g of S-methyl-isothio-! urea sulfate and 5 cm" of water is allowed to boil for 4 hours with a reflux condenser, evaporates
reaksjonsblandingen under forminsket trykk og krystalliserer det erholdte 3-(4-metyl-piperazino) -propyl-guanidinsul- the reaction mixture under reduced pressure and crystallizes the obtained 3-(4-methyl-piperazino)-propyl-guanidine sul-
fat fra vandig etanol, smeltepunkt 99— 100° C. Den frie forbindelse har formelen barrel from aqueous ethanol, melting point 99— 100° C. The free compound has the formula
Utgangsmaterialet får man ved reaksjon av 1-metyl-piperazin med akrylnitril i nærvær av benzyl-trimetyl-ammonium-hydroksyd og følgende reduksjon av det erholdte 0- (4-metyl-piperazino) -propioni-tril med litium-aluminiumhydrid, hvorved det ønskede 3-(4-metyl-piperazino) -pro-pylamin oppstår. The starting material is obtained by reaction of 1-methyl-piperazine with acrylonitrile in the presence of benzyl-trimethyl-ammonium-hydroxide and subsequent reduction of the obtained 0-(4-methyl-piperazino)-propionitrile with lithium-aluminum hydride, whereby the desired 3-(4-methyl-piperazino)-propylamine occurs.
Eksempel 4 Example 4
En blanding av 2,34 g 2-(4-metyl-piperazino)-etyl-guanidin-sulf at og 10 crrv'1 metanol tilsettes 3 cm' vandig 8-N. saltsyre og blandingen opvarmes inntil alt er opp-løst. Det bunnfall som utfelles ved avkjø-ling fraf Utreres og tørkes ved 50—55° C og 20 mm trykk. Det er 2-(4-metyl-piperazino)-etyl-guanidin-dihydroklorid-sul-fathydrat, med smeltepunkt 198,8—200° C. A mixture of 2.34 g of 2-(4-methyl-piperazino)-ethyl-guanidine-sulphate and 10 ml of methanol is added to 3 cm' of aqueous 8-N. hydrochloric acid and the mixture is heated until everything is dissolved. The precipitate that precipitates on cooling from is evaporated and dried at 50-55° C and 20 mm pressure. It is 2-(4-methyl-piperazino)-ethyl-guanidine-dihydrochloride-sulphate hydrate, with a melting point of 198.8-200°C.
Eksempel 5 Example 5
En blanding av 2,05 g 2-(4-fenyl-piperazino)-etylamin, 1,39 g S-metyl-isotiourinstoff-sulfat og 5 cm<3> vann lar man ko-ke i 4 timer med tilbakeløpskjøler, frafil-trerer det bunnfall som er utfelt etter av-kjøling og krystalliserer det fra vann. Man får således 2-(4-fenyl-piperazino)-etyl-guanidin med formelen A mixture of 2.05 g of 2-(4-phenyl-piperazino)-ethylamine, 1.39 g of S-methyl-isothiourea sulfate and 5 cm<3> of water is allowed to boil for 4 hours with a reflux condenser, precipitates the precipitate that has precipitated after cooling and crystallizes it from water. One thus obtains 2-(4-phenyl-piperazino)-ethyl-guanidine with the formula
som sulfat, som smelter under dekomponering ved 256—258° C. as sulphate, which melts during decomposition at 256-258° C.
Eksempel 6 Example 6
En blanding av 3 g 2-(4-p-metyl-fenyl-piperazino)-etylamin, 2,1 g S-etyl-isotiourinstoff-sulfat og vann gir etter kokning med tilbakeløpskjøler og inndampning av reaksjonsblandingen 2- (4-p-metylfenyl-piperazino)-etyl-guanidin med formelen A mixture of 3 g of 2-(4-p-methyl-phenyl-piperazino)-ethylamine, 2.1 g of S-ethyl-isothiourea sulfate and water gives after boiling with a reflux condenser and evaporation of the reaction mixture 2-(4-p- methylphenyl-piperazino)-ethyl-guanidine with the formula
i form av sulfatet. in the form of the sulfate.
