NO744528L - - Google Patents
Info
- Publication number
- NO744528L NO744528L NO744528A NO744528A NO744528L NO 744528 L NO744528 L NO 744528L NO 744528 A NO744528 A NO 744528A NO 744528 A NO744528 A NO 744528A NO 744528 L NO744528 L NO 744528L
- Authority
- NO
- Norway
- Prior art keywords
- general formula
- atoms
- alkyl
- compound
- amino
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 71
- 239000002253 acid Substances 0.000 claims description 29
- -1 cycloalkeny 1 Chemical group 0.000 claims description 25
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 15
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- JZEHWMUIAKALDN-UHFFFAOYSA-N 1-amino-3-phenoxypropan-2-ol Chemical compound NCC(O)COC1=CC=CC=C1 JZEHWMUIAKALDN-UHFFFAOYSA-N 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 5
- 239000007859 condensation product Substances 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000005336 allyloxy group Chemical group 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Chemical group 0.000 claims description 2
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 claims 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- 238000002844 melting Methods 0.000 description 12
- 230000008018 melting Effects 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 8
- 239000002270 dispersing agent Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 229940072033 potash Drugs 0.000 description 7
- 235000015320 potassium carbonate Nutrition 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- YRXCWZJYLNOUEH-UHFFFAOYSA-N 1-(2,4-dimethylpyrimidin-5-yl)butane-1,3-dione Chemical compound CC(=O)CC(=O)C1=CN=C(C)N=C1C YRXCWZJYLNOUEH-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 150000001298 alcohols Chemical class 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 6
- 239000011230 binding agent Substances 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 5
- VXKWVOPELVBBFB-UHFFFAOYSA-N 1-amino-3-(2-ethoxyphenoxy)propan-2-ol Chemical compound CCOC1=CC=CC=C1OCC(O)CN VXKWVOPELVBBFB-UHFFFAOYSA-N 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 235000011054 acetic acid Nutrition 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 229940039009 isoproterenol Drugs 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 229940095064 tartrate Drugs 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-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
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 229960001413 acetanilide Drugs 0.000 description 3
- 150000001408 amides Chemical group 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 239000007795 chemical reaction product Substances 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
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 150000008282 halocarbons Chemical class 0.000 description 3
- 150000004678 hydrides Chemical class 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 230000010412 perfusion Effects 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000002798 polar solvent Substances 0.000 description 3
- NVIFVTYDZMXWGX-UHFFFAOYSA-N sodium metaborate Chemical compound [Na+].[O-]B=O NVIFVTYDZMXWGX-UHFFFAOYSA-N 0.000 description 3
- 150000003462 sulfoxides Chemical class 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- FFWYZFMTHFTYAE-UHFFFAOYSA-N 1-amino-3-(4-pentoxyphenoxy)propan-2-ol Chemical compound CCCCCOC1=CC=C(OCC(O)CN)C=C1 FFWYZFMTHFTYAE-UHFFFAOYSA-N 0.000 description 2
- KZRSOMVVDMLULM-UHFFFAOYSA-N 3-amino-1-(2,4-dimethylpyrimidin-5-yl)butan-1-ol Chemical compound CC(N)CC(O)C1=CN=C(C)N=C1C KZRSOMVVDMLULM-UHFFFAOYSA-N 0.000 description 2
- UIVXJHXNHAYRKW-UHFFFAOYSA-N 3-chloro-1-(2,4-dimethylpyrimidin-5-yl)butan-1-ol;hydrochloride Chemical compound Cl.CC(Cl)CC(O)C1=CN=C(C)N=C1C UIVXJHXNHAYRKW-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
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 239000001358 L(+)-tartaric acid Substances 0.000 description 2
- 235000011002 L(+)-tartaric acid Nutrition 0.000 description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000000150 Sympathomimetic Substances 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000001816 cooling Methods 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
- GKIPXFAANLTWBM-UHFFFAOYSA-N epibromohydrin Chemical compound BrCC1CO1 GKIPXFAANLTWBM-UHFFFAOYSA-N 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N methyl acetate Chemical compound COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 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
- FMCAFXHLMUOIGG-JTJHWIPRSA-N (2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-formamido-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,5-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoic acid Chemical class O=CN[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(=O)N[C@@H](CCSC)C(O)=O)CC1=CC(C)=C(O)C=C1C FMCAFXHLMUOIGG-JTJHWIPRSA-N 0.000 description 1
- FMCAFXHLMUOIGG-IWFBPKFRSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-formamido-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,5-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound O=CN[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(O)=O)CC1=CC(C)=C(O)C=C1C FMCAFXHLMUOIGG-IWFBPKFRSA-N 0.000 description 1
- KZBHCFFMEPZAOJ-UHFFFAOYSA-N 1-(2,4-dimethylpyrimidin-5-yl)butan-1-ol Chemical compound CCCC(O)C1=CN=C(C)N=C1C KZBHCFFMEPZAOJ-UHFFFAOYSA-N 0.000 description 1
- ULFYOIKCNJOCFW-UHFFFAOYSA-N 1-(2,4-dimethylpyrimidin-5-yl)ethanone Chemical compound CC(=O)C1=CN=C(C)N=C1C ULFYOIKCNJOCFW-UHFFFAOYSA-N 0.000 description 1
- CNUPARSCSGAXPV-UHFFFAOYSA-N 1-amino-3-(2-fluorophenoxy)propan-2-ol Chemical compound NCC(O)COC1=CC=CC=C1F CNUPARSCSGAXPV-UHFFFAOYSA-N 0.000 description 1
- QFTYGVICBOHFQU-UHFFFAOYSA-N 1-amino-3-(4-butoxyphenoxy)propan-2-ol Chemical compound CCCCOC1=CC=C(OCC(O)CN)C=C1 QFTYGVICBOHFQU-UHFFFAOYSA-N 0.000 description 1
- VGONYGOUUQLEOY-UHFFFAOYSA-N 1-amino-3-(4-propoxyphenoxy)propan-2-ol Chemical compound CCCOC1=CC=C(OCC(O)CN)C=C1 VGONYGOUUQLEOY-UHFFFAOYSA-N 0.000 description 1
- LPNCSYWIVAILJB-UHFFFAOYSA-N 1-amino-3-(4-tert-butylphenoxy)propan-2-ol Chemical compound CC(C)(C)C1=CC=C(OCC(O)CN)C=C1 LPNCSYWIVAILJB-UHFFFAOYSA-N 0.000 description 1
- FVGVJINLWROTSD-UHFFFAOYSA-N 2,2-dimethyl-1-pyrimidin-2-ylbutane-1,3-dione Chemical compound CC(=O)C(C)(C)C(=O)C1=NC=CC=N1 FVGVJINLWROTSD-UHFFFAOYSA-N 0.000 description 1
- KIUJKZRJNYJQBJ-UHFFFAOYSA-N 2,4-dimethylpyrimidine Chemical compound CC1=C[C]=NC(C)=N1 KIUJKZRJNYJQBJ-UHFFFAOYSA-N 0.000 description 1
- ZGBJAUZQXAADQJ-UHFFFAOYSA-N 2-[(2-fluorophenoxy)methyl]oxirane Chemical compound FC1=CC=CC=C1OCC1OC1 ZGBJAUZQXAADQJ-UHFFFAOYSA-N 0.000 description 1
- FYNKQLMVSLAGNL-UHFFFAOYSA-N 2-[(4-octoxyphenoxy)methyl]oxirane Chemical compound C1=CC(OCCCCCCCC)=CC=C1OCC1OC1 FYNKQLMVSLAGNL-UHFFFAOYSA-N 0.000 description 1
- XQMHRUBVACETAX-UHFFFAOYSA-N 2-[(4-pentoxyphenoxy)methyl]oxirane Chemical compound C1=CC(OCCCCC)=CC=C1OCC1OC1 XQMHRUBVACETAX-UHFFFAOYSA-N 0.000 description 1
- BYDXZYUGDXYSJY-UHFFFAOYSA-N 2-[(4-phenylmethoxyphenoxy)methyl]oxirane Chemical compound C1OC1COC(C=C1)=CC=C1OCC1=CC=CC=C1 BYDXZYUGDXYSJY-UHFFFAOYSA-N 0.000 description 1
- GUZXNTWZQHTMJJ-UHFFFAOYSA-N 2-[(4-propoxyphenoxy)methyl]oxirane Chemical compound C1=CC(OCCC)=CC=C1OCC1OC1 GUZXNTWZQHTMJJ-UHFFFAOYSA-N 0.000 description 1
- JCLFHZLOKITRCE-UHFFFAOYSA-N 4-pentoxyphenol Chemical compound CCCCCOC1=CC=C(O)C=C1 JCLFHZLOKITRCE-UHFFFAOYSA-N 0.000 description 1
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- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
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- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 description 1
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- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
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- NGPGDYLVALNKEG-UHFFFAOYSA-N azanium;azane;2,3,4-trihydroxy-4-oxobutanoate Chemical compound [NH4+].[NH4+].[O-]C(=O)C(O)C(O)C([O-])=O NGPGDYLVALNKEG-UHFFFAOYSA-N 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
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- 230000036772 blood pressure Effects 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002915 carbonyl group Chemical class [*:2]C([*:1])=O 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical compound [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 description 1
- 229960002155 chlorothiazide Drugs 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
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- 239000012230 colorless oil Substances 0.000 description 1
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- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
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- 238000001035 drying Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002168 ethanoic acid esters Chemical class 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960001317 isoprenaline Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 229960004815 meprobamate Drugs 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000007479 molecular analysis Methods 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-Butanol Substances CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- XTEGVFVZDVNBPF-UHFFFAOYSA-L naphthalene-1,5-disulfonate(2-) Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1S([O-])(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-L 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- HVFSJXUIRWUHRG-UHFFFAOYSA-N oic acid Natural products C1CC2C3CC=C4CC(OC5C(C(O)C(O)C(CO)O5)O)CC(O)C4(C)C3CCC2(C)C1C(C)C(O)CC(C)=C(C)C(=O)OC1OC(COC(C)=O)C(O)C(O)C1OC(C(C1O)O)OC(COC(C)=O)C1OC1OC(CO)C(O)C(O)C1O HVFSJXUIRWUHRG-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 150000002917 oxazolidines Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- DURULFYMVIFBIR-UHFFFAOYSA-N practolol Chemical compound CC(C)NCC(O)COC1=CC=C(NC(C)=O)C=C1 DURULFYMVIFBIR-UHFFFAOYSA-N 0.000 description 1
- 229960001749 practolol Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229940080360 rauwolfia alkaloid Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 229940127230 sympathomimetic drug Drugs 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 235000015961 tonic Nutrition 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 229960000716 tonics Drugs 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Fremgangsmåte til fremstilling avMethod for the production of
nye derivater av 1-fenoksy-3-amino-propan-2-ol. new derivatives of 1-phenoxy-3-amino-propan-2-ol.
