CH650768A5 - BASIC ACETANILIDES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE ACETANILIDES. - Google Patents
BASIC ACETANILIDES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE ACETANILIDES. Download PDFInfo
- Publication number
- CH650768A5 CH650768A5 CH5116/82A CH511682A CH650768A5 CH 650768 A5 CH650768 A5 CH 650768A5 CH 5116/82 A CH5116/82 A CH 5116/82A CH 511682 A CH511682 A CH 511682A CH 650768 A5 CH650768 A5 CH 650768A5
- Authority
- CH
- Switzerland
- Prior art keywords
- acetanilides
- basic
- formula
- compounds
- methyl
- Prior art date
Links
- 150000008061 acetanilides Chemical class 0.000 title claims description 14
- 238000000034 method Methods 0.000 title claims description 7
- 229940126601 medicinal product Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 18
- 238000001816 cooling Methods 0.000 claims description 14
- -1 nitro, amino Chemical group 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 150000002367 halogens Chemical group 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 241000251730 Chondrichthyes Species 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 239000003416 antiarrhythmic agent Substances 0.000 claims description 2
- 150000002366 halogen compounds Chemical class 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 239000003589 local anesthetic agent Substances 0.000 claims description 2
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims 1
- 230000003288 anthiarrhythmic effect Effects 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 150000001649 bromium compounds Chemical class 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 150000001805 chlorine compounds Chemical class 0.000 claims 1
- 125000006312 cyclopentyl amino group Chemical group [H]N(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 claims 1
- 150000003840 hydrochlorides Chemical class 0.000 claims 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical class OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims 1
- 150000002688 maleic acid derivatives Chemical class 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 125000000547 substituted alkyl group Chemical group 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- 239000000203 mixture Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- WJXVVJBMBBAWQI-UHFFFAOYSA-N n-(2-amino-6-methylphenyl)-2-(diethylamino)acetamide Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1N WJXVVJBMBBAWQI-UHFFFAOYSA-N 0.000 description 4
- GWVVXBJLIITIRU-UHFFFAOYSA-N 2-(diethylamino)-N-(2-methyl-6-nitrophenyl)acetamide Chemical compound C(C)N(CC(=O)NC1=C(C=CC=C1[N+](=O)[O-])C)CC GWVVXBJLIITIRU-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- RWRXLGIHJKXIQY-UHFFFAOYSA-N 1-(2-amino-3-methylphenyl)propan-1-one Chemical compound CCC(=O)C1=CC=CC(C)=C1N RWRXLGIHJKXIQY-UHFFFAOYSA-N 0.000 description 2
- PQXGRUUJIFRFGC-UHFFFAOYSA-N 2-amino-3-methylbenzonitrile Chemical compound CC1=CC=CC(C#N)=C1N PQXGRUUJIFRFGC-UHFFFAOYSA-N 0.000 description 2
- DCEPUXBREZCBOH-UHFFFAOYSA-N 2-chloro-n-(2-ethoxy-6-methylphenyl)acetamide Chemical compound CCOC1=CC=CC(C)=C1NC(=O)CCl DCEPUXBREZCBOH-UHFFFAOYSA-N 0.000 description 2
- HHQVWQLHIHVNGR-UHFFFAOYSA-N 2-chloro-n-(2-methyl-6-nitrophenyl)acetamide Chemical compound CC1=CC=CC([N+]([O-])=O)=C1NC(=O)CCl HHQVWQLHIHVNGR-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- BAFUTTWRYOSVMT-UHFFFAOYSA-N N-(2-bromo-6-methylphenyl)-2-(diethylamino)acetamide Chemical compound C(C)N(CC(=O)NC1=C(C=CC=C1C)Br)CC BAFUTTWRYOSVMT-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 150000001408 amides Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000008064 anhydrides Chemical group 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- IFYZUHPFZSHBIW-UHFFFAOYSA-N n-(2-methyl-6-nitrophenyl)-2-piperidin-1-ylacetamide Chemical compound CC1=CC=CC([N+]([O-])=O)=C1NC(=O)CN1CCCCC1 IFYZUHPFZSHBIW-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- KWQFZJHENVVLKO-UHFFFAOYSA-N 2-(diethylamino)-N-(2-ethoxy-6-methylphenyl)acetamide Chemical compound C(C)N(CC(=O)NC1=C(C=CC=C1C)OCC)CC KWQFZJHENVVLKO-UHFFFAOYSA-N 0.000 description 1
- CWFVSMFYNPGGFM-UHFFFAOYSA-N 2-(diethylamino)-n-[2-(trifluoromethyl)phenyl]acetamide Chemical compound CCN(CC)CC(=O)NC1=CC=CC=C1C(F)(F)F CWFVSMFYNPGGFM-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- LDUCMSVRKKDATH-UHFFFAOYSA-N 2-bromo-6-methylaniline Chemical compound CC1=CC=CC(Br)=C1N LDUCMSVRKKDATH-UHFFFAOYSA-N 0.000 description 1
- UENGBOCGGKLVJJ-UHFFFAOYSA-N 2-chloro-1-(2,4-difluorophenyl)ethanone Chemical compound FC1=CC=C(C(=O)CCl)C(F)=C1 UENGBOCGGKLVJJ-UHFFFAOYSA-N 0.000 description 1
- XIIQMFOFZWGXOF-UHFFFAOYSA-N 2-chloro-n-(2-methyl-6-propanoylphenyl)acetamide Chemical compound CCC(=O)C1=CC=CC(C)=C1NC(=O)CCl XIIQMFOFZWGXOF-UHFFFAOYSA-N 0.000 description 1
- BZNNHUKHVZUGGQ-UHFFFAOYSA-N 2-chloro-n-(2-propanoylphenyl)acetamide Chemical compound CCC(=O)C1=CC=CC=C1NC(=O)CCl BZNNHUKHVZUGGQ-UHFFFAOYSA-N 0.000 description 1