Eksempel 7 Example 7
En blanding av 3 g 2-[4-(3,4-diklor-fenyl)-piperazino]-etylamin, 1,52 g S- metyl-isotiourinstoff-sulfat og vann gir etter kokning med tilbakeløpskjøler og inndampning av reaksj onsblandingen 2-[4-(3,4-diklorf enyl) -piperazino] -etyl-guanidin med formelen A mixture of 3 g of 2-[4-(3,4-dichloro-phenyl)-piperazino]-ethylamine, 1.52 g of S-methyl isothiourea sulfate and water gives, after boiling with a reflux condenser and evaporation of the reaction mixture 2- [4-(3,4-dichlorophenyl)-piperazino]-ethyl-guanidine of the formula
som sulfat. as sulfate.
Utgangsmaterialet kan fås som beskre-vet i eksempel 1 av l-(3,4-diklorfenyl)-piperazin og kloracetonitril og etterfølgende reduksjon av det erholdte nitril med liti-umaluminiumhydrid. The starting material can be obtained as described in example 1 from 1-(3,4-dichlorophenyl)-piperazine and chloroacetonitrile and subsequent reduction of the obtained nitrile with lithium aluminum hydride.
Eksempel 8 Example 8
En blanding av 3g 2-(5-metyl-5-aza-heptylen-imino)-etylamin, 2,44 g S-metyl-isotiourinstoff-sulfat og 5 cm" vann lar man koke i 4 timer med tilbakeløpskjøler og inndamper deretter ved forminsket trykk. Man får 2-(5-metyl-5-aza-heptyl-enimino) -etyl-guanidin med formelen A mixture of 3 g of 2-(5-methyl-5-aza-heptylene-imino)-ethylamine, 2.44 g of S-methyl-isothiourea sulfate and 5 cm" of water is boiled for 4 hours with a reflux condenser and then evaporated at reduced pressure 2-(5-methyl-5-aza-heptyl-enimino)-ethyl-guanidine is obtained with the formula
hvis sulfat etter omkrysstallisasjon fra metanol-dietyleter smelter ved 198—215° C. whose sulfate, after cross-crystallization from methanol-diethyl ether, melts at 198-215° C.
Utgangsmaterialet kan fås som følger: En blanding av 10,01 g 1,2-trimetylen-pyrazolidin og 200 cm' vannfri aceton tilsettes under iskjøling 15 cm' metylbromid, lar stå noen timer ved romtemperatur og kjøler reaksj onsblandingen deretter til The starting material can be obtained as follows: A mixture of 10.01 g of 1,2-trimethylene-pyrazolidine and 200 cm' of anhydrous acetone is added under ice-cooling to 15 cm' of methyl bromide, allowed to stand for a few hours at room temperature and then cools the reaction mixture to
-12° C. Det utf elte krystallinske bunnfall filtreres hurtig fra, vaskes med en liten mengde tørr aceton og får etter tørkning det hygroskopiske l-metyl-l,2-trimetylen-pyrazolidinium-bromid med smeltepunkt 264—267° C. Den nevnte kvaternære am-moniumforbindelse setter man til alumi-niumamalgam (fremstilt av 4 g aluminium-spon) i 80 cm" eter, tilsetter porsjonsvis i alt 10 cm' vann under iskjøling og lar reaksj onsblandingen stå natten over ved 0° C. Deretter tilsetter man overskudd av kaliumhydroksyd .ekstraherer med eter og -12° C. The precipitated crystalline precipitate is quickly filtered off, washed with a small amount of dry acetone and, after drying, gives the hygroscopic 1-methyl-1,2-trimethylene-pyrazolidinium bromide with a melting point of 264-267° C. The aforementioned quaternary ammonium compound is added to aluminum amalgam (made from 4 g of aluminum shavings) in 80 cm" of ether, a total of 10 cm" of water is added in portions under ice-cooling and the reaction mixture is allowed to stand overnight at 0° C. Then one adds excess of potassium hydroxide .extract with ether and
får etter avdampning av oppøsnings-middelet 5-metyl-5-aza-heptylenimin. obtained after evaporation of the emulsifying agent 5-methyl-5-aza-heptylenimine.