Oppfinnelsen vedrører fremgangsmåter til fremstillingThe invention relates to methods for production
av nye farmakologisk verdifulle derivater av 1-fenoksy-3-amino-propan-2- ol med den generelle'formel I'of new pharmacologically valuable derivatives of 1-phenoxy-3-amino-propan-2-ol with the general 'formula I'
og fenylkjernen I også kan være substituert, en, to elle*1 tre ganger, spesielt med alkyl, alkenyl, alkinyl, cykloalkyl, cykloalkeny1, aikoksy, alkenyloksy, alkinyloksy, benzyloksy, fenyl, halogen eller resten -NR-^F^, idet R^, betyr alkyl eller acyl og betyr hydrogen eller, alkyl, samt deres aldehyd-kondensasjonsprodukter og syreaddisjonssalter. Substituentene av fenylkjernen I kan være, like eller forskjellige. •Forbindelser hvor X betyr ; foretrekkes. ;Innen rammen av oppfinnelsen forstås med forbindelser med den generelle formel I også mulige stereoisomere og optisk aktive^ forbindelser og blandinger herav, spesielt racematet. ;Substituentene■av fenylkjernen I har spesielt følgende betydning: Alkyl med 1 til 4 C-atomer, f.eks. metyl, etyl, propyl, tert.-butyl, ;alkenyl med inntil 6 C-atomer, fortrinnsvis vinyl,, allyl, metally1, krotyl, ;alkinyl med inntil 6■C-atomer, f.eks. progargyl, ;cykloalkyl med en ringstørrelse fra 5 til 8 C-atomer, fortrinnsvis cyklopentyl og cykloheksyl, ;cykloalkeny1 méd en ringstørrelse fra 5 til 8 C-atomer, fortrinnsvis cyklopent.enyl, ;aikoksy med inntil 8 C-atomer, alkenyloksy dg alkinyloksy med hver gang inntil 5 C-atomer, fortrinnsvis me.toksy, etoksy, ;n- og i-propoksy, butoksy, n-pentyloksy, n-oktyloksy, allyloksy, metallyloksy, propargyloksy, benzyloksy. ;Halogen: fortrinnsvis fluor, klor eller brom. ;Alkylrester for R^. og har fortrinnsvis 1 til 2 C-atomer. ;Med acylresten for R^ forstås den fra en aromatisk;eller alifatisk karboksylsyre avledende aryl- eller alkylsubstituert karbonylrest med inntil 11 C-atomer, f.eks. formyl, acetyl, propionyl, ;butyryljbenzoyl, naftoyl, fenylacetyl, fortrinnsvis imidlertid acetyl eller benzoyl. ;Aldehydkondensasjonene av forbindelsene med' den generelle formel I er oksazolidiner med formel II ; . som dannes ved kondensasjon av forbindelser med den generelle formel I med et aldehyd med formel ; hvori R-j betyr, hydrogen eller en lavere alkylrest med inntil 4 C-atomer.. ;Por dannelse av salter med forbindelsene med den generelle formel- I er det egnet uorganiske og organiske . syrer. Egnede syrer er eksempelvis hydrogenklorid., hydrogenbromid, fosforsyre, svovelsyre, oksalsyre, melkesyre, vinsyre, eddiksyre, salicylsyre,. benzosyre, sitronsyre, adipinsyre eller naftalin-1,5-disulfonsyre. Farmasøytisk godtagbare syreaddisjonssalter foretrekkes. ;Fenylkjernen I i følgende formelbilder. kan være substituert som angitt ovenfor ved den generelle formel I. ;For fremstilling av forbindelser med den generelle formel I omsettes et 1-fenoksy-3-amino-propan-2-ol med den generelle formel III med en forbindelse med den generelle formel IV under avspaltning av H-Y til en forbindelse I ifølge oppfinnelsen: ; Herved har X den allerede nevnte betydning og Y betyr halogen, spesielt klor eller brom, og hvis ;X betyr ; Omsetningen gjennomføres normalt i et egnet oppløsnings-eller dispergeringsmiddel, hvori reak.s j onsdeltagerne oppløses resp. suspenderes. Slike oppløsnings- eller dispergeringsmidier er f.eks. aromatiske hydrokarboner, som f.eks. benzen, toluen, xylen; ketoner som f.eks. aceton, metyl-etylketon; halogenerte hydrokarboner som f.eks. kloroform, karbontetraklorid, klorbenzen, metylenklorid;'• etere som f.eks. tetrahydrofuran og dioksan; sulfoksyder som f.eks. dimetylsulfoksyd; tertiære syreamider som f.eks. dimetylformamid og N-metylpyrrolidon. Som oppløsningsmiddel anvendes spesielt polare oppløsningsmidler, som f.eks. alkoholer. Egnede alkoholer er f.eks. metanol, etanol, isbpropanol, tert.-butanol osv. Reaksjonen gjennom-føres ved temperaturer på 20°C til det anvendte oppløsnings- eller dispergeringsmiddels tilbakeløpstemperatur, Reaksjonen forløper ofte allerede ved normaltemperatur. ; akseTlereres reaksjonen ved tilsetning av en syre, fortrinnsvis hydrogenklorid. Eksempler for andre egnede syrer er karboksyl-syrer som f.eks. maursyre, eddiksyre, propionsyre, smørsyre; sul-fonsyrer som f.eks. benzosulfonsyre, p-toluensulfonsyre, mineral-syrer som f.eks. svovelsyre og fosforsyre. Anvendes en forbindelse med den generelle formel IV med Y = OH, da er det for reaksjonsaksellerering allerede bare nødvendig med katalytiske mengder av syren, f.eks. av eddik- eller maursyre. Anvendes forbindelser med den generelle formel IV hvor Y betyr ONa eller.OK, tilsettes ca. 1 mol av syren. Istedenfor å tilsette en syre, kan det for reaksjonsaksellerering også . anvendes forbindelsen med den generelle formel III i form av et salt, f.eks. hydrohalogenidet. Anvendes en forbindelse med den generelle formel IV, hvori Y betyr halogen, da kan denne forbindelse med den generelle formel IV også anvendes i form av hydrohalogenidet. Ved fremstillingsfremgangsmåten ifølge oppfinnelsen kan syreaddisjonssaltene. av forbindelsen I eller ved tilsetning av et syrebindemiddel som pottaske eller soda de fri aminer oppstå. ;De nødvendige utgangsforbindelser med den generelle formel IV er alt etter betydningen av X enten derivater av l-(2,4-dimetyl-5-pyrimidyl)-but-2-en-ons-l med den generelle'' formel V eller av 1-(2,4-dimetyl-5-pyrimidy1)-butan-l-ol med den generelle formel VI: ; Herved har ,Y den allerede angitte betydning og Hal betyr halogen, spesielt klor eller brom. Utgangsforbindelser med den generelle formel V kan fåes, idet man enten omsetter et 2,4-dimetyl-pyrimidin(5) karboksylsyreester, spesielt metyl- eller -etylesteren med aceton under betingelse for en alkalisk esterkondensasjon eller under analoge betingelser en eddiksyreester, spesielt eddiksyre-metyl- eller -etylesteren med 2 , 4-dimety 1-5-acety 1-pyrimidin .' Man får således natrium- resp. kaliumsaltet med formel VII resp. VIII: Ved hydrolyse får man av disse salter den fri 2(dimetyl-pyrimidoyl-l-mety1-vinylalkohol méd formel IX, som er tautomer med dimetylpyrimidoy1-aceton med formel X ; Ved omsetning av forbindelsen med formel IX resp. X med egnede halogeneringsmidler, som f.eks. tionylklorid eller fos-fortribromid får man det tils varende . 3~halogen-l-/_ 2,4-dimetyl-pyrimidy 1 (5_)_7-but-2-en-on-l med den generelle formél XI ; idet Hal betyr halogen, spesielt klor eller brom. Forbindelser med den generelle formel VI kan fremstilles av de tilsvarende forbindelser med formel XI ved hydrering, hensiktsmessig ved komplekse hydrider, som f.eks. litiumaluminiumhydrid, natriumborhydrid eller lignende. De som utgangsforbindelser nødvendige forbindelser med den generelle formel III kan fremstilles ved at. man omsetter en forbindelse med den generelle formel XII eller XIII idet i XIII Hal betyr et halogenatom, spesielt klor eller brom, eller en blanding av en forbindelse XII med en i fenylkjernen I tilsvarende substituert forbindelse XIII med ammoniakk eller ammoniakkav-spaltende- forbindelser. Reaksjonen kan gjennomføres under atmosfære-trykk eller under forhøyet trykk ved omgivelsestemperaturen og aksellereres eller bringes til avslutning ved varmetilførsel, f.eks., ved oppvarmning til 70°C. Forbindelsene med de generelle formler XII og XIII kan fremstilles ved omsetning av en fenol med den generelle formel XIV ; med et epihalogenhydrin, hensiktsmessig med epiklorhydrin og epibromhydrin. Alt etter reaksjonsbetingelsene oppstår derved en forbindelse med den generelle formel XII og XIII eller en blanding av forbindelser med de generelle formler XII og XIII. Det dannede reaksjonsprodukt kan isoleres før- dets videreomsetning med ammoniakk, ;det kan imidlertid også omsettes direkte videre uten isolering. ;Forbindelser med den generelle formel I kan også fremstilles ved at en forbindelse med den generelle formel XV.-omsettes med en' forbindelse med den generelle formel XVI ; idet Hal betyr et halogenatom, spesielt klor eller brom.;Omsetningen gjennomføres vanligvis i et egnet oppløs-nings- e.ller dispergeringsmiddel, hvori reaks j onsdeltagerne oppløses resp. suspenderes. Slike oppløsnings- eller dispergeringsmidler ;er f.eks. aromatiske hydrokarboner som f.eks. benzen, toluen, xylen;. ketoner som f.eks. aceton, metyletylketon; halogenerte hydrokarboner som f.eks. kloroform, karbontetraklorid, klorbenzen, metylenklorid; etere som f.eks. tetrahydrofuran og dioksan; sulfoksyder som f.eks. dimetylsulf oksyd,; tertiære syreamider som. f.eks. dimety lf ormamid og N-metylpyrrolidon. Som oppløsningsmidler'anvendes spesielt polare oppløsningsmidler, som f.eks. alkoholer. Egnede alkoholer er f.eks. metanol, etanol, isopropanol, tert.