NO134868B - - Google Patents
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- NO134868B NO134868B NO2588/72A NO258872A NO134868B NO 134868 B NO134868 B NO 134868B NO 2588/72 A NO2588/72 A NO 2588/72A NO 258872 A NO258872 A NO 258872A NO 134868 B NO134868 B NO 134868B
- Authority
- NO
- Norway
- Prior art keywords
- acid
- chloro
- general formula
- mol
- solution
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims description 42
- -1 methylimino Chemical group 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 18
- 150000002148 esters Chemical class 0.000 claims description 10
- 229910052783 alkali metal Inorganic materials 0.000 claims description 7
- 150000007524 organic acids Chemical class 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 150000007522 mineralic acids Chemical class 0.000 claims description 6
- 150000001340 alkali metals Chemical class 0.000 claims description 5
- 239000007795 chemical reaction product Substances 0.000 claims description 5
- 235000005985 organic acids Nutrition 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000002576 diazepinyl group Chemical class N1N=C(C=CC=C1)* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims 1
- 108090000623 proteins and genes Proteins 0.000 claims 1
- 239000000243 solution Substances 0.000 description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 38
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 239000000047 product Substances 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 15
- 239000002253 acid Substances 0.000 description 14
- 235000011121 sodium hydroxide Nutrition 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 229940098779 methanesulfonic acid Drugs 0.000 description 12
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 235000011152 sodium sulphate Nutrition 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- 239000000155 melt Substances 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-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
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229940049706 benzodiazepine Drugs 0.000 description 6
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 4
- 229940093915 gynecological organic acid Drugs 0.000 description 4
- 239000004312 hexamethylene tetramine Substances 0.000 description 4
- 235000010299 hexamethylene tetramine Nutrition 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 206010010904 Convulsion Diseases 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 239000001961 anticonvulsive agent Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 239000000460 chlorine 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
- 239000012043 crude product Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- KWZYIAJRFJVQDO-UHFFFAOYSA-N (2-amino-5-chlorophenyl)-(2-chlorophenyl)methanone Chemical compound NC1=CC=C(Cl)C=C1C(=O)C1=CC=CC=C1Cl KWZYIAJRFJVQDO-UHFFFAOYSA-N 0.000 description 2
- ZUWXHHBROGLWNH-UHFFFAOYSA-N (2-amino-5-chlorophenyl)-phenylmethanone Chemical compound NC1=CC=C(Cl)C=C1C(=O)C1=CC=CC=C1 ZUWXHHBROGLWNH-UHFFFAOYSA-N 0.000 description 2
- QGABKABYPGLRDR-UHFFFAOYSA-N 1,2-benzodiazepin-2-ylmethanol Chemical compound OCN1C=CC=C2C=CC=CC2=N1 QGABKABYPGLRDR-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000001773 anti-convulsant effect Effects 0.000 description 2
- 229940125681 anticonvulsant agent Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000012954 diazonium Substances 0.000 description 2
- 150000001989 diazonium salts Chemical class 0.000 description 2
- FIRXYFZXNJPHDX-UHFFFAOYSA-N diethyl 2-[(2-chloroacetyl)amino]propanedioate Chemical compound CCOC(=O)C(NC(=O)CCl)C(=O)OCC FIRXYFZXNJPHDX-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 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
- 238000006386 neutralization reaction Methods 0.000 description 2
- 150000007530 organic bases Chemical group 0.000 description 2
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical class [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- QMGVPVSNSZLJIA-FVWCLLPLSA-N strychnine Chemical compound O([C@H]1CC(N([C@H]2[C@H]1[C@H]1C3)C=4C5=CC=CC=4)=O)CC=C1CN1[C@@H]3[C@]25CC1 QMGVPVSNSZLJIA-FVWCLLPLSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 2
- 239000003204 tranquilizing agent Substances 0.000 description 2
- 230000002936 tranquilizing effect Effects 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- GTGMXPIQRQSORU-UHFFFAOYSA-N (2-amino-5-chlorophenyl)-(2-fluorophenyl)methanone Chemical compound NC1=CC=C(Cl)C=C1C(=O)C1=CC=CC=C1F GTGMXPIQRQSORU-UHFFFAOYSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- RZMGZEJEAAVXRG-UHFFFAOYSA-N 1,2-dihydrotriazole-3-carboxylic acid Chemical compound N1NN(C=C1)C(=O)O RZMGZEJEAAVXRG-UHFFFAOYSA-N 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- ONOBXDPYDHTSBQ-UHFFFAOYSA-N 2,3,4,7-tetrahydro-1h-diazepine Chemical compound C1CC=CCNN1 ONOBXDPYDHTSBQ-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- HWTDMFJYBAURQR-UHFFFAOYSA-N 80-82-0 Chemical compound OS(=O)(=O)C1=CC=CC=C1[N+]([O-])=O HWTDMFJYBAURQR-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- QMGVPVSNSZLJIA-UHFFFAOYSA-N Nux Vomica Natural products C1C2C3C4N(C=5C6=CC=CC=5)C(=O)CC3OCC=C2CN2C1C46CC2 QMGVPVSNSZLJIA-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical compound CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 241001279009 Strychnos toxifera Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- FXCLIEYDXXVEAI-UHFFFAOYSA-N benzene;dichloromethane Chemical compound ClCCl.C1=CC=CC=C1 FXCLIEYDXXVEAI-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- GLELQNLTICCTEG-UHFFFAOYSA-N diethyl 2-[(2-benzoylphenyl)diazenyl]-2-[(2-chloroacetyl)amino]propanedioate Chemical class C(C)OC(C(C(=O)OCC)(N=NC1=C(C=CC=C1)C(C1=CC=CC=C1)=O)NC(CCl)=O)=O GLELQNLTICCTEG-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- XTLNYNMNUCLWEZ-UHFFFAOYSA-N ethanol;propan-2-one Chemical compound CCO.CC(C)=O XTLNYNMNUCLWEZ-UHFFFAOYSA-N 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- LLCOIQRNSJBFSN-UHFFFAOYSA-N methane;sulfurochloridic acid Chemical compound C.OS(Cl)(=O)=O LLCOIQRNSJBFSN-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 150000003109 potassium Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 229960005453 strychnine Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Oppfinnelsen vedrører analogifremgangsmåter til fremstilling av nye diazepinderivater med den generelle formel I The invention relates to analogue methods for the production of new diazepine derivatives with the general formula I
hvori in which
R-^ betyr et halogenatom■inntil atomnummer 35, R-^ means a halogen atom ■up to atomic number 35,
R2 betyr hydrogen eller et halogenatom inntil atom- R2 means hydrogen or a halogen atom until atom-
nummer 35 og number 35 and
R-j og R^ betyr hydrogen, metyl- eller etylgrupper, R-j and R^ mean hydrogen, methyl or ethyl groups,
idet sistnevnte gjensidig i g-stilling også kan være forbundet direkte eller over et oksygenatom métyiimino- eller1 ffiétyléngrUp^éft og addisjonssalter av forbindelsene med den generelle formel I the latter being mutually in the g-position can also be connected directly or via an oxygen atom métyiimino- or 1 ffiétyléngrUp^éft and addition salts of the compounds of the general formula I
med uorganiske og organiske syrer. with inorganic and organic acids.