- GCSXEMRXTRHXIS-UHFFFAOYSA-N 2-chloro-n-[2-(trifluoromethyl)phenyl]acetamide Chemical compound FC(F)(F)C1=CC=CC=C1NC(=O)CCl GCSXEMRXTRHXIS-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical group CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- YDPXZINXUVCZKH-UHFFFAOYSA-N 2-ethoxy-6-methylaniline Chemical compound CCOC1=CC=CC(C)=C1N YDPXZINXUVCZKH-UHFFFAOYSA-N 0.000 description 1
- PLLAJAIUQAEKKD-UHFFFAOYSA-N 2-pyrrolidin-1-yl-n-[2-(trifluoromethyl)phenyl]acetamide Chemical compound FC(F)(F)C1=CC=CC=C1NC(=O)CN1CCCC1 PLLAJAIUQAEKKD-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- RPVSUGBUDNVQAJ-UHFFFAOYSA-N N-(2-ethoxy-6-methylphenyl)-2-piperidin-1-ylacetamide Chemical compound N1(CCCCC1)CC(=O)NC1=C(C=CC=C1C)OCC RPVSUGBUDNVQAJ-UHFFFAOYSA-N 0.000 description 1
- DKFSVJLTJMBBOU-UHFFFAOYSA-N N-(2-ethoxy-6-methylphenyl)-2-pyrrolidin-1-ylacetamide Chemical compound N1(CCCC1)CC(=O)NC1=C(C=CC=C1C)OCC DKFSVJLTJMBBOU-UHFFFAOYSA-N 0.000 description 1
- VFFBKGIWYOIKIS-UHFFFAOYSA-N N-(2-propanoylphenyl)-2-pyrrolidin-1-ylacetamide Chemical compound N1(CCCC1)CC(=O)NC1=C(C=CC=C1)C(CC)=O VFFBKGIWYOIKIS-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 238000000297 Sandmeyer reaction Methods 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000003931 anilides Chemical class 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- BDVSONRJQWXMHG-UHFFFAOYSA-N cyclopentylazanium;chloride Chemical compound Cl.NC1CCCC1 BDVSONRJQWXMHG-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 1
- LOQKSYGVWNTCHM-UHFFFAOYSA-N n-(2-amino-6-methylphenyl)-2-piperidin-1-ylacetamide Chemical compound CC1=CC=CC(N)=C1NC(=O)CN1CCCCC1 LOQKSYGVWNTCHM-UHFFFAOYSA-N 0.000 description 1
- WRYADRGFDISCSG-UHFFFAOYSA-N n-(2-chloro-6-methylphenyl)-2-(cyclopropylamino)acetamide Chemical compound CC1=CC=CC(Cl)=C1NC(=O)CNC1CC1 WRYADRGFDISCSG-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229940094025 potassium bicarbonate Drugs 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229940093956 potassium carbonate Drugs 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- CBPYOHALYYGNOE-UHFFFAOYSA-M potassium;3,5-dinitrobenzoate Chemical compound [K+].[O-]C(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 CBPYOHALYYGNOE-UHFFFAOYSA-M 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940001593 sodium carbonate Drugs 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
Landscapes
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Description
35 Die vorliegende Erfindung betrifft neue basische Acetanilide, ein Verfahren zu deren Herstellung und Arzneimittel, die diese neuen Acetanilide enthalten. 35 The present invention relates to new basic acetanilides, a process for their preparation and pharmaceutical compositions containing these new acetanilides.
Das Ziel der vorliegenden Erfindimg besteht darin, neue Verbindungen zur Verfügung zu stellen, die beispielsweise 40 als Lokalanästhetikum und antiarrhythmisch wirksame Mittel verwendet werden können, und die eine geringere Toxizität und eine verbesserte Wirksamkeit als die im Stand der Technik bekannten Verbindungen aufweisen. The aim of the present invention is to provide new compounds which can be used, for example, as a local anesthetic and antiarrhythmic agents, and which have a lower toxicity and an improved activity than the compounds known in the prior art.
Es ist ein weiteres Ziel der vorliegenden Erfindung, ein-45 fach durchzuführende und wirtschaftlich interessante Verfahren zur Herstellung der neuen Verbindungen zur Verfügung zu stellen. It is a further object of the present invention to provide simple and economically interesting processes for the preparation of the new compounds.
Diese Ziele werden erreicht mit den erfindungsgemässen basischen Acetaniliden der Formel III These goals are achieved with the basic acetanilides of the formula III according to the invention
50 50
55 55
NH-C-CVRc n co NH-C-CVRc n co
0 0
m m
X-CO-CHg-Hal worin X-CO-CHg-Hal wherein
Rj Wasserstoff oder gegebenenfalls substituiertes Alkyl-II bedeutet, und worin 65 R4 Halogen, gegebenenfalls substituiertes Alkoxy, gege- Rj is hydrogen or optionally substituted alkyl-II, and in which 65 R4 halogen, optionally substituted alkoxy,
X eine Hydroxylgruppe, einen Esterrest, ein Halogenid, benenfalls substituiertes Alkylthio, Nitro, Amino oder geeinen Amidrest oder einen Anhydridrest oder eine andere gebenenfalls substituiertes Alkylamino, Propionyl öder Tri-geeignete Abgangsgruppe bedeutet, und fluormethyl bedeutet, und X denotes a hydroxyl group, an ester residue, a halide, optionally substituted alkylthio, nitro, amino or a partial amide residue or an anhydride residue or another optionally substituted alkylamino, propionyl or tri-suitable leaving group, and means fluoromethyl, and
4 4th
3 3rd
650768 650768
R5 einen basischen Rest bedeutet, sowie ihren pharmakologisch verwendbaren Salzen. R5 represents a basic radical, and their pharmacologically acceptable salts.