-butanol osv. Reaksjonen gjennom-føres ved temperaturer på 20°C inntil det anvendte oppløsnings- eller dispergeringsmiddels tilbakeløpstemperatur. Reaksjonen forløper hyppig ved temperaturer fra 40 til 50°C. ;Det kan være hensiktsmessig- å anvende utgangs forbindelser med den generelle formel XVI i en til 10 ganger molart overskudd og/eller å tilsette reaksjonskomponentene med den generelle formel XV i oppløst resp. suspendert form til den oppløste resp. suspenderte reaksjonskomponent med den generelle formel XVI. Molforholdet mellom forbindelsene med den generelle formel XV og den generelle formel. XVI kan utgjøre 1 : 1 til 1 : 10 og eventuelt mer. ;Ved reaksjonens gjennomføring kan det som forbindelse;me den generelle formel XV anvendes en forbindelse med den generelle formel XII éller.den generelle formel XIII eller en blanding av .disse to forbindelser. ;Ved nærværet av en forbindelse med .den generelle formel XIII kan omsetningen også gjennomføres i nærvær av sy.rebindende midler som pottaske, soda osv. Uten syrebindende midler får man da vanligvis hydrohalogenidene av forbindelsene med den generelle formel I. ;Fremstilling av u.tgangsforbindelser med den generelle formel XVI er omtalt i eksemplene.. ;For fremstilling av forbindelser med den generelle' formel I kan også et fenol med den■generelle formel XIV omsettes med en forbindelse med den generelle formel XVII til en forbindelse med.den generelle formel I: ; idet Hal betyr et halogenatom, spesielt klor eller brom.;Også denne omsetning gjennomføres normalt i et egnet oppløsnings- eller dispergeringsmiddel, hvori reaksjonsdeltagerne oppløses resp. suspenderes. Slike oppløsnings- eller dispergeringsmidler er f.eks. aromatiske hydrokarboner, som f.eks. benzen, toluen, xylen; ketoner som f.eks. aceton, metyletylketon; halogenerte hydrokarboner som f.eks. kloroform, karbontetraklorid, klorbenzen, metylenklorid; etere som f.eks.'feetrahydrofuran og dioksan; sulfoksyder som f.eks. dimetylsulfoksyd; tertiære syreamider som f.eks. dimetyl-foanmamid og N-metylpyrrolidon. Som oppløsningsmiddél anvendes spesielt polare oppløsningsmidler som f.eks.- alkoholer. Egnede alkoholer er f.eks. metanol, etanol; isopropanol, tert.-butanol osv. Når Z betyr -CH-CHp-Hal gjennomføres reaksjonen for "det meste i nærvær ;OH ;av et syrebindende middel, som f.eks. pottaske, soda,;natriumbikarbo-nat. Man kan også gjennomføre den i vandige alkalier, som f.eks. fortynnet natron- eller, kalilut. Reaks j onstemperaturen kan utgjøre ;20°C til det anvendte oppløsnings- eller dispergeringsmiddels tilbake løpstemperatur. ;Det kan være hensiktsmessig å anvende utgangsforbindel-sen med den generelle formel XVII i en til ti ganger molart overskudd og/eller å tilsette reaksjonskomponentene med den^generelle formel XIV i oppløst resp. suspendert form til de oppløste resp. suspenderte reaksjonskomponenter med den generelle formel XVII. Molforholdet mellom forbindelsene med den generelle formel XIV og XVII kan utgjøre 1 : 1 til 1 : 10 og eventuelt mer. ;Ved reaksjonsgjennomføringen kan det som forbindelse med den generelle formel XVII anvendes en forbindelse med den generelle formel XVIII eller den.generelle formel ,XIX eller en blanding av disse to forbindelser. ; Forbindelsen med den generelle formel XVIII og XIX;kan fremstilles ved omsetning av en forbindelse med den generelle formel XVI med et epihalogenhydrin 3 hensiktsmessig med epiklor- ;hydrin eller epibromhydrin. Alt etter reaksjonsbetingelsene oppstår derved en forbindelse med den generelle formel XVIII eller XIX ;eller en blanding av forbindelser med den generelle formel XVIII og XIX. Det dannede reaksjonsprodukt kan isoleres for dets videre omsetning, det kan imidlertid også direkte videreomsettes uten isolering. ;Forbindelsene med den generelle formel I, hvori X betyr resten ; og som således har den generelle formel XX kan også fremstilles ved at man hydrerer en forbindelse med den generelle formel XXI, XXII eller XXIII ; Til hy.dreringen anvendes fortrinnsvis komplekse hydrider som f.eks. litiumaluminiumhydrid, natriumborhydrid og lignende. Reaksjonen foretas under" de for disse hydrider kjente omsetningsbe-tingelser, vanligvis i alkohol eller en alkohol/vanriblanding ved værelses- eller forhøyet temperatur, f.eks. under kokning ved tilbakeløp. Videreføringen.kan i mange tilfeller også gjennomføres katalytisk, f.eks. under anvendelse av en palladium-kull-kåtalysator. ;Utgangsforbindelsene med den • generelle formel XXI. er forbindelser ifølge oppfinnelsen med den generelle formel I, hvori X betyr resten ; Omsetningen mellom forbindelsene med de generelle formler XXIV og.XI resp. XXIV og VI gjennomføres i oppløsningsmidler som benzen, toluen, kloroform, metyleriklorid, dioksan osv. ved normal- eller forhøyet temperatur i nærvær av minst molare mengder syrebindende middel som pottaske eller soda eller i fravær av syrebindende midler, idet man i sistnevnte tilfellet vanligvis får hydrohalogenidene av forbindelsene XXII resp. XIII. ;Fremstillingen av forbindelser med den generelle formel XXIV kan f.eks. foregå ved svak oksydasjon av amirio.propanolene i ;III ; ; Aldehydkondensasjonsproduktene med formel II fåes, idet man omsetter forbindelser med den generelle formel I med et aldehyd med formel. R-^-CHO, hvori R^. betyr hydrogen eller en lavere alkylrest, i et fortynnings- eller et pppløsningsmiddel, f.eks. etanol,- fortrinnsvis i nærvær av en sur katalysator, f.eks. eddiksyre eller saltsyre og fortrinnsvis ved forhøyet temperatur. Det ved reaksjonen dannede vann kan fjernes ved hjelp av et slepemiddel, f.eks. benzen, ved azeotrop destillering eller ved hjelp av et dehydrat.i-seringsmiddel, som vannfritt kaliumkarbonat. ;Syreaddisjonssaltene av forbindelser med den generelle formel I kan 'fremstilles på i og for seg kjent måte fra komponentene. Herved er det fordelaktig med anvendelse av et fortynningsmiddel, idet man ved et overskudd av syre, vanligvis for di-saltene av forbindelser med den generelle formel I. Monosyreaddisjonssaltene får man enten ved tilsiktet tilsetning av bare 1 mol syre eller ved partiell hydrolyse av di-syreaddisjonssaltene. ;Forbindelsene med den generelle formel I, deres aldehyd-kondensas j onsprodukter II og deres.farmasøytisk godtagbare syreaddi-'sjonssalter har verdifulle farmasøytiske egenskaper. Således er de f.eks. egnet for behandling eller profylaks av hjertesykdommer. Dessuten har de delvis sterkt utpregede B-adrenolytiske og anti-arytmiske egenskaper.- Forbindelsene kan derfor anvendes alene, i blanding med hverandre eller i blanding med farmasøytisk tålbare fortynningsmidler eller bærere, som farmasøytiske preparater. De farmasøytiske preparater kan foreligge i form av f.eks. tabletter, kapsler, vandige eller oljeaktige oppløsninger eller suspensjoner, emulsjoner, injiserbare vandige eller oljeaktige oppløsninger eller suspensjoner, dispergerbare pulvere eller aerosolblandinger. De farmasøytiske preparater kan ved siden av forbindelsene<%>med den generelle formel I også dessuten inneholde en eller flere andre farmasøytiske virksomme stoffer, eksempelvis beroligende midler som f.eks. luminal, meprobamat og klorpromazin; vasodilatorer som f.eks. glyceroltrinitrat og karbokromer, diuretika som f.eks. kloro-tiazid; .hjertetoniserende midler som f.eks. digitalis-preparater, hypotensjonsmidler som f.eks. rauwolfiaalkaloider; bronkodilatatorer og sympatomimetiske midler som f.eks. isoprenalin og efedrin. ;Av forbindelsene som er fremstillbare ifølge oppfinnelsen og som har den generelle formel I er de spesielt fore-trukket, hvori X har betydningen ; ; Den blokkerende virkning av forbindelsene ifølge oppfinnelsen på hjertets Bl-reseptorer og på karsystemets B2-reseptorer ble undersøkt på følgende måte: På bastard-hunder av begge kjønn ble det i en kloralose-uretan-morfin-narkose målt blodtrykket i venstre ventrikkel og trykk-signalet kontinuerlig differensiert ved hjelp av analogregner (BRUSH Instruments, Cleveland/Ohio) og blant annet registrert trykkøknings-hastigheten (Dp/dt). Videre ble det målt gjennomblødningen av en Arteria femoralis ved hjelp av et elektromagnetisk . flowmeter (Firma Statham, Modell M4000) og registrert gjennomblødning ml/minutt. ;Endring av.den maksimale trykkøkningshastighet (Dp/dt maks.) i forhold til null-verdien ble utløst ved hjelp av i.v.-inngivning av isoproterenol (0,5 gamma/kg), et kjent sympatikomime-tikum (31-reaksjon), mens endringer av den perifere gjennomblødning i forhold til null-verdien ble indusert ved intraarteriell admini-strering av isoproterenol (0,05 gamma/kg) (62-reaksjon) (D. Dunlop og R.G. Shanks: Selective blockade of adrenoceptive beta-receptors in the heart. Brit. J. Pharmac. Chemother. (1968) 32 201-218). ;Stoffene som skulle undersøkes på deres B-reseptor-blokkering ble applisert i narkotiserte og med isoproterenol stimu-lerte dyr i økende dosering i.v. og den stoffmengde bestemt, hvor det opptrådte en 50$-ig hemming av de to ved isoproterenol frem-bragte reaksjoner (ED50). • ;I følgende tabell er det angitt ED 50-verdien av 81-reseptorhemningen (mg/kg i.v.) og ED 50-verdien av 82-reseptorhemming (mg/kg i.v.). Dessuten ble det for begge tilfeller beregnet de relative ED 50-verdier under til grunnlegging av det som sammenligningsstoff anvendte 4-(2-hydroksy-3-isopropylamino-propoksy)-acetanilid, idet dets ED 50-verdi ble satt lik 100. Den av ED 50 av'B2-reseptorhemmingen og ED 50 av Bl-resptorhemmingen dannede kvotient er et mål for undersøkelsesstoffets kardioselektive virkning. Jo større denne kvotient er desto bedre er den kardioselektive virkning. Setter man kvotienten av sammenligningsstoffet 4-(2-hydroksy-3-isopropy'lamino-propoksy)-acetanilid lik 1, så angir den relative faktor hvor meget bedre den kardioselektive virkning av forbindelsene ifølge oppfinnelsen er i forhold til sammenlignings-stof fet.