R^ og B.^ er som halogenatomer fluor-, klor- eller bromatomer, idet R-j^ fortrinnsvis betyr klor og .R2 som halogenatom fortrinnsvis er fluor eller klor. R 1 and B 2 are, as halogen atoms, fluorine, chlorine or bromine atoms, with R 2 preferably meaning chlorine and R 2 as a halogen atom preferably being fluorine or chlorine.
Gjensidig i (3-stilling i ovenfor definerte måte for-bundede etylgrupper R^ og R^ danner sammen med det vedliggende nitrogenatom 1-pyrrolidinyl-, piperidino-, morfolino- eller -4-mety1-1-piperazinylgruppen. Ethyl groups R 1 and R 2 , which are mutually bonded in the 3-position in the manner defined above, together with the adjacent nitrogen atom form the 1-pyrrolidinyl, piperidino, morpholino or -4-methyl-1-piperazinyl group.
Forbindelsene med den generelle formel I og addi-sjonssaltene av forbindelsene med den generelle formel I med uorganiske og organiske syrer har verdifulle farmakologiske egen-skaper. Spesielt er de virksomme antikonvulsive, slik det f.eks. kan fastslås på mus i pentetrazolkrampeprøve etter administrer-ing av orale doser fra ca. 0,2 mg/kg samt i strykninkrampeprøve og i elektrosjokkprøve. The compounds of the general formula I and the addition salts of the compounds of the general formula I with inorganic and organic acids have valuable pharmacological properties. In particular, they are effective anticonvulsants, as e.g. can be determined in mice in the pentetrazole convulsion test after administration of oral doses from approx. 0.2 mg/kg as well as in the strychnine seizure test and in the electroshock test.
Den antikonvulsive virkning av forbindelsene med The anticonvulsant effect of the compounds with
den generelle formel I i pentetrazolkrampeprøven er vesentlig sterkere enn de tidligere -kjente,-:som tranquiliser meget ofte anvendte 7-klor-l,3-dihydro-l-metyl-5-fenyl-2H-l,4-benzodiazepin-2-on og betydelig sterkere enn virkningen av det strukturelt til forbindelsen ifølge oppfinnelsen nærmeststående 2-metyl-6-fenyl-8-klor-^H-s-triazolo/_—l,5-a7/—l,-4_7benzodiazepin kjent fra DOS 2.055.889. the general formula I in the pentetrazole seizure test is significantly stronger than the previously -known,-: which tranquilizers very often used 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2- on and significantly stronger than the effect of the structurally closest to the compound according to the invention 2-methyl-6-phenyl-8-chloro-^H-s-triazolo/_—1,5-a7/—1,-4_7benzodiazepine known from DOS 2,055,889 .