Das erfindungsgemässe Verfahren zur Herstellung der neuen basischen Acetanilide der Formel III The process according to the invention for the preparation of the new basic acetanilides of the formula III
pharmakologisch verwendbaren Salzen, ist dadurch gekennzeichnet, dass man ein Anilin der Formel I pharmacologically acceptable salts, is characterized in that an aniline of the formula I
worin Ri und R4 weiter oben definiert sind, mit einer Halogenverbindung der Formel II wherein Ri and R4 are defined above, with a halogen compound of formula II
X-CO-CH2-Hal II X-CO-CH2-Hal II
worin wherein
X eine Hydroxylgruppe, einen Esterrest, ein Halogenid, einen Amidrest oder einen Anhydridrest oder eine andere geeignete Abgangsgruppe bedeutet, und X represents a hydroxyl group, an ester radical, a halide, an amide radical or an anhydride radical or another suitable leaving group, and
Hai ein Halogenatom oder eine andere geeignete Abgangsgruppe bedeutet, unter Kühlung oder bei Zimmertemperatur in einem Lösungsmittel und in Gegenwart einer Base zu einer Verbindung der Formel IV Hai represents a halogen atom or another suitable leaving group, with cooling or at room temperature in a solvent and in the presence of a base to give a compound of the formula IV
worin R1; R4 und Hai weiter oben definiert sind, umsetzt, diese Verbindungen anschliessend mit einer den Rest R5 abgebenden Verbindung in einem inerten Lösungsmittel bei erhöhter Temperatur umsetzt, und erhaltene Verbindungen gegebenenfalls in ihre pharmakologisch verwendbaren Salze überführt. wherein R1; R4 and shark are defined above, reacted, these compounds are then reacted with a compound which gives off the radical R5 in an inert solvent at elevated temperature, and the compounds obtained are optionally converted into their pharmacologically acceptable salts.
Die Zwischenprodukte der Formel IV werden so hergestellt, dass man Halogenfettsäuren oder geeignete Derivate, wie deren Ester, Halogenide (z.B. Säurechlorid oder Bromid), Amide oder Anhydride auf ein Anilin unter Kühlung oder bei Zimmertemperatur in einem Lösungsmittel, z.B. Aceton, Essigsäure, Essigsäureethylester, Chloroform, in Gegenwart einer Base, wie Natriumcarbonat, Kaliumcarbonat, Natriumoder Kaliumbicarbonat, Natriumacetat, oder in wässrigem Natrium-acetat-Puffer einwirken lässt. Die Halogenacet-anilide der allgemeinen Formel IV werden mit einem Amin in einem inerten Lösnugsmittel, vorzugsweise Benzol, bei 5 erhöhter Temperatur umgesetzt. The intermediates of formula IV are prepared by halogen fatty acids or suitable derivatives such as their esters, halides (e.g. acid chloride or bromide), amides or anhydrides on an aniline with cooling or at room temperature in a solvent, e.g. Acetone, acetic acid, ethyl acetate, chloroform, in the presence of a base such as sodium carbonate, potassium carbonate, sodium or potassium bicarbonate, sodium acetate, or in aqueous sodium acetate buffer. The haloacetanilides of the general formula IV are reacted with an amine in an inert solvent, preferably benzene, at an elevated temperature.
Die Acetanilide der allgemeinen Formel III können auch ohne Isolierung des Zwischenproduktes der Formel IV hergestellt werden, indem man nach der Halogenalkanoylie-rung das entsprechende Amin in einem höher siedenden io inerten Lösungsmittel, z.B. Toluol oder Xylol, dem Reaktionsgemisch beifügt und nachher erhitzt. The acetanilides of the general formula III can also be prepared without isolation of the intermediate of the formula IV by, after the haloalkanoylation, the corresponding amine in a higher boiling io inert solvent, e.g. Toluene or xylene, added to the reaction mixture and then heated.
Die Verbindungen der allgemeinen Formel III, in denen R4 Amino bedeutet, können aus den entsprechenden Acet-aniliden der Formel III, in denen R4 Nitro bedeutet, durch 15 Reduktion hergestellt werden. The compounds of the general formula III in which R4 is amino can be prepared from the corresponding acetanilides of the formula III in which R4 is nitro by reduction.
Die Acetanilide der Formel III, in denen R4 Halogen bedeutet, können entweder aus den entsprechenden Anili-nen, wie oben beschrieben, oder aus den Acetaniliden, in denen R44 Amino bedeutet, mit der Sandmeyer Reaktion 20 hergestellt werden. The acetanilides of the formula III in which R4 is halogen can either be prepared from the corresponding anilines, as described above, or from the acetanilides in which R44 is amino, using the Sandmeyer reaction 20.
Unter einem basischen Rest wird irgend ein Rest verstanden, der wenigstens ein basisches Stickstoffatom enthält. A basic radical is understood to mean any radical which contains at least one basic nitrogen atom.
Gegebenenfalls können im erfindungsgemässen Verfah-« ren auch Katalysatoren eingesetzt werden. Die passenden Reaktionstemperaturen und Reaktionszeiten können leicht vom Fachmann ermittelt werden. Gewöhnlich wird unter Normaldruck gearbeitet, wobei aber Überdruck und Unterdruck (Vakuum) nicht ausgeschlossen sind. 30 Die Verabfolgung der erfindungsgemässen Verbindungen der Formel III erfolgt in üblicher Weise, wie sie im Stand der Technik für die bekannten Verbindungen üblich ist. If appropriate, catalysts can also be used in the process according to the invention. The appropriate reaction temperatures and reaction times can easily be determined by a person skilled in the art. Usually work is carried out under normal pressure, but overpressure and underpressure (vacuum) are not excluded. The compounds of the formula III according to the invention are administered in the customary manner as is customary in the prior art for the known compounds.