- ;Videre er de relative ED 50-verdier for Bl-reseptor-hemningen (spalte 2 i følgende tabell) et -mål for virkningen av stoffene som skal undersøkes. Jo mindre verdiene er, desto mere virksomt er stoffene, dvs. desto mindre er den for frembringelse av terapeutisk effekt nødvendige mengde. ;Det som sammenligningsstoff anvendte 4-(2-hydroksy-3_ isopropyl-amino-propoksy)-acetanilid er et preparat som er kjent i handelen som B-blokkerer og som har det internasjonale navn "Practolol". ; En tablett med en forbindelse ifølge oppfinnelsen og ;.100 mg samlet vekt kan f'.eks. ha følgende sammensetning:;5,0 mg 1-(2 ,4-dimetyl-5-pyrimidyl)-3-(l-/_ p-acetamino-fenoksy/-2-hydroksy-propyl(3)-amino)-butan-1-ol, 10,0 mg kolloidal kiselsyre (Aerosil), ;72,.5 mg laktose DAB7, 1,5 mg gelatin, ;8,5 mg maisstivelse DAB7.,;2,5 mg Mg-stearat USPXVIII.;Alt et.ter tyngden av tilfellet som skal behandles kan eksempelvis administreres tre ganger daglig 1 til 2 av disse tabletter til en pasient . ;Fremstillingen av forbindelser med den generelle formel I forklares nærmere ved hjelp av følgende eksempler. Forbindelsen er ofte ikke destillerbare oljer, således at i mange tilfeller er det ikke. angitt smeltepunkt. I alle tilfeller er imidlertid den angitte struktur sikret ved molekylanaiyse og/eller infra-rød- resp.'kjerneresonansspektrum. ;Eksempel 1.;9,6 g 2 , 4-dimetyl-5-pyrimidylkarbonyl-a.ceton ; 10,6 g racemisk 1-(o-etoksy-fenoksy)-3-amino-propan-2-ol og 100 ml etanol omrøres i 20 timer ved værelsestemperatur. Ved frasugning av den i.savkjølte oppløsning utvinner man 12,3 g racemisk ,l-( 2 , 4-dimetyl-5-pyrimidy 1) - 3- (l-/.-o-etoksy-fenoksy_7-2-hydroksy-propyl-3-amino)-but-2-en-on-l med 'formel ; Smeltepunkt: 105-106 o C. Fra ' filtratet lar det seg ytterligere, utvinne 5,6 g av stoffet: Utbytte 93% av det teoretiske. Analyse: (C21H?7N^0i() . ; Det som utgangsstoff anvendte 2,4-dimetyl-5-pyrimidyl-karbonyl-aceton kan fremstilles på følgende måte: 222,7 g 5-acetyl-2,4-dimetylpyrimidin, 5 liter vannfri toluen, 245 g eddiksyremetylester og 405 g kalium-tert.-butylat oppvarmes under nitrogen 4 timer ved 60°C. Man heller på 2 liter isvann og 205 ml eddiksyre, adskiller og får ved opparbeidelse av t oluenoppløsningen 252,3 g 2 , 4-dimetyl-5_py'rimidylkarbonyl-aceton, kokepunkt 112-ll8°C/0,2 torr, smeltepunkt 65-66°C (fra ligroin). ;Analyse: (C]_oHi2N2°2 ^; ; Eksempel 2.;<1>Behandler man istedenfor det racemiske l-(o-etoksy-fenoksy)-3-amino-propan-2-ol dets venstredreiende isomer ;* and the phenyl nucleus I can also be substituted, one, two or three times, especially with alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, benzyloxy, phenyl, halogen or the residue -NR-^F^, as R^, means alkyl or acyl and means hydrogen or, alkyl, as well as their aldehyde condensation products and acid addition salts. The substituents of the phenyl nucleus I can be the same or different. Compounds where X means ; preferred. Within the scope of the invention, compounds of the general formula I also include possible stereoisomers and optically active compounds and mixtures thereof, especially the racemate. ;The substituents of the phenyl nucleus I in particular have the following meaning: Alkyl with 1 to 4 C atoms, e.g. methyl, ethyl, propyl, tert-butyl, alkenyl with up to 6 C atoms, preferably vinyl, allyl, metallic, crotyl, alkynyl with up to 6 C atoms, e.g. progargyl, cycloalkyl with a ring size of from 5 to 8 C atoms, preferably cyclopentyl and cyclohexyl, cycloalkeny with a ring size of from 5 to 8 C atoms, preferably cyclopentenyl, oxy with up to 8 C atoms, alkenyloxy and alkynyloxy each time up to 5 C atoms, preferably methoxy, ethoxy, n- and i-propoxy, butoxy, n-pentyloxy, n-octyloxy, allyloxy, metalyloxy, propargyloxy, benzyloxy. Halogen: preferably fluorine, chlorine or bromine. ;Alkyl residues for R^. and preferably has 1 to 2 C atoms. By the acyl residue for R^ is understood the aryl- or alkyl-substituted carbonyl residue deriving from an aromatic or aliphatic carboxylic acid with up to 11 C atoms, e.g. formyl, acetyl, propionyl, butyrylbenzoyl, naphthoyl, phenylacetyl, preferably, however, acetyl or benzoyl. The aldehyde condensations of the compounds of the general formula I are oxazolidines of the formula II; . which is formed by the condensation of compounds of the general formula I with an aldehyde of the formula; in which R-j means, hydrogen or a lower alkyl residue with up to 4 C atoms..; For the formation of salts with the compounds of the general formula- I, inorganic and organic are suitable. acids. Suitable acids are, for example, hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, oxalic acid, lactic acid, tartaric acid, acetic acid, salicylic acid. benzoic acid, citric acid, adipic acid or naphthalene-1,5-disulfonic acid. Pharmaceutically acceptable acid addition salts are preferred. ;The phenyl nucleus I in the following formula pictures. may be substituted as indicated above by the general formula I. To prepare compounds of the general formula I, a 1-phenoxy-3-amino-propan-2-ol of the general formula III is reacted with a compound of the general formula IV during cleavage of H-Y to a compound I according to the invention: ; Hereby, X has the meaning already mentioned and Y means halogen, especially chlorine or bromine, and if ;X means ; The reaction is normally carried out in a suitable solvent or dispersant, in which the reaction participants are dissolved or be suspended. Such dissolving or dispersing media are e.g. aromatic hydrocarbons, such as benzene, toluene, xylene; ketones such as acetone, methyl ethyl ketone; halogenated hydrocarbons such as chloroform, carbon tetrachloride, chlorobenzene, methylene chloride;' ethers such as tetrahydrofuran and dioxane; sulfoxides such as dimethyl sulfoxide; tertiary acid amides such as dimethylformamide and N-methylpyrrolidone. As a solvent, particularly polar solvents are used, such as e.g. alcohols. Suitable alcohols are e.g. methanol, ethanol, isopropanol, tert.-butanol, etc. The reaction is carried out at temperatures of 20°C to the reflux temperature of the solvent or dispersant used. The reaction often already proceeds at normal temperature. ; The reaction is accelerated by adding an acid, preferably hydrogen chloride. Examples of other suitable acids are carboxylic acids such as e.g. formic acid, acetic acid, propionic acid, butyric acid; sulfonic acids such as e.g. benzosulfonic acid, p-toluenesulfonic acid, mineral acids such as e.g. sulfuric acid and phosphoric acid. If a compound of the general formula IV with Y = OH is used, only catalytic amounts of the acid are required for reaction acceleration, e.g. of acetic or formic acid. If compounds with the general formula IV are used where Y means ONa or OK, add approx. 1 mole of the acid. Instead of adding an acid, it can also be used for reaction acceleration. the compound with the general formula III is used in the form of a salt, e.g. the hydrohalide. If a compound of the general formula IV is used, in which Y means halogen, then this compound of the general formula IV can also be used in the form of the hydrohalide. In the production process according to the invention, the acid addition salts can. of the compound I or by adding an acid binder such as pot ash or soda, the free amines occur. ;The necessary starting compounds with the general formula IV are, depending on the meaning of X, either derivatives of 1-(2,4-dimethyl-5-pyrimidyl)-but-2-en-ones-1 with the general'' formula V or of 1-(2,4-Dimethyl-5-pyrimidinyl)-butan-1-ol of the general formula VI: ; Hereby, Y has the meaning already indicated and Hal means halogen, especially chlorine or bromine. Starting compounds of the general formula V can be obtained by either reacting a 2,4-dimethyl-pyrimidine(5) carboxylic acid ester, especially the methyl or -ethyl ester with acetone under conditions for an alkaline ester condensation or under analogous conditions an acetic acid ester, especially acetic acid- the methyl or -ethyl ester with 2,4-dimethyl 1-5-acety 1-pyrimidine.' You thus get sodium or the potassium salt of formula VII or VIII: By hydrolysis, one obtains from these salts the free 2(dimethyl-pyrimidoyl-1-methyl-1-vinyl alcohol with formula IX, which is a tautomer with dimethylpyrimidoyl-acetone with formula X; By reacting the compound with formula IX or X with suitable halogenating agents , such as thionyl chloride or phosphonium tribromide, it is obtained permanently . formula XI ; where Hal means halogen, especially chlorine or bromine. Compounds of the general formula VI can be prepared from the corresponding compounds of formula XI by hydrogenation, suitably with complex hydrides, such as lithium aluminum hydride, sodium borohydride or the like. Those as starting compounds necessary compounds with the general formula III can be prepared by reacting a compound with the general formula XII or XIII, where in XIII Hal means a halogen atom, especially chlorine or bromine, or a mixture of a compound XII with a corresponding in the phenyl nucleus I substituted compound XIII with ammonia or ammonia-decomposing compounds. The reaction can be carried out under atmospheric pressure or under elevated pressure at ambient temperature and is accelerated or brought to completion by the addition of heat, for example, by heating to 70°C. The compounds with the general formulas XII and XIII can be prepared by reacting a phenol with the general formula XIV; with an epihalohydrin, suitably with epichlorohydrin and epibromohydrin. Depending on the reaction conditions, a compound with the general formulas XII and XIII or a mixture of compounds with the general formulas XII and XIII is thereby produced. The reaction product formed can be isolated before further reaction with ammonia, but it can also be reacted directly without isolation. Compounds with the general formula I can also be prepared by reacting a compound with the general formula XV with a compound with the general formula XVI; wherein Hal means a halogen atom, especially chlorine or bromine. The reaction is usually carried out in a suitable solvent or dispersant, in which the reaction participants are dissolved or be suspended. Such dissolving or dispersing agents are e.g. aromatic hydrocarbons such as benzene, toluene, xylene;. ketones such as acetone, methyl ethyl ketone; halogenated hydrocarbons such as chloroform, carbon tetrachloride, chlorobenzene, methylene chloride; ethers such as tetrahydrofuran and dioxane; sulfoxides such as dimethyl sulfoxide,; tertiary acid amides such as. e.g. dimethyl lf ormamide and N-methylpyrrolidone. As solvents, polar solvents are used in particular, such as e.g. alcohols. Suitable alcohols are e.g. methanol, ethanol, isopropanol, tert.