En blanding av 8,5 g av det rå 5-metyl 5-aza-heptylenimin og 160 cm3 toluol settes under omrøring til en blanding av 5,02 g acetonitril 50 cm' toluol og 15 g natriumkarbonat, reaksj onsblanding holdes i 6 timer ved kokning, filtreres varmt og filtratet inndampes til lite volum. Resten gir etter vakuumdestillasjon (5-metyl-5-aza-heptylenimino)-acetonitril med kokepunkt 0i4 83—85° C. A mixture of 8.5 g of the crude 5-methyl 5-aza-heptylenimine and 160 cm3 of toluene is added with stirring to a mixture of 5.02 g of acetonitrile 50 cm' of toluene and 15 g of sodium carbonate, the reaction mixture is kept for 6 hours at boiling, filtered hot and the filtrate evaporated to a small volume. The residue gives after vacuum distillation (5-methyl-5-aza-heptylenimino)-acetonitrile with boiling point 0i4 83-85° C.
Blandingen av 5,44 g av det erholdte nitril og 30 cm" dietyleter setter man under omrøring til en suspensjon av 2 g litium-aluminiumhydrid i 100 cm<3> eter, lar reaksj onsblandingen koke i 6 timer med til-bakeløpskjøler og rører videre natten over. Reaksj onsblandingen tilsettes deretter i rekkefølge 2 cm<3> vann, 2,6 cm<3> 20 pst.-ig vandig natronlut og 7 cm" vann, filtrerer, inndamper under forminsket trykk og destillerer. Derved går det ønskede 2-(5-metyl-5-aza-heptylenimino) -etylamin over ved 112—117° C og 13 mm Hg. The mixture of 5.44 g of the nitrile obtained and 30 cm" of diethyl ether is added with stirring to a suspension of 2 g of lithium aluminum hydride in 100 cm<3> of ether, the reaction mixture is allowed to boil for 6 hours with a reflux condenser and further stirring overnight. The reaction mixture is then added in order to 2 cm<3> of water, 2.6 cm<3> of 20% aqueous sodium hydroxide solution and 7 cm" of water, filtered, evaporated under reduced pressure and distilled. Thereby the desired 2-(5-methyl-5-aza-heptyleniimino)-ethylamine is converted at 112-117° C and 13 mm Hg.
Eksempel 9 Example 9
En blanding av 1,46 g benzoyl-cyanamid og 1,5 g 2-(4-metyl-piperazino)-etylamin tilsettes en liten mengde konsentrert vandig saltsyre, man oppvarmer blandingen på vannbad 10—15 min., avkjøler den og fortynner med etanol. Ved tilsetning av dietyleter faller 1-[2-(4-metyl-piperazino) A mixture of 1.46 g of benzoyl-cyanamide and 1.5 g of 2-(4-methyl-piperazino)-ethylamine is added to a small amount of concentrated aqueous hydrochloric acid, the mixture is heated on a water bath for 10-15 min., cooled and diluted with ethanol. On addition of diethyl ether, 1-[2-(4-methyl-piperazino)
-etyl]-3-benzoyl-guanidin med formelen -ethyl]-3-benzoyl-guanidine with the formula
ut som hydroklorid. Det viser i kloroform et IR-absorbsjonsbånd på 1678 cm-<1>. out as hydrochloride. It shows in chloroform an IR absorption band at 1678 cm-<1>.