Av spesiell betydning er 2-/~(dimetylamino)-metyl7-6-fenyl-8-klor-4H-s-triazolo/__2,3-a7/-l,_47benzodiazepin, 2-/~(me-tylamino)-metyl7-6-f enyl-8-klor-4H-s-triazolo'/~l, 5-a7/~l,47 benzodiazepin, 2-/~(dimetylamino)-metyl7-6-(o-fluorfenyl)-8-klor-4H-s-triazolo/~l, 5- a/ lTl,47benzodiazepin, 2-/~(metylamino)-metyl7-6-(o-fluorfenyl) -8-klor-4H-s-triazolo/~l, 5-a7/__l, ^benzodiazepin og 2-/~(metylamino)-metyl7-6-(o-klorfenyl)-8-klor-4H-s-triazolo/_ lj5-a//. 1, Vbenzodiazepin og deres farmasøytisk tålbare syreaddisjonssalter. Den sedative virkning er sammenlignet med den antikonvulsive mindre utpreget. De nevnte og ytterligere virkningskvaliteter som kunne finnes ved utvalgte standardfor-søk l_ sammenlign Vf. Theobald og H.A. Kunz, Arzneimittelforsch. l3, 122 (1963) samt W. Theobald et al., Arzneimittelforsch. 17, 561 (1967^/> karakteriserer forbindelsene med den generelle formel I og deres farmasøytisk tålbare addisjonssalter med uorganiske Of particular importance is 2-/~(dimethylamino)-methyl7-6-phenyl-8-chloro-4H-s-triazolo/__2,3-a7/-1,_47benzodiazepine, 2-/~(methylamino)-methyl7 -6-phenyl-8-chloro-4H-s-triazolo'/~l, 5-α7/~1,47 benzodiazepine, 2-/~(dimethylamino)-methyl7-6-(o-fluorophenyl)-8- chloro-4H-s-triazolo/~l, 5- a/ lTl,47benzodiazepine, 2-/~(methylamino)-methyl7-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo/~l, 5-a7/__l, ^benzodiazepine and 2-/~(methylamino)-methyl7-6-(o-chlorophenyl)-8-chloro-4H-s-triazolo/_ lj5-a//. 1, Vbenzodiazepine and their pharmaceutically acceptable acid addition salts. Compared to the anticonvulsant, the sedative effect is less pronounced. The aforementioned and further effective qualities that could be found in selected standard tests l_ compare Vf. Theobald and H.A. Kunz, Arzneimittelforsch. 13, 122 (1963) and W. Theobald et al., Arzneimittelforsch. 17, 561 (1967^/> characterizes the compounds of general formula I and their pharmaceutically acceptable addition salts with inorganic
og organiske syrer som virksomme stoffer for psykosedativa (tranquiliser) og antikonvulsiva, som f.eks. er anvendbare til behandling av spennings- og opphissingstilstander, uten eller med bare liten påvirkning av vigilitet, samt til behandling av epilepsi. Som spesiell fordel ved forbindelsene' fremstillet ifølge oppfinnelsen er videre f.eks. i forhold til de to overnevnte tidligere kjente forbindelser å nevne muligheten for fremstilling av stabile tilnærmet nøytrale salter. and organic acids as active substances for psychosedatives (tranquilizers) and anticonvulsants, such as e.g. are applicable for the treatment of states of tension and excitement, without or with only a slight effect on vigilance, as well as for the treatment of epilepsy. As a special advantage of the compounds' produced according to the invention, e.g. in relation to the two above-mentioned previously known compounds to mention the possibility of producing stable, approximately neutral salts.
Forbindelsene med generell formel I og tilsvarende syreaddisjonssalter fremstilles i henhold til oppfinnelsen idet man The compounds of general formula I and corresponding acid addition salts are prepared according to the invention by
a) omsetter en reaktiv ester av en forbindelse med generelle formel II a) reacts a reactive ester of a compound of general formula II
hvor R-L og R2 har betydning som angitt under formel I" med en forbindelse med generell formel III where R-L and R2 have the meaning as indicated under formula I" with a compound of general formula III
hvor R^ og Rjj har betydning som angitt til formel I, eller med et alkalimetallderivat av en slik forbindelse, eller where R^ and Rjj have the meaning as indicated for formula I, or with an alkali metal derivative of such a compound, or
b) reduserer en forbindelse med generell formel IV b) reduces a compound of general formula IV
hvor R-^ og R2 har betydning som angitt under formel I og eventuelt where R 1 and R 2 have the meaning as indicated under formula I and optionally
overfører reaksjonsproduktet oppnådd ifølge a) .eller b) til et addisjonssalt med en organisk eller uorganisk syre. transfers the reaction product obtained according to a) or b) to an addition salt with an organic or inorganic acid.
Som reaktiv ester av hydroksyforbindelser med generell formel II vil det f.eks. egne seg sulfonsyreestere som metansulfonsyreesteren, o- og p-toluensulfonsyreesteren, o- eller p-nitrobenzensulfonsyreesteren eller o- eller p-klorbenzensulfon-syreesteren. Videre kan man som reaktive estere av forbindelser med generell formel II også bruke deres hydrogenhalogenidsyreestere, særlig klorider eller bromider, samt jodider fremstilt fra disse in situ-. Som reaksjonsmedium og samtidig syretiltrekkende middel kan man benytte et overskudd av den basiske forbindelse som skal omsettes med generell formel III. I tillegg eller istedenfor den overskytende forbindelse kan man som reaksjonsmedium også velge et inert organisk oppløsningsmiddel, f.eks. As reactive esters of hydroxy compounds with general formula II, it will e.g. suitable sulfonic acid esters such as the methanesulfonic acid ester, the o- and p-toluenesulfonic acid ester, the o- or p-nitrobenzenesulfonic acid ester or the o- or p-chlorobenzenesulfonic acid ester. Furthermore, one can also use as reactive esters of compounds of general formula II their hydrogen halide acid esters, especially chlorides or bromides, as well as iodides prepared from these in situ. An excess of the basic compound to be reacted with general formula III can be used as a reaction medium and at the same time an acid-attracting agent. In addition to or instead of the excess compound, an inert organic solvent can also be chosen as the reaction medium, e.g.
en lavere alkanol som metanol, etanol, propanol, isopropanol eller butanol, et keton som aceton eller metyletylketon, videre f.eks. dioksan, tetrahydrofuran, dimetylformamid eller dimetylsulfoksyd, idet man eventuelt også benytter forbindelsen med generell formel III i overskudd som vanlig oppløsning eller på den annen side istedenfor et overskudd av denne eller i tillegg et annet syretiltrekkende reagens, f.eks. benytter en tertiær organisk base som etyldiisopropylamin eller collidin, eller et uorganisk basisk reagens som f.eks. kaliumkarbonat. a lower alkanol such as methanol, ethanol, propanol, isopropanol or butanol, a ketone such as acetone or methyl ethyl ketone, further e.g. dioxane, tetrahydrofuran, dimethylformamide or dimethylsulfoxide, possibly also using the compound of general formula III in excess as a normal solution or, on the other hand, instead of an excess of this or in addition another acid-attracting reagent, e.g. uses a tertiary organic base such as ethyldiisopropylamine or collidine, or an inorganic basic reagent such as e.g. potassium carbonate.