-butanol, etc. The reaction is carried out at temperatures of 20°C up to the reflux temperature of the solvent or dispersant used. The reaction frequently proceeds at temperatures from 40 to 50°C. It may be appropriate to use starting compounds with the general formula XVI in a to 10-fold molar excess and/or to add the reaction components with the general formula XV in dissolved or suspended form to the dissolved resp. suspended reaction component of the general formula XVI. The mole ratio between the compounds of the general formula XV and the general formula XVI can amount to 1:1 to 1:10 and possibly more. When carrying out the reaction, a compound of the general formula XV can be used as a compound of the general formula XII or the general formula XIII or a mixture of these two compounds. In the presence of a compound with the general formula XIII, the reaction can also be carried out in the presence of acid-binding agents such as pot ash, soda etc. Without acid-binding agents, the hydrohalides of the compounds of the general formula I are then usually obtained. Compounds of the general formula XVI are discussed in the examples. For the preparation of compounds of the general formula I, a phenol of the general formula XIV can also be reacted with a compound of the general formula XVII to a compound of the general formula I : ; wherein Hal means a halogen atom, especially chlorine or bromine. This reaction is also normally carried out in a suitable solvent or dispersant, in which the reaction participants are dissolved or be suspended. Such solvents or dispersants are e.g. aromatic hydrocarbons, such as benzene, toluene, xylene; ketones such as acetone, methyl ethyl ketone; halogenated hydrocarbons such as chloroform, carbon tetrachloride, chlorobenzene, methylene chloride; ethers such as tetrahydrofuran and dioxane; sulfoxides such as dimethyl sulfoxide; tertiary acid amides such as dimethylfoanamide and N-methylpyrrolidone. Particularly polar solvents such as alcohols are used as solvents. Suitable alcohols are e.g. methanol, ethanol; isopropanol, tert.-butanol, etc. When Z means -CH-CHp-Hal, the reaction is mostly carried out in the presence of an acid-binding agent, such as pot ash, soda ash, sodium bicarbonate. You can also carry it out in aqueous alkalis, such as, for example, dilute caustic soda or potassium hydroxide. The reaction temperature can be ;20°C to the reflux temperature of the solvent or dispersant used. ;It may be appropriate to use the starting compound with the general formula XVII in a one to tenfold molar excess and/or adding the reaction components of the general formula XIV in dissolved or suspended form to the dissolved or suspended reaction components of the general formula XVII The molar ratio between the compounds of the general formula XIV and XVII may amount to 1 : 1 to 1 : 10 and possibly more. When carrying out the reaction, a compound of the general formula XVIII or the general formula can be used as a compound of the general formula XVII, XIX or a mixture of these two compounds. ; The compound of the general formula XVIII and XIX can be prepared by reacting a compound of the general formula XVI with an epihalohydrin 3 suitably with epichlorohydrin or epibromohydrin. Depending on the reaction conditions, a compound with the general formula XVIII or XIX is thereby produced; or a mixture of compounds with the general formula XVIII and XIX. The reaction product formed can be isolated for further conversion, but it can also be directly further converted without isolation. ;The compounds of the general formula I, in which X represents the residue ; and which thus has the general formula XX can also be prepared by hydrogenating a compound with the general formula XXI, XXII or XXIII; Complex hydrides such as e.g. lithium aluminum hydride, sodium borohydride and the like. The reaction is carried out under the reaction conditions known for these hydrides, usually in alcohol or an alcohol/alcohol mixture at room or elevated temperature, e.g. under reflux. The continuation can in many cases also be carried out catalytically, e.g. . using a palladium-charcoal catalyst. ; The starting compounds of the general formula XXI. are compounds according to the invention of the general formula I, in which X represents the residue ; The reaction between the compounds of the general formulas XXIV and.XI or XXIV and VI carried out in solvents such as benzene, toluene, chloroform, methyl chloride, dioxane etc. at normal or elevated temperature in the presence of at least molar amounts of acid-binding agents such as pot ash or soda ash or in the absence of acid-binding agents, in which case the hydrohalides of the compounds are usually obtained XXII or XIII.; The production of compounds with the general formula XXIV can e.g. take place by weak oxidation on of the amirio.propanols in ;III ; ; The aldehyde condensation products of formula II are obtained by reacting compounds of general formula I with an aldehyde of formula R-^-CHO, wherein R^. means hydrogen or a lower alkyl residue, in a diluent or ppp solvent, e.g. ethanol, - preferably in the presence of an acidic catalyst, e.g. acetic acid or hydrochloric acid and preferably at an elevated temperature. The water formed during the reaction can be removed with the help of a towing agent, e.g. benzene, by azeotropic distillation or by means of a dehydrating agent, such as anhydrous potassium carbonate. The acid addition salts of compounds of the general formula I can be prepared in a manner known per se from the components. Here it is advantageous to use a diluent, since in the case of an excess of acid, usually for the di-salts of compounds with the general formula I. The monoacid addition salts are obtained either by the intentional addition of only 1 mol of acid or by partial hydrolysis of the di- the acid addition salts. The compounds of the general formula I, their aldehyde condensation products II and their pharmaceutically acceptable acid addition salts have valuable pharmaceutical properties. Thus, they are e.g. suitable for the treatment or prophylaxis of heart diseases. In addition, they have partly strongly pronounced B-adrenolytic and anti-arrhythmic properties. The compounds can therefore be used alone, in admixture with each other or in admixture with pharmaceutically acceptable diluents or carriers, as pharmaceutical preparations. The pharmaceutical preparations can be in the form of e.g. tablets, capsules, aqueous or oily solutions or suspensions, emulsions, injectable aqueous or oily solutions or suspensions, dispersible powders or aerosol mixtures. The pharmaceutical preparations may, in addition to the compounds <%> of the general formula I, also contain one or more other pharmaceutical active substances, for example sedatives such as e.g. luminal, meprobamate and chlorpromazine; vasodilators such as glycerol trinitrate and carbochromes, diuretics such as chlorothiazide; .cardiac tonics such as e.g. digitalis preparations, hypotensive agents such as rauwolfia alkaloids; bronchodilators and sympathomimetic agents such as isoprenaline and ephedrine. Of the compounds which can be produced according to the invention and which have the general formula I, those in which X has the meaning ; ; The blocking effect of the compounds according to the invention on the heart's B1 receptors and on the vascular system's B2 receptors was investigated in the following way: In bastard dogs of both sexes, in a chloralose-urethane-morphine anesthesia, the blood pressure in the left ventricle and pressure- the signal is continuously differentiated using an analogue calculator (BRUSH Instruments, Cleveland/Ohio) and, among other things, the rate of pressure increase (Dp/dt) is recorded. Furthermore, the perfusion of an Arteria femoralis was measured using an electromagnetic. flowmeter (Company Statham, Model M4000) and recorded perfusion ml/minute. ;Change in the maximum rate of pressure increase (Dp/dt max.) relative to the zero value was induced by i.v. administration of isoproterenol (0.5 gamma/kg), a known sympathomimetic (31 reaction), while changes in the peripheral perfusion relative to the zero value were induced by intra-arterial administration of isoproterenol (0.05 gamma/kg) (62 reaction) (D. Dunlop and R.G. Shanks: Selective blockade of adrenoceptive beta-receptors in the heart. Brit. J. Pharmac. Chemother. (1968) 