Die bevorzugten Ausführungsformen sind aus den Bei-35 spielen ersichtlich, wo auch einige neue Ausgangs- und Zwischenprodukte beschrieben werden. The preferred embodiments can be seen in Examples 35-, where some new starting and intermediate products are also described.
A. Mit Isolierung des Zwischenproduktes der Formel IV A. With isolation of the intermediate of formula IV
40 Beispiel 1 40 Example 1
Zu einem Gemisch von 53 g (0,35 Mol) 2-Ethoxy-6-me-thylanilin in 525 ml absol. Aceton und 70 g Natriumbi-carbonat wird unter Eiskühlung während einer Stunde 46 g (0,4 Mol) Chloracetylchlorid zugetropft, nachher eine Stunde 45 bei Raumtemperatur gerührt. Das anorganische Salz wird abgesaugt und mit Aceton gewaschen. Das Filtrat' wird im Vakuum der Wasserstrahlpumpe eingeengt, zum Rückstand wird Wasser beigefügt und die ausgeschiedenen Kristalle des 2-Chlor-2'-ethoxy-6'-methyl-acetanilids, Smp. 148-149°, 50 werden abgesaugt. To a mixture of 53 g (0.35 mol) of 2-ethoxy-6-methylaniline in 525 ml of absolute. Acetone and 70 g of sodium bicarbonate are added dropwise with ice cooling, 46 g (0.4 mol) of chloroacetyl chloride over an hour, after which the mixture is stirred for 45 hours at room temperature. The inorganic salt is filtered off and washed with acetone. The filtrate is concentrated in vacuo in the water jet pump, water is added to the residue and the crystals of 2-chloro-2'-ethoxy-6'-methyl-acetanilide which have separated out, mp. 148-149 °, 50 are suctioned off.
Beispiel 2 Example 2
In der gleichen Weise wie im Beispiel 1 beschrieben wird 2-Chlor-2'-methyl-6'-nitro-acetanilid erhalten, Smp. 55 140-141,5°C, wenn anstelle von 2-Ethoxy-6-methyl-anilin 2-MethyI-6-nitro-anilin eingesetzt wird. In the same way as described in Example 1, 2-chloro-2'-methyl-6'-nitro-acetanilide is obtained, mp 55 140-141.5 ° C., if instead of 2-ethoxy-6-methyl-aniline 2-Methyl-6-nitro-aniline is used.
Aminierung Amination
60 Beispiel 1 60 Example 1
Zu 10,25 g (0,045 Mol) 2-Chlor-2'-ethoxy-6'-methyl-acetanilid in 100 ml Benzol werden 10 g (0,136 Mol) Di-ethylamin beigefügt und das Gemisch 6 Stunden unter Rückfluss gekocht. Nach Erkalten wird das ausgeschiedene 65 Diethylamin-hydrochlorid abgesaugt, mit Benzol gewaschen, das Filtrat im Vakuum der Wasserstrahlpumpe eingeengt. Der Rückstand wird mit Wasser und Ether versetzt, die Base aus der Ether-Schicht in 5% Salzsäure extrahiert, die wäss 10 g (0.136 mol) of di-ethylamine are added to 10.25 g (0.045 mol) of 2-chloro-2'-ethoxy-6'-methyl-acetanilide in 100 ml of benzene and the mixture is boiled under reflux for 6 hours. After cooling, the 65 diethylamine hydrochloride which has separated out is filtered off with suction, washed with benzene and the filtrate is concentrated in vacuo of the water jet pump. The residue is mixed with water and ether, the base extracted from the ether layer in 5% hydrochloric acid, the aq
650768 650768
4 4th
rige saure Lösung alkalisiert und mit Ether ausgeschüttelt. Nach Trocknen und Abdampfen des Ethers wird der Rückstand in Ethanol gelöst und unter Kühlung etherischer Chlorwasserstoff zugetropft und das Hydrochlorid des 2-Di-ethylamino-2'-ethoxy-6'-methyl-acetanilids, Smp. 107-109°, erhalten. alkaline acid solution and shaken with ether. After the ether has been dried and evaporated, the residue is dissolved in ethanol and ethereal hydrogen chloride is added dropwise with cooling, and the hydrochloride of 2-di-ethylamino-2'-ethoxy-6'-methyl-acetanilide, mp 107-109 °, is obtained.
Beispiel 2 Example 2
In der gleichen Weise wie im Beispiel 1 wird 2-Piperidi-no-2'-ethoxy-6'-mehyl-acetanilid, Smp. 79-80°, erhalten und die Base zum Hydrochlorid, Smp. 192-193°, umgesetzt, falls anstatt Diethylamin Piperidin eingesetzt wird. In the same way as in Example 1, 2-piperidino-2'-ethoxy-6'-methyl-acetanilide, mp. 79-80 °, is obtained and the base is converted to the hydrochloride, mp. 192-193 °, if piperidine is used instead of diethylamine.
Beispiel 3 Example 3
Wird anstatt Diethylamin Pyrrolidin eingesetzt, wird wie im Beispiel 1 2-Pyrrolidino-2'-ethoxy-6'-methyl-acetanilid, Smp. 60,5-62°, erhalten, das zum Hydrochlorid, Smp. 180-181,5°, umgesetzt wird. If pyrrolidine is used instead of diethylamine, 2-pyrrolidino-2'-ethoxy-6'-methyl-acetanilide, mp. 60.5-62 °, is obtained, as in Example 1, to give the hydrochloride, mp. 180-181.5 ° , is implemented.