Bruker man som reaksjonskomponent istedenfor forbindelsen med generell formel III et alkalimetallderivat av denne, f.eks. et natrium-, litium- eller kaliumderivat, benyttes fortrinnsvis hydrokarboner som benzen, toluen eller xylen, eter-aktige væsker som 1,2-dimetoksyetan, tetrahydrofuran eller dioksan eller syreamidet som dimetylformamid eller heksametylfosfor-syretriamid eller sulfoksydet som dimetylsulfoksyd. Dannelsen -av alkalimetallderivater av forbindelser med formel III, unntatt ammoniakk, skjer fortrinnsvis in situ, f.eks. ved tilsetning av minst ekvimolar mengde alkalimetallhydrid som natriumhydrid, alkalimetallamid som natrium- eller litiumamid eller en alkali-metallorganisk forbindelse som fenyl- eller butyllitium. Reak-sjonstemperaturen ligger fortrinnsvis mellom 0 og 120°C, eller på reaksjonsmediets kokepunkt. Fremstillingen av forbindelser med generell formel II og deres reaktive estere forklares nøyere i det følgende. Instead of the compound of general formula III, an alkali metal derivative thereof is used as a reaction component, e.g. a sodium, lithium or potassium derivative, hydrocarbons such as benzene, toluene or xylene, ether-like liquids such as 1,2-dimethoxyethane, tetrahydrofuran or dioxane or the acid amide such as dimethylformamide or hexamethylphosphoric acid triamide or the sulphoxide such as dimethyl sulphoxide are preferably used. The formation of alkali metal derivatives of compounds of formula III, excluding ammonia, preferably takes place in situ, e.g. by adding at least an equimolar amount of alkali metal hydride such as sodium hydride, alkali metal amide such as sodium or lithium amide or an alkali metal organic compound such as phenyl or butyl lithium. The reaction temperature is preferably between 0 and 120°C, or at the boiling point of the reaction medium. The preparation of compounds of general formula II and their reactive esters is explained in more detail below.
Reduksjonen av azider med generell formel IV, hvor fremstillingen er forklart videre nedenfor, kan både foretas kjemisk og ved katalytisk hydrogenering, f.eks. i nærvær av palladium-kull-katalysatorer, platinaoksyd eller Raney-nikkel, The reduction of azides of general formula IV, the preparation of which is explained further below, can be carried out both chemically and by catalytic hydrogenation, e.g. in the presence of palladium-charcoal catalysts, platinum oxide or Raney nickel,
i et organisk oppløsningsmiddel som dioksan, etanol, metanol eller tetrahydrofuran, ved romtemperatur - og normalt trykk. Blant de kjemiske metoder er særlig reduksjon med tinn(II)-klorid i lavalkanolisk-vandig, særlig etanolisk-vandig alkalilut og spesielt natronlut, aktuelt, ved temperaturer mellom ca. 0° og reaksjonsblandingens koketemperatur, fortrinnsvis mellom ca. 0° og in an organic solvent such as dioxane, ethanol, methanol or tetrahydrofuran, at room temperature - and normal pressure. Among the chemical methods, reduction with tin(II) chloride in low-alkanolic-aqueous, especially ethanolic-aqueous alkaline lye and especially caustic soda is relevant, at temperatures between approx. 0° and the boiling temperature of the reaction mixture, preferably between approx. 0° and
13401)3 romtemperatur. 13401)3 room temperature.
Forbindelsene med generell formel II som ligger til grunn for de reaktive estere som benyttes som utgangsstoffer for fremgangsmåte a) fremstilles f.eks. ut fra forbindelser med generell formel Ila The compounds of general formula II which form the basis of the reactive esters used as starting materials for method a) are prepared, e.g. from compounds of general formula IIa
hvor Rj og R2 har den under formel I angitte betydning. Slike forbindelser er beskrevet i litteraturen, f.eks. 2-amino-5-klor-benzofenon (se F.D. Chattaway, J. Chem. Soc. 85, 344 (1904) where Rj and R2 have the meaning given under formula I. Such compounds are described in the literature, e.g. 2-amino-5-chloro-benzophenone (see F.D. Chattaway, J. Chem. Soc. 85, 344 (1904)
eller 2-amino-2',5-diklor-benzofenon (se L.H. Sternbach et al., or 2-amino-2',5-dichloro-benzophenone (see L.H. Sternbach et al.,
J. Org. Chem. 26, 4488 (1961). Forbindelsene med generell J. Org. Chem. 26, 4488 (1961). The connections with general
formel Ila blir diazotert og derpå blir de dannede diazonium-salter koplet med (2-kloracetamido)-malonsyredietylester (se Ajay Kumar Bose, J. Indian Chem. Soc. 31, 108-110 (1954) til de tilsvarende (2-kloracetamido)-(2-benzoyl-fenylazo)-malonsyredi-etylestere. Deretter overføres koplingsproduktene ved behandling med minst den dobbeltmolare og fortrinnsvis tre-fire-molare mengde natriumhydroksyd og påfølgende nøytralisering til forbindelsene med generell formel IIb formula IIa is diazotized and then the diazonium salts formed are coupled with (2-chloroacetamido)-malonic acid diethyl ester (see Ajay Kumar Bose, J. Indian Chem. Soc. 31, 108-110 (1954) to the corresponding (2-chloroacetamido) -(2-benzoyl-phenylazo)-malonic acid diethyl esters Then the coupling products are transferred by treatment with at least the double molar and preferably three to four molar amount of sodium hydroxide and subsequent neutralization to the compounds of general formula IIb
hvor R-^ og R2 har betydning som angitt til formel I. Disse forbindelsene omsettes, eventuelt etter forbehandling med kaliumjodid, med vandig ammoniakk eller med heksametylentetramin, hvor-med kloratomet erstattes med aminogruppen og det samtidig foregår where R-^ and R2 have the meaning as stated in formula I. These compounds are reacted, optionally after pretreatment with potassium iodide, with aqueous ammonia or with hexamethylenetetramine, with which the chlorine atom is replaced by the amino group and it simultaneously takes place
avspaltning av vann under ringslutning til karbonsyrer med generell formel Ild hvor R-j_ og R2 har betydning som under formel I. Man kan også først behandle forbindelsene med generell formel IIb med natriumazid i nærvær av kaliumjodid og omsette disse til forbindelser med generell formel lic cleavage of water during cyclization to carboxylic acids of general formula Ild where R-j_ and R2 have the same meanings as under formula I. One can also first treat the compounds of general formula IIb with sodium azide in the presence of potassium iodide and convert these into compounds of general formula lic
hvor R]_ og R2 har betydning som under formel I og behandle sistnevnte forbindelser med trifenylfosfin under nitrogenutvikling og ringslutte til forbindelser med generell formel Ild. where R]_ and R 2 have meanings as under formula I and treat the latter compounds with triphenylphosphine under nitrogen evolution and ring closure to compounds of general formula Ild.