32 201-218). The substances to be examined for their B-receptor blocking were applied to anesthetized and isoproterenol-stimulated animals in increasing doses i.v. and the amount of substance determined, at which there was a 50% inhibition of the two reactions produced by isoproterenol (ED50). ;In the following table, the ED 50 value of the 81-receptor inhibition (mg/kg i.v.) and the ED 50 value of the 82-receptor inhibition (mg/kg i.v.) are indicated. In addition, for both cases, the relative ED 50 values below were calculated on the basis of the 4-(2-hydroxy-3-isopropylamino-propoxy)-acetanilide used as a comparison substance, its ED 50 value being set equal to 100. That of The quotient formed by the ED 50 of the B2 receptor inhibition and the ED 50 of the B1 receptor inhibition is a measure of the test substance's cardioselective effect. The greater this quotient, the better the cardioselective effect. If you set the quotient of the comparison substance 4-(2-hydroxy-3-isopropylamino-propoxy)-acetanilide equal to 1, then the relative factor indicates how much better the cardioselective effect of the compounds according to the invention is compared to the comparison substance fet. Furthermore, the relative ED 50 values for the B1 receptor inhibition (column 2 in the following table) are a measure of the effect of the substances to be investigated. The smaller the values, the more effective the substances, i.e. the smaller the quantity required to produce a therapeutic effect. The 4-(2-hydroxy-3-isopropyl-amino-propoxy)-acetanilide used as a comparison substance is a preparation which is known in the trade as a B-blocker and which has the international name "Practolol". ; A tablet with a compound according to the invention and ;.100 mg total weight can e.g. have the following composition: 5.0 mg 1-(2,4-dimethyl-5-pyrimidyl)-3-(1-/_ p-acetamino-phenoxy/-2-hydroxy-propyl(3)-amino)-butane -1-ol, 10.0 mg colloidal silicic acid (Aerosil), ;72..5 mg lactose DAB7, 1.5 mg gelatin, ;8.5 mg corn starch DAB7.,;2.5 mg Mg stearate USPCVXVIII. Depending on the severity of the case to be treated, for example, 1 to 2 of these tablets can be administered three times a day to a patient. The preparation of compounds of the general formula I is explained in more detail by means of the following examples. The compound is often not distillable oils, so that in many cases it is not. stated melting point. In all cases, however, the specified structure is ensured by molecular analysis and/or infrared or nuclear resonance spectrum. ;Example 1.;9.6 g of 2,4-dimethyl-5-pyrimidylcarbonyl-acetone; 10.6 g of racemic 1-(o-ethoxy-phenoxy)-3-amino-propan-2-ol and 100 ml of ethanol are stirred for 20 hours at room temperature. By suctioning off the cooled solution, 12.3 g of racemic 1-(2,4-dimethyl-5-pyrimidy 1)-3-(1-/.-o-ethoxy-phenoxy-7-2-hydroxy-propyl -3-amino)-but-2-en-one-1 of formula; Melting point: 105-106 o C. From the filtrate it is possible to further recover 5.6 g of the substance: Yield 93% of the theoretical. Analysis: (C21H? 7N^Oi() . ; The 2,4-dimethyl-5-pyrimidyl-carbonyl-acetone used as starting material can be prepared in the following way: 222.7 g of 5-acetyl-2,4-dimethylpyrimidine, 5 liters of anhydrous toluene, 245 g of acetic acid methyl ester and 405 g of potassium tert.-butylate are heated under nitrogen for 4 hours at 60° C. One pours 2 liters of ice water and 205 ml of acetic acid, separates and, by working up the toluene solution, obtains 252.3 g 2 , 4-dimethyl-5_pyrimidylcarbonyl-acetone, boiling point 112-118°C/0.2 torr, melting point 65-66°C (from naphtha). <1>Instead of the racemic l-(o-ethoxy-phenoxy)-3-amino-propan-2-ol, one treats its levorotatory isomer;*
på samme måte som omtalt i eksempel l,.så får man det venstredreiende ( - ) -1- (2 , 4 -dimetyl-5-pyrimidyl) - 3- (l-/_ o-etoksy-fenoksy/-2-hydroksy-propyl-3-amino)-but-2-§n-on-l med formel in the same way as discussed in example 1, one obtains the left-handed (-)-1-(2,4-dimethyl-5-pyrimidyl)-3-(1-/_ o-ethoxy-phenoxy/-2-hydroxy -propyl-3-amino)-but-2-§n-one-1 of formula
Smeltepunkt: 103-105°C. u^5: -10°. Analyse: (C^Hv, ^N^O^ ) . Melting point: 103-105°C. u^5: -10°. Analysis: (C^Hv, ^N^O^ ) .
Det som utgangsstoff anvéndte venstredreiende (-)-l-(o-etoksy-fenoksy)-3-amino-propan-2-ol kan fremstilles av racematet på følgende måte: 20 g (o-etoksyfenoksy)-3-amiho-propan-2-ol (racemat) oppløses i 295 ml isopropanol og blandes med en oppløsning av 7,1 g L( + )-vinsyre i 100 ml isopropanol-, idet det faller ut en voluminøs hvit utfelling. Det hvite produkt frasuges, vaskes godt med"isopropanol og tørkes i vakuum. Man får således 26,7 g av tartratet ( 95% av det teoretiske) av 1-(o-etoksyfenoksy)-3-amino-propan-2-ol med en optisk dreieverdi på +12°. The levorotatory (-)-1-(o-ethoxy-phenoxy)-3-amino-propan-2-ol used as starting material can be prepared from the racemate in the following way: 20 g of (o-ethoxyphenoxy)-3-amiho-propane- 2-ol (racemate) is dissolved in 295 ml of isopropanol and mixed with a solution of 7.1 g of L( + )-tartaric acid in 100 ml of isopropanol, as a voluminous white precipitate falls out. The white product is suctioned off, washed well with isopropanol and dried in a vacuum. You thus get 26.7 g of the tartrate (95% of the theoretical) of 1-(o-ethoxyphenoxy)-3-amino-propan-2-ol with an optical rotation value of +12°.
Disse 2'6,7 g omkrystalliseres tre ganger fra en blanding av 40 deler dimetylformamid og 10 deler vann. Mån får således endelig tartratet av (-)-1-(o-etoksy-fenoksy)-3-amino-propan-2-ol (2 mol amin på 1 mol vinsyre) av optisk dreieverdi -1° (smeltepunkt 201°C). 4 g av dette finpulveriserte salt suspenderes i 60 ml dioksan og ved værelsestemperatur (reaksjonsvarmen bort føres - ved avkjøling), innføres 1/2 time NH^-gass..Det suges fra ammoniumtar-trat og dioksanfiltratet inndampes i vakuum. Det faste hvite residuet omkrystalliseres fra ligroin. Man får således det venstredreiende (-)-l-(o-etoksyfenoksy)-3-amino-propan-2-ol av smeltepunkt 87°C. These 2.6.7 g are recrystallized three times from a mixture of 40 parts of dimethylformamide and 10 parts of water. Moon thus finally gets the tartrate of (-)-1-(o-ethoxy-phenoxy)-3-amino-propan-2-ol (2 mol amine in 1 mol tartaric acid) of optical rotation value -1° (melting point 201°C) . 4 g of this finely powdered salt are suspended in 60 ml of dioxane and at room temperature (the heat of reaction is carried away - on cooling), NH 2 gas is introduced for 1/2 hour. It is sucked from ammonium tartrate and the dioxane filtrate is evaporated in vacuum. The solid white residue is recrystallized from naphtha. The levorotatory (-)-1-(o-ethoxyphenoxy)-3-amino-propan-2-ol of melting point 87°C is thus obtained.
Utbytte: 2,6 g = 88$ av det teoretiske (beregnet på tartratet av dreieverdi -1°); optisk dreieverdi: - 5° • Yield: 2.6 g = 88$ of the theoretical (calculated on the tartrate of rotation value -1°); optical rotation value: - 5° •
Eksempel 3.Example 3.
En blanding av 15>0 g racemisk 1-(2,4-dimetyl-5_ pyrimidyl) -3 - (l-/_ o-etoksy-fenoksy / -2-hydroksy-propy 1-3-amino) -but - 2-en-on-l med formel 140 ml etanol, 50- ml vann og 4,0 g natriumboranat oppvarmes 3 timer ved 70°C, inndampes deretter under nedsatt trykk og residuet opptas i vann og pentan-l-ol. Den klare pentanoloppløsning inndampes igjen og residuet utrøres med eddiksyreetylester og vanri ved pH 6. Eddiksyreety lesteren kasseres, den vandige oppløsningen innstilles med lut på pH 10 og utrøres igjen med eddiksyreety lester. Véd i n-n damp-ning av denne eddiksyreetylester får man som residu 8,3 g rått racemisk 1-(2,4-dimety1-5-pyrimidy1)-3~(1-/"o-etoksy-fenoksy/-2-hydroksy-propyl-3-amino)-butan-l-ol med formel A mixture of 15>0 g of racemic 1-(2,4-dimethyl-5_pyrimidyl)-3-(1-/_ o-ethoxy-phenoxy/-2-hydroxy-propyl 1-3-amino)-but-2 -en-on-l with formula 140 ml of ethanol, 50 ml of water and 4.0 g of sodium boranate are heated for 3 hours at 70°C, then evaporated under reduced pressure and the residue taken up in water and pentan-l-ol. The clear pentanol solution is evaporated again and the residue is stirred with acetic acid ethyl ester and water at pH 6. The acetic acid ethyl ester is discarded, the aqueous solution is adjusted with lye to pH 10 and stirred again with acetic acid ethyl ester. After evaporation of this acetic acid ethyl ester, 8.3 g of crude racemic 1-(2,4-dimethyl-5-pyrimidinyl)-3~(1-/"o-ethoxy-phenoxy/-2-hydroxy -propyl-3-amino)-butan-1-ol of formula
som seig olje, som dessuten-kan vidererens.es søylekromatograf isk. as a viscous oil, which can also be further purified by column chromatography.
Analyse: (C21H^1N^01)) . •..•''Analysis: (C21H^1N^O1)) . •..•''
Anvender man istedenfor overnevnte racemiske utgangsstoff dens venstredreiende isomere, som kan fremstilles ifølge eksempel 2,, så får man det venstredreiende (-)-1-(2 , 4-dimetyl-5-pyrimidyl) -3 - (!-/_ o-etoksy-f enoksy7-2-hydroksy-propy 1^-3-amino) -butan-l-ol med formel If one uses instead the above-mentioned racemic starting material its levorotatory isomers, which can be prepared according to example 2, then the levorotatory (-)-1-(2,4-dimethyl-5-pyrimidyl)-3 - (!-/_ o- ethoxy-phenoxy7-2-hydroxy-propyl 1^-3-amino)-butan-1-ol of formula
-i ■ ■ 25 ■ n „o ' -i ■ ■ 25 ■ n „o '
som seig olje, aD : -1,4 . as viscous oil, aD : -1.4 .
Analyse: (C21H,;,N,Oi() . Analysis: (C21H,;,N,Oi() ).
Eksempel 4. Example 4.