Eksempel 10 Example 10
En blanding av 2,3 g 2-(4-metyl-piperazino)-etyl-guanidin-hydroklorid og 1 g propionylklorid oppvarmer man noen timer i et lukket rør til 100° C. Etter av-kjøling oppløser man reaksj onsblandingen i etanol og utfeller ved tilsetning av dietyleter det dannede l-propionyl-3-[2-(4-metyl-piperazino) -etyl]-guanidin med formelen A mixture of 2.3 g of 2-(4-methyl-piperazino)-ethyl-guanidine hydrochloride and 1 g of propionyl chloride is heated for a few hours in a closed tube to 100° C. After cooling, the reaction mixture is dissolved in ethanol and precipitates on addition of diethyl ether the formed l-propionyl-3-[2-(4-methyl-piperazino)-ethyl]-guanidine with the formula
som hydroklorid. as hydrochloride.
Eksempel 11 Example 11
En blanding av 2,01 g l-guanyl-3,5-dimetyl-pyrazolnitrat og 14,3 g 2-(4-metyl-piperazino)-etylamin oppvarmer man 2l/ 2 time under omrøring, destillerer deretter overskudd av amin fra under forminsket trykk og oppløser resten i vann. For overføring av basen i 2-(4-metyl-piperazino)-etyl-guanidin-sulfat lar man den erholdte vandige oppløsning løpe gjennom en utvekslersøyle med en sterk anion- A mixture of 2.01 g of 1-guanyl-3,5-dimethyl-pyrazole nitrate and 14.3 g of 2-(4-methyl-piperazino)-ethylamine is heated for 2 l/2 hours with stirring, then the excess of amine is distilled from under reduced pressure and dissolves the remainder in water. For transfer of the base in 2-(4-methyl-piperazino)-ethyl-guanidine-sulfate, the obtained aqueous solution is allowed to run through an exchange column with a strong anion-
(sulfat)-utvekslerharpiks, f. eks. den ifølge det amerikanske patent nr. 2 591 573, inndamper oppløsningen under forminsket trykk og krystalliserer resten fra vandig etanol. Det erholdte 2-( 4-metyl-piperazino)-etyl-guanidin-sulfat er identisk med det produkt som fås ifølge eksmpel 1. (sulphate) exchange resin, e.g. that of U.S. Patent No. 2,591,573, evaporates the solution under reduced pressure and crystallizes the residue from aqueous ethanol. The obtained 2-(4-methyl-piperazino)-ethyl-guanidine-sulphate is identical to the product obtained according to example 1.
Eksempel 12 Example 12
En blanding av 12,6 g 2-(4-metyl-piperazino)-etylamin-trihydroklorid, 3,15 g cyanamid og 100 cm" etanol lar man koke med tilbakeløpskjøler i 6 timer, avdamper oppløsningsmiddelet under forminsket trykk og kan overføre den erholdte forbindelse som angitt i foregående eksempel, med en utvekslingsharpiks til 2-(4-metyl-piperazino)-etyl-guanidin-sulfat. A mixture of 12.6 g of 2-(4-methyl-piperazino)-ethylamine trihydrochloride, 3.15 g of cyanamide and 100 cm" of ethanol is allowed to boil with a reflux condenser for 6 hours, the solvent is evaporated under reduced pressure and the obtained compound as indicated in the previous example, with an exchange resin to 2-(4-methyl-piperazino)-ethyl-guanidine-sulfate.
Eksempel 13 Example 13
En blanding av 2,45 g 2-(4-p-klorfenyl-piperazino)-etylamin, 1,42 g S-metyl-isotiourinstoff-sulfat og vandig etanol oppvarmer man i 4 timer til kokning, lar av-kjøle, f raf Utrerer bunnfallet og krystalliserer 2- (4-p-klorf enyl-piperazino) -etyl-guanidin med formelen A mixture of 2.45 g of 2-(4-p-chlorophenyl-piperazino)-ethylamine, 1.42 g of S-methylisothiourea sulfate and aqueous ethanol is heated to boiling for 4 hours, allowed to cool, from Evaporate the precipitate and crystallize 2-(4-p-chlorophenyl-piperazino)-ethyl-guanidine with the formula
som foreligger som sulfat, fra vandig eta- which exists as sulfate, from aqueous eta-
nol med smeltepunkt 250—265° C (dekomponering). nol with melting point 250-265° C (decomposition).