Beispiel 4 Example 4
In gleicher Weise wie im Beispiel 1 wird aus 2-Chlor--2'-methyl-6'-nitroacetanilid und Diethylamin das 2-Diethyl-amino-2'-methyl-6'-nitro-acetanilid, Smp. 60-61°, und dessen Hydrochlorid, Smp. 166-168°, erhalten. In the same way as in Example 1, 2-chloro-2'-methyl-6'-nitroacetanilide and diethylamine become 2-diethylamino-2'-methyl-6'-nitro-acetanilide, mp 60-61 ° , and its hydrochloride, mp. 166-168 °, obtained.
Beispiel 5 Example 5
Wird anstatt Diethylamin Piperidin eingesetzt, wird wie im Beispiel 1 2-Piperidino-2'-methyl-6'-nitro-acetanilid, Smp. 72-73°, und das Hydrochlorid, Smp. 192-194°, hergestellt. If piperidine is used instead of diethylamine, 2-piperidino-2'-methyl-6'-nitro-acetanilide, mp 72-73 °, and the hydrochloride, mp 192-194 °, are prepared as in Example 1.
Beispiel 6 Example 6
In gleicher Weise wie im Beispiel 1 wird das Hydrochlorid des 2-Diethylamino-2'-trifluormethyl-acetanilids, Smp. 160,1°, hergestellt, wenn 2-Chlor-2'-trifluormethyl-acetanilid und Diethylamin eingesetzt werden. In the same way as in Example 1, the hydrochloride of 2-diethylamino-2'-trifluoromethyl-acetanilide, mp. 160.1 °, is prepared if 2-chloro-2'-trifluoromethyl-acetanilide and diethylamine are used.
Beispiel 7 Example 7
Wird anstelle von Diethylamin Pyrrolidin eingesetzt, wird wie im Beispiel 1 und 6 das Hydrochlorid des 2-Pyrrolidino--2'-trifluormethyl-acetanilids, Smp. 229,4°, erhalten. If pyrrolidine is used instead of diethylamine, the hydrochloride of 2-pyrrolidino - 2'-trifluoromethyl-acetanilide, mp 229.4 °, is obtained as in Examples 1 and 6.
Beispiel 8 Example 8
Wie im Beispiel 1 beschrieben, wird das Hydrochlorid des 2-Pyrrolidino-2'-propionyl-acetanilids hergestellt, wenn 2-Ch]or-2'-propionyl-acetanilid und Pyrrolidin eingesetzt werden. As described in Example 1, the hydrochloride of 2-pyrrolidino-2'-propionyl-acetanilide is produced when 2-chloro-2'-propionyl-acetanilide and pyrrolidine are used.
Beispiel 9 Example 9
Wie im Beispiel 1 beschrieben, wird das Hydrochlorid des 2-Pyrrolidino-2'-methyl-6'-propionyl-acetaniIids, Smp. 192,6°, hergestellt, wenn 2-Chlor-2'-methyl-6'-propionyl-acet-anilid und Pyrrolidin eingesetzt werden. As described in Example 1, the hydrochloride of 2-pyrrolidino-2'-methyl-6'-propionylacetanide, mp. 192.6 °, is prepared when 2-chloro-2'-methyl-6'-propionyl- acetanilide and pyrrolidine are used.
Das als Ausgangsprodukt verwendet 2-Methyl-6-propio-nyl-anilin wird aus 2-Amino-3-methyl-benzonitril wie folgt hergestellt: The 2-methyl-6-propionyl-aniline used as the starting product is prepared from 2-amino-3-methyl-benzonitrile as follows:
Aus 6,3 g (0,26 Mol) Magnesium und 25,5 g Ethylbro-mid in 130 ml absol. Ether wird das Ethylmagnesiumbro-mid hergestellt und 30 Minuten auf dem Wasserbad erwärmt. Anschliessend wird eine Lösung von 6,65 g (0,05 Mol) 2-Amino-3-methyl-benzonitril in 100 ml absol. Ether langsam zugetropft und die Mischung 15 Stunden unter Rühren am Rückfluss gekocht. Nach Erkalten wird es auf 110 g Eis geschüttet und die Lösung von 15,6 g Ammoniumchlorid in 67 ml Wasser wird hinzugegeben. Die Ether-Schicht wird abgetrennt, und die wässrige Schicht wird mit Ether ausgeschüttelt. Von den vereinigten Ether-Phasen wird der Ether abdestilliert und der Rückstand mit 9,5 ml Wasser und 11,2 ml konzentrierter Salzsäure 30 Minuten am Rückfluss gekocht. Nach dem Erkalten wird mit Ether ausgeschüttelt, die wässrige Schicht alkalisiert und mit Ether extrahiert. Nach Trocknen und Abdampfen des Ethers wird 5 das 2-Methyl-6-propionyl-anilin erhalten, das als Hydrochlorid, Smp. 191,2°, charakterisiert wurde. From 6.3 g (0.26 mol) of magnesium and 25.5 g of ethyl bromide in 130 ml of absolute. The ethylmagnesium bro-mid is produced in ether and heated on a water bath for 30 minutes. A solution of 6.65 g (0.05 mol) of 2-amino-3-methyl-benzonitrile in 100 ml of absolute. Ether slowly added dropwise and the mixture was refluxed for 15 hours with stirring. After cooling, it is poured onto 110 g of ice and the solution of 15.6 g of ammonium chloride in 67 ml of water is added. The ether layer is separated and the aqueous layer is shaken out with ether. The ether is distilled off from the combined ether phases and the residue is refluxed for 30 minutes with 9.5 ml of water and 11.2 ml of concentrated hydrochloric acid. After cooling, the mixture is shaken out with ether, the aqueous layer is alkalized and extracted with ether. After drying and evaporation of the ether, 5 the 2-methyl-6-propionyl-aniline is obtained, which was characterized as the hydrochloride, mp. 191.2 °.