Karboksylsyrér med generell formel Ild overføres på kjent måte, f.eks. med saltsyreholdig etanol eller metanol, til etyl- eller metylestrene, og .disse reduseres med litiumaluminium-hydrid i eterholdig oppløsningsmiddel som tetrahydrofuran ved temperaturer omkring 0°C til forbindelser med generell formel II. Man kan også komme frem til etylestere av karboksylsyrene med generell formel II, som utgjør utgangspunkt for reduksjon, idet man behandler de ovenfor nevnte koplingsprodukter med høyst den dobbeltmolare mengde natriumhydroksyd under milde reaksjonsbe-tingelser, dvs. f.eks. ved romtemperatur og under nøytralisering før opparbeidingen, og omsetter etylesteren av karboksylsyrér med generell formel Ilb, som utgjør hovedproduktet, med heksametylentetramin i absolutt etanol i analogi med de frie syrer. Forbindelser med generell formel II fremstillet ved reduksjonen blir overført på forøvrig kjent måte, f.eks. ved omsetning med et sulfonsyreklorid som metansulfonsyreklorid eller p-toluen-sulfonsyreklorid, i et inert organisk oppløsningsmiddel som metylenklorid og i nærvær av en organisk base som trietylamin eller etyldiisopropylamin, eller ved omsetning med tionylklorid eller fosfortribromid og eventuelt deretter med kaliumjodid, Carboxylic acids of general formula Ild are transferred in a known manner, e.g. with hydrochloric acid-containing ethanol or methanol, to the ethyl or methyl esters, and these are reduced with lithium aluminum hydride in an ethereal solvent such as tetrahydrofuran at temperatures around 0°C to compounds of general formula II. It is also possible to arrive at ethyl esters of the carboxylic acids of general formula II, which form the starting point for reduction, by treating the above-mentioned coupling products with at most the double molar amount of sodium hydroxide under mild reaction conditions, i.e. e.g. at room temperature and under neutralization before work-up, and reacts the ethyl ester of carboxylic acid with general formula Ib, which constitutes the main product, with hexamethylenetetramine in absolute ethanol in analogy with the free acids. Compounds of general formula II produced by the reduction are transferred in an otherwise known manner, e.g. by reaction with a sulfonic acid chloride such as methanesulfonic acid chloride or p-toluenesulfonic acid chloride, in an inert organic solvent such as methylene chloride and in the presence of an organic base such as triethylamine or ethyldiisopropylamine, or by reaction with thionyl chloride or phosphorus tribromide and optionally then with potassium iodide,
til egnede reaktive estere. to suitable reactive esters.
Forbindelser med generell formel Iv som tjener som utgangsstoffer for fremgangsmåte b) fremstilles ved omsetning av reaktive estere av forbindelse med generell formel II, f.eks. metansulfonsyreestere, med alkalimétallazider soin natriumazid i inerte organiske eller organisk-vandige oppløsningsmidler, f.eks. vannholdig aceton. Compounds of general formula Iv which serve as starting materials for method b) are produced by reacting reactive esters of compounds of general formula II, e.g. methanesulfonic acid esters, with alkali metal azides such as sodium azide in inert organic or organic-aqueous solvents, e.g. aqueous acetone.
I forbindelser med generell formel I og deres 5-oksyder blir om ønsket på kjent måte overført til deres addisjonssalter med uorganiske eller organiske syrer. F.eks. tilsettes en oppløsning av en forbindelse med generell formel I In compounds of general formula I and their 5-oxides, if desired, are transferred in a known manner to their addition salts with inorganic or organic acids. E.g. is added to a solution of a compound of general formula I
i et organisk oppløsningsmiddel den syren som ønskes som salt-komponent. Fortrinnsvis velger man for omsetningen organiske oppløsningsmidler hvor det dannede saltet er tungt oppløselig slik at det kan skilles ved filtrering. Slike oppløsningsmidler er f.eks. metanol, eter, aceton, metyletylketon, aceton-eter, aceton-etanol, metanol-eter eller etanol-eter. in an organic solvent the acid desired as salt component. Preferably, organic solvents are chosen for the reaction where the formed salt is poorly soluble so that it can be separated by filtration. Such solvents are e.g. methanol, ether, acetone, methyl ethyl ketone, acetone-ether, acetone-ethanol, methanol-ether or ethanol-ether.