En oppløsning av 5,8 g 2,4-dimetyl-5-pyrimidylkarbonyl-aceton A solution of 5.8 g of 2,4-dimethyl-5-pyrimidylcarbonyl-acetone
og 7,5 g 1-(p-n-butoksy-fenoksy)-3_amino-propan-2-ol i 50 ml vannfri etanol lar man henstå 30 timer ved værelsestemperatur. Man inndamper under nedsatt trykk, krystalliserer residuet fra toluen og får 7,6 g 1-(.2 , 4-dimetyl-5-pyrimidyl)-3-1-/_ p-n-butoksy-fenoksy7-2-hydroksy-propyl-3-amino)-but-2-en-on-l med formel Smeltepunkt: 8l-83°C. Fra filtratet lar det seg utvinne ytterligere 3,3.g av stoffet. Analyse: (C2 -,H, ^N.O^ ) . Ved reduksjon av dette stoff med natriumboranat, som angitt i eksempel 3 får man 1-(2,4-dimetyl-5-pyrimidyl)-3_ (l-/. p-n-butoksy-f enoksyT-2-hydroksy-propy 1-3-amino)-butan-l-ol. med formel and 7.5 g of 1-(p-n-butoxy-phenoxy)-3-amino-propan-2-ol in 50 ml of anhydrous ethanol is allowed to stand for 30 hours at room temperature. One evaporates under reduced pressure, crystallizes the residue from toluene and obtains 7.6 g of 1-(.2,4-dimethyl-5-pyrimidyl)-3-1-/_ p-n-butoxy-phenoxy7-2-hydroxy-propyl-3 -amino)-but-2-en-one-1 with formula Melting point: 81-83°C. A further 3.3 g of the substance can be recovered from the filtrate. Analysis: (C2 -,H, ^N.O^ ) . By reducing this substance with sodium boranate, as stated in example 3, 1-(2,4-dimethyl-5-pyrimidyl)-3_ (l-/.p-n-butoxy-phenoxyT-2-hydroxy-propy 1-3 -amino)-butan-1-ol. with formula
som seig olje. like tough oil.
En oppløsning av dette stoff i ca. 5 volum eddiksyreetylester utrøres med en vandig oppløsning av den ekvivalente mengde . naf talin-1,5-disulf osyre . Den rene vandige oppløsning (pH 4)' inndampes og residuet utrøres med vannfri eter. Man får i 89%-ig utbytte det nøytrale naftalin-1,5-disulfonat av 1-(2,4-dimetyl-5~A solution of this substance in approx. 5 volumes of acetic acid ethyl ester are stirred with an aqueous solution of the equivalent amount. naphthalene-1,5-disulf oic acid . The pure aqueous solution (pH 4) is evaporated and the residue is stirred with anhydrous ether. The neutral naphthalene-1,5-disulfonate of 1-(2,4-dimethyl-5~) is obtained in 89% yield
• pyr imi dy 1) - 3- (p-n-butoksy-f enoksy_/- 2-hy droksy-propy 1-3-amino) - butan-l-ol med formel • pyrimidy 1)-3-(p-n-butoxy-phenoxy_/- 2-hydroxy-propyl 1-3-amino)-butan-l-ol of formula
i form av svakt gulaktige krystaller med' smeltepunkt l63-l67°C under spaltning. in the form of slightly yellowish crystals with a melting point of 163-167°C during cleavage.
Analyse: (C~oH^qN^CuS)Analysis: (C~oH^qN^CuS)
Eksempel 5. Example 5.
5,6 g 1-(4-acetamino-ferioksy)-3-aminb-propan-2-ol 5.6 g 1-(4-acetamino-ferroxy)-3-aminob-propan-2-ol
5,3 g 2,4-dimetyl-5-pyrimidylkarbonyl-aceton og 50 ml vannfri etanol oppvarmes 20 timer ved 4o°C I reaksjonsblandingen innfører man ved 70°C porsjonsvis 3,0 g natriumboranat og oppvarmer videre i 7'timer ved 70°C. Deretter inndampes under nedsatt trykk og residuet opptas i vann og n-pentanol. Pentanolopp-løsningen utrører man med vann og innstiller derved sistnevnte ved tilsetning av fortynnet svovelsyre til pH 6,5, adskiller og utrører den klare vandige oppløsning ved .pH 9,5 igjen med n-pentan<p>l. Ved inndampning av denne pentanoloppløsning får man .4,5 g bare svakt forurenset 1- (2 , 4-dimetyl-5-pyrimidyl)-3- (l-/__p-acetamino-f enoksy_7-2-hydroksy-propyl-3-amino)-butan-l-ol med formel 5.3 g of 2,4-dimethyl-5-pyrimidylcarbonyl-acetone and 50 ml of anhydrous ethanol are heated for 20 hours at 4o°C. In the reaction mixture, 3.0 g of sodium borate are introduced in portions at 70°C and further heated for 7 hours at 70° C. It is then evaporated under reduced pressure and the residue taken up in water and n-pentanol. The pentanolop solution is stirred with water and thereby the latter is adjusted by the addition of dilute sulfuric acid to pH 6.5, the clear aqueous solution is separated and stirred again at pH 9.5 with n-pentane<p>l. Evaporation of this pentanol solution gives 4.5 g of only slightly contaminated 1-(2,4-dimethyl-5-pyrimidyl)-3-(l-/__p-acetamino-phenoxy_7-2-hydroxy-propyl-3- amino)-butan-1-ol of formula
som seig olje, som kan.vidererenses søylekromatografisk. as a viscous oil, which can be further purified by column chromatography.
Analyse: (C2-j^H qN^O^ ) . Analysis: (C2-j^H qN^O^ ) .
Til en oppløsning av basen i etanol.har man 0,48 mol-ekvivalenter L-(+)-vinsyre, inndamper reaksjonsblandingen under nedsatt trykk og utrører overnevnte residu flere ganger med ren eddik syreetylester. Man får hvite hygroskopiske krystaller av det nøy-trale tartrat av 1-(2,4-dimetyl-5-pyrimidyl)-3-(1-_/p-acetamino-fénoksy_7-2-hydroksy-propy 1-3-amino)-butan-l-ol med formel For a solution of the base in ethanol, one has 0.48 mol equivalents of L-(+)-tartaric acid, evaporates the reaction mixture under reduced pressure and stirs the above-mentioned residue several times with pure acetic acid ethyl ester. White hygroscopic crystals of the neutral tartrate of 1-(2,4-dimethyl-5-pyrimidyl)-3-(1-_/p-acetamino-phenoxy_7-2-hydroxy-propyl 1-3-amino) are obtained -butan-l-ol of formula
Smeltepunkt 83-87 C under spaltning. Melting point 83-87 C during decomposition.
Analyse: (C2 H^N^O,.. 2H20). Analysis: (C 2 H^N^O,.. 2H 2 O).
Ekse mpel 6. Example 6.
På samme måte som i eksemplene 1 til 4 fremstilles følgende stofjfer: In the same way as in examples 1 to 4, the following substances are produced:
De som utgangsstbffer anvendte 1-aryloksy-3-amino-propan-2-oler kan fremstilles etter vanlige metoder, f.eks. ved omsetning av ammoniakk.med 1-aryloksy-2,3-epoksypropaner The 1-aryloxy-3-amino-propan-2-ols used as starting materials can be prepared by usual methods, e.g. by reaction of ammonia with 1-aryloxy-2,3-epoxypropanes
Sistnevnte oppstår på kjent måte.også av tilsvarende fenoler og epiklorhydrin. The latter occurs in a known manner, also from corresponding phenols and epichlorohydrin.
Man får således f.eks: , 1-(4-n-propoksy-fenoksy)'-2 ,3pepoksy-propan Sm.punkt 43-45° 1-(4-nppropoksy-fenoksy)-3-amino-propan-2-ol " 99-101° 1-(4-i-propoksy-fenoksy)-2,3-epoksy-propan olje, kokepunkt 112-115 / One thus obtains, for example: -ol " 99-101° 1-(4-i-propoxy-phenoxy)-2,3-epoxy-propane oil, boiling point 112-115 /
0,2 torr 1-(4-i-propoksy-fenoksy)-3-amino-propan-2-ol Sm.punkt 76-78 l-'(3-n-butoksy-fen.oksy)-2,3-epoksy-propan olje, kokepunkt 133-137°/ 0.2 torr 1-(4-i-propoxy-phenoxy)-3-amino-propan-2-ol Sm. point 76-78 1-(3-n-butoxy-phen.oxy)-2,3- epoxy-propane oil, boiling point 133-137°/
0,1 torr 1-(3-n-but.oksy-fenoksy )-3-amino-propan-2-ol Sm.punkt 59-60° 1-(2-fluor-fenoksy)-2,3-epoksy-propan olje, kokepunkt 90-92°/ 0.1 torr 1-(3-n-but.oxy-phenoxy)-3-amino-propan-2-ol Melting point 59-60° 1-(2-fluoro-phenoxy)-2,3-epoxy- propane oil, boiling point 90-92°/
0,1 torr 1-(2-fluor-fenoksy)-3-amino-propan-2-ol Sm.punkt 64-66° 1-(4-n-oktyloksy-fenoksy)-2,3-epoksy-propan 46-48 1-.( 4-n-oktyloksy-f enoksy )-3-åmino-prop'an-2-ol " 106-107 1-(4-benzyloksy-fenoksy)-2,3-epoksy-propan ". 55 1-(4-benzyloksy-fenoksy)-3-aminb-propan-2-ol " l43-l45 l-(4-tert.pbutyl-fenoksy)-2,3-epoksy-propan olje, kokepunkt 110-112°/ 0.1 torr 1-(2-fluoro-phenoxy)-3-amino-propan-2-ol Melting point 64-66° 1-(4-n-octyloxy-phenoxy)-2,3-epoxy-propane 46 -48 1-.( 4-n-octyloxy-phenoxy )-3-amino-prop'an-2-ol " 106-107 1-(4-benzyloxy-phenoxy)-2,3-epoxy-propane ". 55 1-(4-benzyloxy-phenoxy)-3-aminob-propan-2-ol " l43-l45 l-(4-tert.pbutyl-phenoxy)-2,3-epoxy-propane oil, boiling point 110-112° /
0,2 torr 1-(4-tert.-butyl-fenoksy)-3-amino-propan-2-ol Sm.punkt 106-108° 1-(4-n-pentyloksy-fenoksy)-2,3-epoksy-propan " 37_38° 1-(4-n-pentyloksy-fenoksy)-3-amino-propån-2-ol " 101-103°' 0.2 torr 1-(4-tert-butyl-phenoxy)-3-amino-propan-2-ol Melting point 106-108° 1-(4-n-pentyloxy-phenoxy)-2,3-epoxy -propane " 37_38° 1-(4-n-pentyloxy-phenoxy)-3-amino-propan-2-ol " 101-103°'
Eksempel 7-Example 7-
2,2 g l-(2,4-dimetyl-5-pyrimidyl)-3-(l-/~p-n-butoksy-fenoksy7-2-hydroksy-propyl-3-amino)-butan-l-ol med formel 2.2 g of 1-(2,4-dimethyl-5-pyrimidyl)-3-(1-/~p-n-butoxy-phenoxy-7-2-hydroxy-propyl-3-amino)-butan-1-ol of formula
oppvarmes med 20 ml etanol og 0,55 ml av en 39%- ig.vandig formaldehyd-.oppløsning i 4 timer under tilbakeløp. Reaksjonsblandingen inndampes og residuet opptas i 200 ml ligroin. Ved inndampning av den med litt aktivkull klare oppløsning får man 1,7 g 3-(l-hydroksy-l-/_ 2,4-dimetyl-5-pyrimidyl7-3-butyl)-5-(4-n-butyloksy-fenoksymetyl)-oksazolidin med formel is heated with 20 ml of ethanol and 0.55 ml of a 39% aqueous formaldehyde solution for 4 hours under reflux. The reaction mixture is evaporated and the residue taken up in 200 ml of naphtha. By evaporating the clear solution with a little activated carbon, 1.7 g of 3-(1-hydroxy-1-/_ 2,4-dimethyl-5-pyrimidyl7-3-butyl)-5-(4-n-butyloxy- phenoxymethyl)-oxazolidine of formula
som farveløs olje. as colorless oil.