Beispiel 10 Example 10
Zu 10,9 g (0,05 Mol) 2-Chlor-2'-chlor-6'-mehylacet-io anilid in 30 ml absol. Toluol werden 12,75 g (0,15 Mol) Cyclopentylamin in 50 ml Toluol beigefügt und 6 Stunden am Rückfluss gekocht. Nach Erkalten wird das ausgeschiedene Cyclopentylamin-hydrochlorid abgesaugt, das Filtrat eingeengt und der Rückstand mit Wasser und Ether versetzt 's Vom Ether wird in 5% Salzsäurelösung extrahiert, aus der das Hydrochlorid des 2-Cyclopentylamino-2'-chlor-6'-me-thyl-acetanilids auskristallisiert, Smp. 209,7°. To 10.9 g (0.05 mol) of 2-chloro-2'-chloro-6'-mehylacet-io anilide in 30 ml of absolute. Toluene, 12.75 g (0.15 mol) of cyclopentylamine in 50 ml of toluene are added and the mixture is boiled under reflux for 6 hours. After cooling, the cyclopentylamine hydrochloride which has separated out is filtered off with suction, the filtrate is concentrated and the residue is mixed with water and ether. The ether is extracted in 5% hydrochloric acid solution, from which the hydrochloride of 2-cyclopentylamino-2'-chloro-6'-me -thyl-acetanilids crystallized, mp. 209.7 °.
Aus 1 g des Hydrochlorids wurde die Base, Smp. 76,8°, hergestellt. The base, mp 76.8 °, was prepared from 1 g of the hydrochloride.
20 20th
Beispiel 11 Example 11
Wird zum 2-Chlor-2'-chlor-6'-methyl-acetanilid Cyclo-propylamin in Benzol zugefügt und in einem mit Glaseinsatz versehenen Autoklaven 10 Stunden auf 100° erhitzt und 25 nach dem Erkalten wie im Beispiel 1 verarbeitet, wird das Hydrochlorid des 2-Cyclopropylamino-2'-chlor-6'-methyl--acetanilids, Smp. 257°, erhalten. Is added to the 2-chloro-2'-chloro-6'-methyl-acetanilide cyclo-propylamine in benzene and heated in an autoclave provided with glass for 10 hours at 100 ° and processed 25 after cooling as in Example 1, the hydrochloride of 2-cyclopropylamino-2'-chloro-6'-methyl-acetanilide, mp. 257 °, obtained.
B. Ohne Isolierung des Zwischenproduktes der Formel IV B. Without isolation of the intermediate of formula IV
30 30th
Beispiel 1 example 1
Zu 18,6 g (0,1 Mol) 2-Brom-6-methyl-anilin in 150 ml absol. Aceton und 20 g Natriumbicarbonat wird unter Eiskühlung während einer Stunde 12 g (0,11 Mol) Chloracetyl-35 chlorid zugetropft und nachher bei Raumtemperatur 30 Minuten gerührt. Zum Gemisch werden 22 g (0,3 Mol) Diethylamin in 50 ml Toluol zugegeben und unter Rückfluss 6 Stunden gekocht. Die Verarbeitung erfolgt in der gleichen Weise wie unter A im Beispiel 1 beschrieben. To 18.6 g (0.1 mol) of 2-bromo-6-methyl-aniline in 150 ml of absolute. Acetone and 20 g of sodium bicarbonate are added dropwise to 12 g (0.11 mol) of chloroacetyl-35 chloride while cooling with ice and then stirred at room temperature for 30 minutes. 22 g (0.3 mol) of diethylamine in 50 ml of toluene are added to the mixture and the mixture is boiled under reflux for 6 hours. The processing is carried out in the same way as described under A in Example 1.
40 Es wird das Hydrochlorid des 2-Diethylamino-2'-brom--6'-methyl-acetanilids, Smp. 172-174°, erhalten. 40 The hydrochloride of 2-diethylamino-2'-bromo-6'-methyl-acetanilide, mp 172-174 °, is obtained.
a) Dasselbe 2-Diethylamino-2'-brom-6'-methyl-acet-anilid kann aus 2-Diethylamino-2'-amino-6'-methyl-acet-anilid nach Sandmeyer wie folgt hergestellt werden: 45 11,75 g (0,05 Mol) 2-Diethylamino-2'-amino-6'-methyl--acetanilid in 30 ml 48% Bromwasserstoff werden im Eisbad gekühlt und bei —5° mit 3,45 g Natriumnitrit in 20 ml Wasser während 30 Minuten diazotiert (Jodstärke-Papier Prüfung) und nachher 40 Minuten bei —5°C gerührt Die 50 Suspension wird langsam zu einem auf 70° erhitzten Gemisch von 4 g CuBr in 20 ml 48% Bromwasserstoff zugegeben und 2 Stunden bei dieser Temperatur gerührt. Nach dem Erkalten wird mit Ether ausgeschüttelt, die saure Lösung alkalisiert und mit Ether extrahiert. Nach Trocknen 55 und Abdampfen des Etherse wird der Rückstand in Ethanol gelöst und mit etherischem Chlorwasserstoff ins Hydrochlorid umgesetzt, das mit dem im Beispiel 1 beschriebenen Produkt, Smp. 172-174°, identisch ist. a) The same 2-diethylamino-2'-bromo-6'-methyl-acet-anilide can be prepared from 2-diethylamino-2'-amino-6'-methyl-acet-anilide according to Sandmeyer as follows: 45 11.75 g (0.05 mol) of 2-diethylamino-2'-amino-6'-methyl-acetanilide in 30 ml of 48% hydrogen bromide are cooled in an ice bath and at -5 ° with 3.45 g of sodium nitrite in 20 ml of water for 30 Diazotized for minutes (iodine starch paper test) and then stirred for 40 minutes at -5 ° C. The 50 suspension is slowly added to a mixture of 4 g of CuBr in 20 ml of 48% hydrogen bromide heated to 70 ° and stirred for 2 hours at this temperature. After cooling, the mixture is shaken out with ether, the acidic solution is alkalized and extracted with ether. After drying 55 and evaporation of the ether, the residue is dissolved in ethanol and reacted with ethereal hydrogen chloride in the hydrochloride, which is identical to the product described in Example 1, mp. 172-174 °.