For bruk som legemidler kan istedenfor de frie baser benyttes farmasøytiske syreaddisjonssalter, dvs. salter med slike syrer.hvis anioner i de aktuelle doseringer ikke er giftige. Videre er det gunstig om de salter som brukes til legemidlene For use as pharmaceuticals, pharmaceutical acid addition salts can be used instead of the free bases, i.e. salts with such acids, if the anions in the relevant dosages are not toxic. Furthermore, it is beneficial if the salts are used for the medicines
er godt krystalliserbare og er lite eller ikke hygroskopiske. For saltdannelse med forbindelser med generell formel I kan man f.eks. bruke saltsyre, hydrogenbromsyre, svovelsyre, fosforsyre, metansulfonsyre, etansulfonsyre, 2-hydroksy-etansulfonsyre, eddiksyre, melkesyre, ravsyre, fumarsyre, maleinsyre, eplesyre, vinsyre, sitronsyre, benzosyre, salicylsyre, fenyleddiksyre, mandelsyre og embonsyre. are easily crystallizable and are little or not hygroscopic. For salt formation with compounds of general formula I, one can e.g. use hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid and embonic acid.
De nye virksomme stoffer gir peroralt, rektalt eller parenteralt. Doseringen avhenger av administrasjonsvéien, pasi-enten, alder og den individuelle tilstand. De daglige doser av frie baser, deres 5-oksyder eller farmasøytisk anvendelige salter av disse baser ligger mellom 0,02 mg/kg og 2 mg/kg for varmblodige dyr og mennesker. Egnede doseringsenhets-former som drasjeer, tabletter, suppositorier eller ampuller inneholder med fordel 0,5 - 25 mg av virksomt stoff i henhold til oppfinnelsen. The new active substances are administered orally, rectally or parenterally. The dosage depends on the route of administration, the patient, age and the individual condition. The daily doses of free bases, their 5-oxides or pharmaceutically usable salts of these bases are between 0.02 mg/kg and 2 mg/kg for warm-blooded animals and humans. Suitable dosage unit forms such as dragees, tablets, suppositories or ampoules advantageously contain 0.5 - 25 mg of active substance according to the invention.
De følgende eksempler angår fremstilling av de The following examples relate to their production
nye forbindelser med generell formel I. Temperaturene er i Celsiusgrader. new compounds of general formula I. Temperatures are in degrees Celsius.
Eksempel 1. Example 1.
a) 8,05 g (0,02. mol) metansulfonsyreester av 6-fenyl-8-klor-4H-s-triazol/~l, 5-a7/_~1,47benzodiazepin-2-metanol opp-løses i 80 ml dimetylsulfoksyd og tildryppes under røring ved 5 - 10° til en blanding av 10 g (0,09 mol) 40,5#-ig vandig a) 8.05 g (0.02 mol) methanesulfonic acid ester of 6-phenyl-8-chloro-4H-s-triazole/~1,5-α7/_~1,47benzodiazepine-2-methanol is dissolved in 80 ml of dimethylsulfoxide and added dropwise with stirring at 5 - 10° to a mixture of 10 g (0.09 mol) 40.5#-ig aqueous
dimetylaminløsning og 20 ml dimetylsulfoksyd. Derpå oppvarmes reaksjonsblandingen til romtemperatur og den røres i en time ved 20 - 25°. Derpå helles blandingen ut i 0,5 liter iskaldt vann som ekstraherer to ganger med to ganger 250 ml benzen. De samlede benzenekstrakter vaskes med fem ganger 100 ml vann, tørkes over natriumsulfat og inndampes i vakuum. Residuet opp-løses i kloroform og kromatograferes på en kolonne inneholdende 120 g basisk aluminiumoksyd. Ved eluering med kloroform, inn-damping og omkrystallisering "av residuet fra cykloheksan får man 2-/"(dimetylamino)-metyl7-6-fenyl-8-klor-4H-s-triazol/<->l,5-•a7/~l,47 benzodiazepin med smeltepunkt 133 - 135°. Utgangsstoffet metansulfonsyreester fremstilles slik: b) En oppløsning av 58,0 g (0,25 mol) 2-amino-5-klor-benzofenon (se P.D. Chattaway, J. Chem. Soc. 85, 3^4 (1904)) i dimethylamine solution and 20 ml of dimethylsulfoxide. The reaction mixture is then heated to room temperature and stirred for one hour at 20 - 25°. The mixture is then poured into 0.5 liters of ice-cold water which is extracted twice with twice 250 ml of benzene. The combined benzene extracts are washed with five times 100 ml of water, dried over sodium sulphate and evaporated in vacuo. The residue is dissolved in chloroform and chromatographed on a column containing 120 g of basic aluminum oxide. By elution with chloroform, evaporation and recrystallization of the residue from cyclohexane, 2-/(dimethylamino)-methyl7-6-phenyl-8-chloro-4H-s-triazole is obtained /~1.47 benzodiazepine with melting point 133 - 135°. The starting material methanesulphonic acid ester is prepared as follows: b) A solution of 58.0 g (0.25 mol) 2-amino-5-chloro-benzophenone (see P.D. Chattaway, J. Chem. Soc. 85, 3^4 (1904)) in