Utgangsproduktet kan man få som The output product can be obtained as
følger: following:
En blanding av 10,6 g kloracetonitril, A mixture of 10.6 g of chloroacetonitrile,
300 cm' toluol og 30 g vannfritt natrium- 300 cm' of toluene and 30 g of anhydrous sodium
karbonat tilsettes under omrøring en opp- carbonate is added while stirring a
løsning av 27,5 g 1-p-klorfenyl-piperazin i 400 cm' toluol, lar reaksj onsblandingen koke natten over, filtrerer, inndamper under forminsket trykk og krystalliserer det erholdte (4-p-klorfenyl-piperazino) - solution of 27.5 g of 1-p-chlorophenyl-piperazine in 400 cm' of toluene, allows the reaction mixture to boil overnight, filters, evaporates under reduced pressure and crystallizes the obtained (4-p-chlorophenyl-piperazino) -
acetonitril fra n-heptan, smeltepunkt 120— acetonitrile from n-heptane, melting point 120—
125° C. 10 g av det erholdte nitril oppløst i 1000 cm' dietyler tilsettes langsomt under omrøring og avkjøling til en blanding av 2,25 g litium-aluminiumhydrid og 500 cm' dietyleeter, lar reaksj onsblandingen koke natten over og stå ennå 2y2 dag. Deretter tilsetter man i rekkefølge 2,25 cm' vann, 125° C. 10 g of the obtained nitrile dissolved in 1000 cm' of diethyl ether are added slowly with stirring and cooling to a mixture of 2.25 g of lithium aluminum hydride and 500 cm' of diethyl ether, the reaction mixture is allowed to boil overnight and stand for a further 2y2 days . Then 2.25 cm' of water is added in sequence,
3 cm' 20 pst.-ig vandig natronlut og 18 cm' 3 cm' 20% aqueous sodium lye and 18 cm'
vann, filtrerer, inndamper under formins- water, filters, evaporates under reduced
ket trykk og destillerer. Det dannede 2-(4-p-klorfenyl-piperazino)-etylamin går over ved 152—158° C og 0,3 mm, og det størkner etter noen tid. ket presses and distills. The 2-(4-p-chlorophenyl-piperazino)-ethylamine formed converts at 152-158° C. and 0.3 mm, and it solidifies after some time.
Eksempel 14 Example 14
En blanding av 4 g 2-(4-metyl-2,6-cis-dimetyl-piperazino)-etylamin, 3,25 g S-metyl-isotiourinstoff-sulfat og 5 cm" vann oppvarmer man i 4 timer til kokning og inndamper reaksj onsblandingen under for- A mixture of 4 g of 2-(4-methyl-2,6-cis-dimethyl-piperazino)-ethylamine, 3.25 g of S-methyl-isothiourea sulfate and 5 cm" of water is heated to boiling for 4 hours and evaporated the reaction mixture under
minsket trykk. Man får 2-(4-metyl-2,6-cis-dimetyl-piperazino) -etyl-guanidin med formelen reduced pressure. 2-(4-methyl-2,6-cis-dimethyl-piperazino)-ethyl-guanidine is obtained with the formula
som sulfat, som etter omkrystallisasjon fra etanol-dietyleter smelter ved 225—231° C as sulfate, which after recrystallization from ethanol-diethyl ether melts at 225-231° C
under dekomponering. during decomposition.
Utgangsproduktet fremstiller man som The starting product is produced as
følger: following:
En blanding av 85,5 g 2,6-cis-dimetyl- A mixture of 85.5 g of 2,6-cis-dimethyl-
piperazin og 40 g maursyremetylester opp- piperazine and 40 g formic acid methyl ester up-
varmer man i 5 timer til 85° C, inndamper reaksj onsblandingen under forminsket heating for 5 hours to 85° C, the reaction mixture is evaporated under reduced pressure
trykk og destillerer det erholdte 1-formyl-3,5-cis-dimetyl-piperazin, kokepunkt 0 s 112—115° C. pressure and distills the 1-formyl-3,5-cis-dimethyl-piperazine obtained, boiling point 0 s 112-115° C.