m Reduktion der 2-Diethylamino- und 2-Piperidino-2'-me-thyl-6'-nitro-acetanilide. m Reduction of the 2-diethylamino and 2-piperidino-2'-methyl-6'-nitro-acetanilides.
Beispiel 1 example 1
a) Zu 25 g (0,094 Mol) 2-Diethylamino-2'-methyl-6'--nitro-acetanilid in 500 ml konz. Salzsäure wird unter Rüh-65 ren während einer Stunde 100 g Zinn(II)-chlorid beigefügt. Das Gemisch wird 30 Minuten auf dem siedenden Wasserbad erhitzt, nach dem Erkalten unter Eiskühlung mit 35% Natronlauge-Lösung alkalisiert und mit Ether extrahiert. a) Concentrated to 25 g (0.094 mol) of 2-diethylamino-2'-methyl-6 '- nitro-acetanilide in 500 ml. Hydrochloric acid is added with stirring to 100 g of stannous chloride over an hour. The mixture is heated on the boiling water bath for 30 minutes,, after cooling, alkalized with 35% sodium hydroxide solution with ice cooling and extracted with ether.
5 5
650768 650768
Nach Waschen, Trocknen und Abdampfen des Ethers wird das 2-Diethylamino-2'-amino-6'-methyl-acetanilid, Smp. 105-106,5°C, erhalten, das mit etherischem Chlorwasserstoff ins Dihydrochlorid, Smp. 182-184°C, umgesetzt wird. After washing, drying and evaporating the ether, the 2-diethylamino-2'-amino-6'-methyl-acetanilide, mp. 105-106.5 ° C, is obtained, which with ethereal hydrogen chloride into the dihydrochloride, mp. 182-184 ° C, is implemented.
b) Dasselbe 2-Diethylamino-2'-amino-6'-methyl-acetanilid wird auch in folgender Weise erhalten: b) The same 2-diethylamino-2'-amino-6'-methyl-acetanilide is also obtained in the following way:
Zu einem mit Stickstoff begasten Gemisch von 300 mg Pd/C in 60 ml Wasser werden 4,8 g Natriumborhydrid in 90 ml Wasser zugefügt. Danach wird die Lösung von 15,9 g (0,06 Mol) 2-Diethylamino-2'-methyl-6'-nitro-acetanilids in 150 ml Methanol während 30 Minuten zugetropft und weitere 20 Minuten gerührt. Es wird filtriert, das Filtrat im 4.8 g of sodium borohydride in 90 ml of water are added to a mixture of 300 mg of Pd / C in 60 ml of water which has been gassed with nitrogen. The solution of 15.9 g (0.06 mol) of 2-diethylamino-2'-methyl-6'-nitro-acetanilide in 150 ml of methanol is then added dropwise over 30 minutes and the mixture is stirred for a further 20 minutes. It is filtered, the filtrate in
Vakuum der Wasserstrahlpumpe eingeengt, mit Wasser versetzt und die ausgeschiedenen Kristalle abgesaugt. Smp. 105-106,5°. The vacuum of the water jet pump is concentrated, water is added and the crystals which have separated out are filtered off with suction. 105-106.5 °.
s Beispiel 2 s Example 2
In der gleichen Weise wie im Beispiel lb) beschrieben, wird 2-Piperidino-2'-amino-6'-methyl-acetanilid, Smp. 169-170°, hergestellt mit dem Unterschied, dass das Gemisch vor der Filtrierung erhitzt wird, da das Produkt in kaltem Meie thanol wenig löslich ist. Die Base wird in Ethanol gelöst und mit etherischem Chlorwasserstoff ins Dihydrochlorid umgesetzt. Smp. 259-260°. In the same manner as described in Example 1b), 2-piperidino-2'-amino-6'-methyl-acetanilide, mp. 169-170 °, is produced, with the difference that the mixture is heated before filtration because the product is insoluble in cold Meol thanol. The base is dissolved in ethanol and converted into dihydrochloride with ethereal hydrogen chloride. Mp 259-260 °.