Analyse: (C^<H>^<N>^) Analysis: (C^<H>^<N>^)
Eksempel 8. Example 8.
5,0 g 1-(2,4-dimetyl-5-pyrimidyl)-3-amino-n-butanol,5.0 g of 1-(2,4-dimethyl-5-pyrimidyl)-3-amino-n-butanol,
50 ml. etanol ( 96%- ig) og 9,1 g 1-(4-n-amyloksy-fenoksy)-2,3-epoksy-propan omrøres 20 timer ved værelsestemperatur og oppvarmes deretter 3 timer ved 40°C. Ved reaksjonsblandingens inndampning i vakuum får man 13,5 g rått 1-(2 , 4-dimetyl-5-pyrimidyl)-3-(l-/_p-n-amyloksy-fenoksy7-2-hydrpksy-propy1-(3)-amino)-butan-l-ol med formel 50 ml. ethanol (96% strength) and 9.1 g of 1-(4-n-amyloxy-phenoxy)-2,3-epoxy-propane are stirred for 20 hours at room temperature and then heated for 3 hours at 40°C. Evaporation of the reaction mixture in vacuo gives 13.5 g of crude 1-(2,4-dimethyl-5-pyrimidyl)-3-(l-/_p-n-amyloxy-phenoxy7-2-hydroxy-propyl-1-(3)- amino)-butan-1-ol of formula
Den ovenfor som utgangsprodukt anvendte 1-(2,4-dimety1-■5-pyrimidy 1)-3-amino-n-butanol fremstilles på følgende måte: 19,6 g (2,4-dim'etyl-5-pyrimidylkarbonyl)-aceton, 200 ml etanol og 0,3 g ammoniumbromid mettes ved 50°C med ammoniakk og., oppvarmes under ytterligere innføring av ammoniakk i 20 timer ved 50°C. I den således dannede oppløsning av 1-(2,4-dimetyl-5-pyrimidy1)-3-amino-but-2-en-on-l med formel The 1-(2,4-dimethyl-5-pyrimidinyl)-3-amino-n-butanol used above as starting product is prepared as follows: 19.6 g (2,4-dimethyl-5-pyrimidylcarbonyl) -acetone, 200 ml of ethanol and 0.3 g of ammonium bromide are saturated at 50°C with ammonia and., heated with further introduction of ammonia for 20 hours at 50°C. In the thus formed solution of 1-(2,4-dimethyl-5-pyrimidinyl)-3-amino-but-2-en-one-1 of formula
innføres i løpet av 1 time 8,0 g natriumboranat porsjonsvis og blandingen omrøres 7 timer ved 70°C. Man avdamper oppløsningsmidlet under vakuum og opptar residuet i vandig pottaskeoppløsning ( 20%) og 8.0 g of sodium boranate are introduced in portions over the course of 1 hour and the mixture is stirred for 7 hours at 70°C. The solvent is evaporated under vacuum and the residue is taken up in an aqueous potash solution (20%) and
■pentaol-1. Etter opparbeidelse på vanlig måte får man fra pentanol-oppløsningen 18,5 g rått 1-(2,4-dimetyl-5-pyrimidy1)-3-amirio-n-butanol med formel ■pentaol-1. After working up in the usual way, 18.5 g of crude 1-(2,4-dimethyl-5-pyrimidy1)-3-amirio-n-butanol with the formula is obtained from the pentanol solution
som olje, som kan vidererenses på søylekromatografisk måte. Analyse: (C-^H-^N^O) . Eksemp el 9• I en suspensjon av 8,0 g 1-(4-n-pentyloksy-fenoksy)-3-amino-propan-2-ol (fremstillet av p-n-pentoksy-fenol med epiklorhydrin og omsetning av reaksjonsproduktet med ammoniakk) og 16,0 g vannfri pottaske i 100 ml vannfritt toluen innføres i småporsjoner 8,9 g 1-(2,4-dimetyl-5-pyrimidyl)-3-klor-butan-l-ol-hydroklorid. Man omrører blandingen videre 10 timer ved værelsestemperatur og oppvarmer 5 timer i vannbad-. Etter avkjøling f rasuges. sålt og filtratet utrøres med vann og så meget saltsyre at det i den vandige fase innstiller seg pH • 3 Den sure oppløsning adskilles fra toluen og vaskes med eddikester. Deretter innstiller man alkalisk med pottaske og ekstraherer flere.ganger med kloroform. Ved tørkning og inndampning av kloroformoppløsningen får man 9,3 g rått'1-(2,4-di-metyl-5-pyr,imidyl)-3- (1-/__p-n-.penty loksy-f enoksy/-2-hy droksy-propy 1 (3)-amino)-butan-l-ol med formel as an oil, which can be further purified by column chromatography. Analysis: (C-^H-^N^O) . Example 9• In a suspension of 8.0 g of 1-(4-n-pentyloxy-phenoxy)-3-amino-propan-2-ol (prepared from p-n-pentoxy-phenol with epichlorohydrin and reaction of the reaction product with ammonia) and 16.0 g of anhydrous pot ash in 100 ml of anhydrous toluene are introduced in small portions 8.9 g of 1-(2,4-dimethyl-5-pyrimidyl)-3-chloro-butan-1-ol hydrochloride. The mixture is stirred for a further 10 hours at room temperature and heated for 5 hours in a water bath. After cooling f rasuke. salt and the filtrate is stirred with water and enough hydrochloric acid that the pH is set in the aqueous phase • 3 The acidic solution is separated from the toluene and washed with acetic acid. It is then made alkaline with pot ash and extracted several times with chloroform. By drying and evaporating the chloroform solution, 9.3 g of crude 1-(2,4-dimethyl-5-pyrimidyl)-3-(1-/__p-n-.pentyloxy-phenoxy) are obtained 2-hydroxy-propyl 1 (3)-amino)-butan-1-ol of formula
som olje, som vidererenses søylekromatografisk. as an oil, which is further purified by column chromatography.
Analyse: (C2 [(H ^N^O^ ) .Analysis: (C2 [(H ^N^O^ ) .
Det som.utgangsstoff anvendte 1-(2,4-dimetyl-5-pyrimidyl)-3^klor-butan-l-ol-hydroklorid fremstilles som følger: En suspensjon av natriumsaltet av (2,4-dimetyl-5-pyrimidylkarbony1)-aceton i vannfri toluen mettes méd hydrogenklorid og omsettes deretter på kjent måte med tionylklorid. Fra' reaksjons- . produktet får man ved reduksjon 1-(2 ^-dime-tyl-S-pyrimidyD^-klor-butan-l-ol-hydroklorid, som anvendes uten ytterligere rengjøring.. The 1-(2,4-dimethyl-5-pyrimidyl)-3-chloro-butan-1-ol hydrochloride used as starting material is prepared as follows: A suspension of the sodium salt of (2,4-dimethyl-5-pyrimidylcarbonyl) -acetone in anhydrous toluene is saturated with hydrogen chloride and then reacted in a known manner with thionyl chloride. From' reaction- . the product is obtained by reduction 1-(2^-dimethyl-S-pyrimidyD^-chloro-butan-l-ol-hydrochloride, which is used without further purification..
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DD (1) | DD115906A5 (en) |
DK (1) | DK654574A (en) |
FI (1) | FI362974A (en) |
HU (1) | HU170673B (en) |
NO (1) | NO744528L (en) |
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1974
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- 1974-12-16 FI FI3629/74A patent/FI362974A/fi unknown
- 1974-12-16 NO NO744528A patent/NO744528L/no unknown
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- 1974-12-19 SU SU742085463A patent/SU585813A3/en active
- 1974-12-19 HU HUCA378A patent/HU170673B/hu unknown
- 1974-12-19 AT AT1016374A patent/AT340436B/en not_active IP Right Cessation
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- 1974-12-19 DD DD183212A patent/DD115906A5/xx unknown
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DD115906A5 (en) | 1975-10-20 |
ATA1016374A (en) | 1977-04-15 |
ATA1016574A (en) | 1977-07-15 |
AT342055B (en) | 1978-03-10 |
SU553930A3 (en) | 1977-04-05 |
FI362974A (en) | 1975-06-21 |
SU580830A3 (en) | 1977-11-15 |
SE7415759L (en) | 1975-06-23 |
AT340436B (en) | 1977-12-12 |
AT340435B (en) | 1977-12-12 |
ATA1016274A (en) | 1977-04-15 |
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