En blanding av 5,7 g litium-aluminiumhydrid og 400 cm" dietyleter tilsetter man 14 g av det i 50 cm" dietyleter opp- A mixture of 5.7 g of lithium aluminum hydride and 400 cm" of diethyl ether is added to 14 g of it in 50 cm" of diethyl ether
løste 1-formyl-piperazin under omrøring og isavkjøling, rører ennå 2 timer videre og spalter overskudd av reduksjonsmiddel ved tilsetning av 10 cm' vann, 5 cm" 20 pst.-ig vandig natronlut og 15 cm" vann. Den fra- dissolved 1-formyl-piperazine while stirring and ice-cooling, stirs for a further 2 hours and splits the excess of reducing agent by adding 10 cm' of water, 5 cm' of 20 per cent aqueous sodium hydroxide solution and 15 cm' of water. The from-
skilte organiske fase inndamper man vidt- separate organic phases are evaporated widely
gående og destillerer det dannede 1-metyl-3,5-cis-dimetyl-piperazin i vakuum, koke- walking and distills the 1-methyl-3,5-cis-dimethyl-piperazine formed in a vacuum, boil-
punkt „ r< 114—160° C. Dette overfører man, point „ r< 114—160° C. This is transferred,
slik som det ble vist i de foregående eksem- as was shown in the preceding examples
pler, til (4-metyl-2,6-cis-dimetyl-piperazino)-acetonitril med kokepunkt ,:, 125— pler, to (4-methyl-2,6-cis-dimethyl-piperazino)-acetonitrile with boiling point ,:, 125—
126° C, som ved reduksjon kan overføres til det ønskede 2-(4-metyl-2,6-cis-dimetyl-piperazino)-etylamin med kokepunkt 126° C, which by reduction can be transferred to the desired 2-(4-methyl-2,6-cis-dimethyl-piperazino)-ethylamine with boiling point
102—103° C. 102-103°C.
Eksempel 15 Example 15
En blanding av 5 g 2-(4-metyl-4-aza-heksylenimino)-etylamin, 4,42 g S-metyl-isotiourinstoff-sulfat og 5 cm" vann lar man koke i 4 timer og avdamper vannet under forminsket trykk. Man får 2-(4-metyl-4-aza-heksylen-imino) -etyl-gua- A mixture of 5 g of 2-(4-methyl-4-aza-hexyleneimino)-ethylamine, 4.42 g of S-methyl-isothiourea sulfate and 5 cm" of water is allowed to boil for 4 hours and the water is evaporated under reduced pressure. 2-(4-methyl-4-aza-hexylene-imino)-ethyl-gua-
nidin med formelen nidin with the formula
som sulfat, som etter omkrystallisasjon fra vandig etanol smelter ved 137—140° C. Utgangsmaterialet får man ved reak- as sulfate, which after recrystallization from aqueous ethanol melts at 137-140° C. The starting material is obtained by reacting
sjon av 18 g l-metyl-l,4-diaza-cykloheptan med 11,91 g kloracetonitril i nærvær av 33 g vannfritt natriumkarbonat og derpå reaction of 18 g of 1-methyl-1,4-diaza-cycloheptane with 11.91 g of chloroacetonitrile in the presence of 33 g of anhydrous sodium carbonate and then
følgende reduksjon av 8,6 g av det erholdte nitril med kokepunkt „., 68—72 g litium-aluminiumhydrid. Det ønskede 2-(4-metyl-4-aza-heksylenimino)-etylamin koker ved 104° C og 13 mm Hg. following reduction of 8.6 g of the obtained nitrile with boiling point „., 68-72 g of lithium aluminum hydride. The desired 2-(4-methyl-4-aza-hexyleneimino)-ethylamine boils at 104°C and 13 mm Hg.
Claims (2)
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