Claims (6)
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH5116/82A CH650768A5 (en) | 1982-08-27 | 1982-08-27 | BASIC ACETANILIDES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE ACETANILIDES. |
DE19833328186 DE3328186A1 (en) | 1982-08-27 | 1983-08-01 | BASIC ACETANILIDES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE ACETANILIDES |
GB08321953A GB2129424B (en) | 1982-08-27 | 1983-08-15 | Basic acetanilides |
SE8304456A SE8304456L (en) | 1982-08-27 | 1983-08-17 | BASIC ACETANILIDES, PROCEDURES FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE ACETANILIDES |
FR838313761A FR2532306B1 (en) | 1982-08-27 | 1983-08-26 | BASIC ACETANILIDES, PROCESS FOR THEIR PREPARATION AND MEDICAMENTS CONTAINING THEM |
IT48886/83A IT1168212B (en) | 1982-08-27 | 1983-08-26 | BASIC ACETANILIDES, PROCEDURE FOR THEIR PRODUCTION AND MEDICATIONS CONTAINING THEM |
CA000435457A CA1214776A (en) | 1982-08-27 | 1983-08-26 | Basic acetanilides, a process for their preparation and a pharmacological composition containing these acetanilides |
JP58157050A JPS59130250A (en) | 1982-08-27 | 1983-08-27 | Basic acetanilide, manufacture and medicine |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH5116/82A CH650768A5 (en) | 1982-08-27 | 1982-08-27 | BASIC ACETANILIDES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE ACETANILIDES. |
Publications (1)
Publication Number | Publication Date |
---|---|
CH650768A5 true CH650768A5 (en) | 1985-08-15 |
Family
ID=4288192
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CH5116/82A CH650768A5 (en) | 1982-08-27 | 1982-08-27 | BASIC ACETANILIDES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE ACETANILIDES. |
Country Status (8)
Country | Link |
---|---|
JP (1) | JPS59130250A (en) |
CA (1) | CA1214776A (en) |
CH (1) | CH650768A5 (en) |
DE (1) | DE3328186A1 (en) |
FR (1) | FR2532306B1 (en) |
GB (1) | GB2129424B (en) |
IT (1) | IT1168212B (en) |
SE (1) | SE8304456L (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7067666B2 (en) * | 2003-06-27 | 2006-06-27 | Research Triangle Institute | 7-substituted camptothecin and camptothecin analogs and methods for producing the same |
BRPI0404222A (en) * | 2004-06-07 | 2006-02-07 | Fundacao Oswaldo Cruz | Lidocaine derivatives, pharmaceutical compositions containing them, use of the respective pharmaceutical compositions in the treatment, prevention or inhibition of diseases as well as the method of treating, preventing or inhibiting diseases with said pharmaceutical compositions |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE534406A (en) * | ||||
BE517755A (en) * | ||||
GB859355A (en) * | ||||
US2689853A (en) * | 1954-09-21 | Certain i | ||
NL73080C (en) * | 1950-03-03 | |||
GB726864A (en) * | 1952-05-13 | 1955-03-23 | Geistlich Soehne Ag | New ª‰-dialkyl-aminobutyric acid anilide derivatives and a process for preparing thesame |
GB782971A (en) * | 1952-08-18 | 1957-09-18 | Hoechst Ag | Basically substituted carboxylic acid amides and a process for making them |
DE1005075B (en) * | 1952-08-18 | 1957-03-28 | Hoechst Ag | Process for the production of new locally anesthetically acting, basic substituted carboxamides |
GB726050A (en) * | 1953-10-16 | 1955-03-16 | James Arthur Cooke | A holder for chisels and plane irons whilst honing |
GB759744A (en) * | 1953-12-24 | 1956-10-24 | Cilag Ltd | Process for the production of mono- and di-substituted amino fatty acid-2-halogeno-6-methyl-anilides |
GB809286A (en) * | 1954-07-05 | 1959-02-18 | Hoechst Ag | Basically substituted butyric acid anilides and process for their manufacture |
CH329572A (en) * | 1954-07-29 | 1958-04-30 | Cilag Ag | Process for the preparation of basic amides |
CH306793A (en) * | 1955-04-30 | 1955-04-30 | Cilag Ag | Process for making a new salt. |
US2948736A (en) * | 1957-08-05 | 1960-08-09 | Cilag Chemie | New anilides and process for their production |
BE601542A (en) * | 1960-03-23 | |||
NL6704169A (en) * | 1966-04-06 | 1967-10-09 | ||
GB1187118A (en) * | 1967-07-06 | 1970-04-08 | Shell Int Research | Electrodeposition of Synthetic Resin Coatings |
GB1307250A (en) * | 1970-06-16 | 1973-02-14 | May & Baker Ltd | Benzene derivatives |
CA1002951A (en) * | 1971-12-13 | 1977-01-04 | Yoshiaki Takebayashi | Anilide derivatives and production thereof |
CS195321B2 (en) * | 1975-12-23 | 1980-01-31 | Ciba Geigy Ag | Plant growth suppressing agents |
GB1514151A (en) * | 1977-01-24 | 1978-06-14 | Gallardo Antonio Sa | Piperidine derivatives |
-
1982
- 1982-08-27 CH CH5116/82A patent/CH650768A5/en not_active IP Right Cessation
-
1983
- 1983-08-01 DE DE19833328186 patent/DE3328186A1/en not_active Withdrawn
- 1983-08-15 GB GB08321953A patent/GB2129424B/en not_active Expired
- 1983-08-17 SE SE8304456A patent/SE8304456L/en not_active Application Discontinuation
- 1983-08-26 IT IT48886/83A patent/IT1168212B/en active
- 1983-08-26 CA CA000435457A patent/CA1214776A/en not_active Expired
- 1983-08-26 FR FR838313761A patent/FR2532306B1/en not_active Expired
- 1983-08-27 JP JP58157050A patent/JPS59130250A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
FR2532306A1 (en) | 1984-03-02 |
SE8304456L (en) | 1984-02-28 |
GB8321953D0 (en) | 1983-09-14 |
SE8304456D0 (en) | 1983-08-17 |
GB2129424A (en) | 1984-05-16 |
DE3328186A1 (en) | 1984-03-01 |
IT8348886A0 (en) | 1983-08-26 |
GB2129424B (en) | 1986-07-09 |
CA1214776A (en) | 1986-12-02 |
FR2532306B1 (en) | 1989-03-10 |
JPS59130250A (en) | 1984-07-26 |
IT1168212B (en) | 1987-05-20 |
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PL | Patent ceased |