310 ml iseddik-konsentrert saltsyre (4:1) diazoteres ved romtemperatur under røring med 50 ml (0,25 mol) vandig natriumnitrit-oppløsning. Den dannede diazoniumsaltoppløsning tilsettes 150 g is og dråpevis og hurtig en oppløsning av 52,4 g (0,208 mol) (2-kloracetamido)-malonsyredietylester (se Ajay Kumar Bose, J. Indian Chem.Soc, 31, 108 - 110 (1954)) i 600 ml aceton. Derpå drypper man til ved 5 - 10° og i løpet av 20 minutter en oppløs-ning av 276,0 g (2 mol) kaliumkarbonat i 500 ml vann, rører videre en time og tilsetter benzen og mettet natriumoksydoppløs-ning. Benzenoppløsningen skilles fra, vaskes med mettet natrium-kloridoppløsning, tørkes over natriumsulfat og inndampes, og dette gir 121 g rå (2-benzoyl-4-klor-fenylazo)-(2-kloracetamido)- 310 ml of glacial acetic acid-concentrated hydrochloric acid (4:1) is diazotized at room temperature while stirring with 50 ml (0.25 mol) of aqueous sodium nitrite solution. To the formed diazonium salt solution is added 150 g of ice and dropwise and rapidly a solution of 52.4 g (0.208 mol) of (2-chloroacetamido)-malonic acid diethyl ester (see Ajay Kumar Bose, J. Indian Chem. Soc, 31, 108 - 110 (1954) ) in 600 ml of acetone. A solution of 276.0 g (2 mol) of potassium carbonate in 500 ml of water is then added drop by drop at 5 - 10° over the course of 20 minutes, stirring is continued for an hour and benzene and saturated sodium oxide solution are added. The benzene solution is separated, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated, yielding 121 g of crude (2-benzoyl-4-chloro-phenylazo)-(2-chloroacetamido)-
«-» x- W «-» x-W
malonsyredietylester. Dette råproduktet oppløses i 1,5 liter dioksan, man tilsetter 36 g (0,9 mol) natriumhydroksyd oppløst 1 2 liter vann, det hele røres i 30 minutter og man inndamper dioksan i vakuum. Residuet fortynnes med 500 ml vann, 20 g aktivkull tilsettes, blandingen røres godt og filtreres gjennom renset diatomejord. Man tilsetter filtratet under god røring 2 N saltsyre til kongosur reaksjon, frafiltrerer utfelt karboksylsyre, vasker med vann og krystalliserer om fra varm metanol.' De fremstilte krystaller av 1-(2-benzoyl-4-klor-fenyl)-5~(klor-metyl)-lH-l,.2,.4-triazol-3-karboksylsyre som inneholder en ekvimolar mengde metanol sintrer ved 137 - 138° og smelter under dekomponering ved 169 - 170°C. malonic acid diethyl ester. This crude product is dissolved in 1.5 liters of dioxane, 36 g (0.9 mol) of sodium hydroxide dissolved in 1 2 liters of water are added, the whole is stirred for 30 minutes and the dioxane is evaporated in a vacuum. The residue is diluted with 500 ml of water, 20 g of activated charcoal is added, the mixture is stirred well and filtered through purified diatomaceous earth. 2 N hydrochloric acid is added to the filtrate with good stirring to form a congo acid reaction, the precipitated carboxylic acid is filtered off, washed with water and recrystallized from hot methanol.' The prepared crystals of 1-(2-benzoyl-4-chloro-phenyl)-5~(chloro-methyl)-1H-1,.2,.4-triazole-3-carboxylic acid containing an equimolar amount of methanol sintered at 137 - 138° and melts during decomposition at 169 - 170°C.
c) 33,2 g (0,200 mol) kaliumjodid oppløses i 85 ml vann. Oppløsningen fortynnes med 850 ml dioksan, man tilsetter c) Dissolve 33.2 g (0.200 mol) of potassium iodide in 85 ml of water. The solution is diluted with 850 ml of dioxane, which is added
ved 25° under røring 71,5 g (0,175 mol) forbindelse fremstilt ifølge b) og oppvarmer oppløsningen.i en time ved 45 - 50°. at 25° with stirring 71.5 g (0.175 mol) of compound prepared according to b) and heating the solution for one hour at 45 - 50°.
Man tilsetter 0,5 liter konsentrert vandig ammoniakkoppløsning, varmer blandingen i 2 timer ved 45 - 50° og inndamper i vakuum. Residuet oppløses i 2 liter vann og man tilsetter oppløsningen 0.5 liter of concentrated aqueous ammonia solution is added, the mixture is heated for 2 hours at 45 - 50° and evaporated in a vacuum. The residue is dissolved in 2 liters of water and the solution is added
2 N saltsyre til kongosur reaksjon.' Den frie karboksylsyre 2 N hydrochloric acid to Congo acid reaction.' The free carboxylic acid
faller ut, frafiltreres, vaskes med vann til nøytralitet, etter-vaskesmed metanol og tørkes, i vakuum: ved 120 130°. Den dannede 6-fenyl-8-klor-4H-s-triazo'l_/~l, 5'-a7/~l, 47benzodiazepin-2-karboksylsyre dekomponeres ved l70°. precipitates, is filtered off, washed with water to neutrality, after-washing with methanol and dried, in vacuum: at 120 130°. The 6-phenyl-8-chloro-4H-s-triazo'l_/~l,5'-α7/~l,47benzodiazepine-2-carboxylic acid formed decomposes at 170°.
Denne karboksylsyre kan fremstilles ut fra klor-metylforbindelsen fra b) også etter forskrift d) nedenfor; This carboxylic acid can be prepared from the chloro-methyl compound from b) also according to regulation d) below;
d) 0,408 g (0,001 mol) klormetylforbindelse fremstilt ifølge b), inneholdende en ekvimolar mengde metanol, samt 0,320 g d) 0.408 g (0.001 mol) chloromethyl compound prepared according to b), containing an equimolar amount of methanol, as well as 0.320 g
(0,003 mol) heksametylentetramin oppløses i 20 ml etanol og oppløsningen kokes i 12 timer ved tilbakeløp. Derpå inndampes oppløsningen ved 40° i vakuum, residuet oppløses i 20 ml .0,05 N natronlut, tilsettes 2 N saltsyre til kongosur reaksjon og det utskilte råproduktet opparbeides ,som .under c). Det dannede 6-fenyl-8-klor-4H-s-triazol/~ 1,5-a7/_~I,'47benzodiazepin-2-karboksylsyre smelter ved 170°. e) 6,77 g (0,020 mol) 6-fenyl-8-klor-4H-s-triazol-l<_>l,5-a/</_> l,_4/benzodiazepin-2-karboksylsyre (fremstilet ifølge c) eller d)) suspenderes i 250 ml absolutt etanol. Oppløsningen mettes under røring og koking med tilbakeløp med saltsyregass. (0.003 mol) of hexamethylenetetramine is dissolved in 20 ml of ethanol and the solution is refluxed for 12 hours. The solution is then evaporated at 40° in a vacuum, the residue is dissolved in 20 ml of 0.05 N caustic soda, 2 N hydrochloric acid is added for a congo acid reaction and the separated crude product is worked up, as under c). The 6-phenyl-8-chloro-4H-s-triazole/~ 1,5-α7/_~1,'47benzodiazepine-2-carboxylic acid formed melts at 170°. e) 6.77 g (0.020 mol) 6-phenyl-8-chloro-4H-s-triazole-l<_>l,5-a/</_>l,_4/benzodiazepine-2-carboxylic acid (prepared according to c) or d)) is suspended in 250 ml of absolute ethanol. The solution is saturated while stirring and refluxing with hydrochloric acid gas.
Den klare oppløsning som dannes kokes videre i 10 timer under tilbakeløp og inndampes derpå i vakuum ved 40°. Residuet opp-løses i 100 ml iskald 5#-ig natriumbikarbonatoppløsning og 100 ml metylenklorid, den organiske, fasen skilles fra, vaskes med vann, tørkes over natriumsulfat og inndampes ved 40° i vakuum. Den rå og oljeaktige rest kokes en time med 100 ml eter under tilbakeløp, hvorved det inntrer krystallisasjon. Etter avkjøl-ing til 0° frafiltreres krystallene og .vaskes med eter. Man får 6-fenyl-8-klor-4H-s-triazo'l/~l, 5-a7/_— l,47benzodiazepin-2-karboksylsyreetylester med smeltepunkt 137 - 138°. The clear solution that forms is further boiled for 10 hours under reflux and then evaporated in vacuo at 40°. The residue is dissolved in 100 ml of ice-cold 5% sodium bicarbonate solution and 100 ml of methylene chloride, the organic phase is separated, washed with water, dried over sodium sulphate and evaporated at 40° in vacuum. The crude and oily residue is boiled for one hour with 100 ml of ether under reflux, whereby crystallization occurs. After cooling to 0°, the crystals are filtered off and washed with ether. One obtains 6-phenyl-8-chloro-4H-s-triazo'l/~1,5-a7/_— 1,47benzodiazepine-2-carboxylic acid ethyl ester with melting point 137 - 138°.
f) 11,0 g (0,030 mol) 6-fenyl-8-klor-4H-s-triazol-l_ l,5-a7/_ 1,47benzodiazepin-2-karboksylsyreetylester oppløst i f) 11.0 g (0.030 mol) 6-phenyl-8-chloro-4H-s-triazole-1_1,5-α7/_ 1,47benzodiazepine-2-carboxylic acid ethyl ester dissolved in
110 ml absolutt tetrahydrofuran dryppes under isavkjøling og i løpet av en time til en suspensjon av 2,3 g (0,06 mol) litium-aluminiumhydrid i 150 ml absolutt tetrahydrofuran. Man rører blandingen i ytterligere 30 minutter ved 0 - 5° og tildrypper deretter 11,5 ml 1 N natronlut. De uorganiske saltene filtreres fra. Derpå inndampes filtratet i vakuum, residuet opp-løses i 200 ml kloroform, vaskes med 1 N natronlut og deretter med vann. Etter tørking overnatriumsulfat inndampes kloroform-oppløsningen i vakuum og man krystalliserer residuet fra isopropanol. Etter tørking smelter det dannede 6-fenyl-8-klor-4H-s-triazol/<->l»5-a7/~1,47benzodiazepin-2-metanol ved 185 - 186°. g) 16,25 g (0,05 mol) alkohol fremstilt etter f) og 7,6 g (0,075 mol) trietyiamin oppløses i 200 ml absolutt mety-.lenklorid. Under isavkjøling og røring ved 3 - 10° blir 8,6 g (0,075 mol) metansulfoklorid, oppløst i 50 ml absolutt metylenklorid, tildryppet. Etter-avsluttet tildrypping oppvarmes reaksjonsblandingen til 20° og røres i 30 minutter. Deretter av-kjøles til 5° og man tilsetter 100 ml isvann. Metyleringsklorid-fasen skilles fra og vaskes med tre ganger 100 ml isvann, tørkes med natriumsulfat og inndampes i vakuum ved 30°. 110 ml of absolute tetrahydrofuran are added dropwise under ice-cooling and over the course of one hour to a suspension of 2.3 g (0.06 mol) of lithium aluminum hydride in 150 ml of absolute tetrahydrofuran. The mixture is stirred for a further 30 minutes at 0 - 5° and then 11.5 ml of 1 N caustic soda is added dropwise. The inorganic salts are filtered off. The filtrate is then evaporated in vacuo, the residue is dissolved in 200 ml of chloroform, washed with 1 N caustic soda and then with water. After drying over sodium sulphate, the chloroform solution is evaporated in vacuo and the residue is crystallized from isopropanol. After drying, the formed 6-phenyl-8-chloro-4H-s-triazole/<->1»5-α7/~1,47benzodiazepine-2-methanol melts at 185-186°. g) 16.25 g (0.05 mol) of alcohol prepared according to f) and 7.6 g (0.075 mol) of triethylamine are dissolved in 200 ml of absolute methylene chloride. Under ice-cooling and stirring at 3 - 10°, 8.6 g (0.075 mol) of methane sulphochloride, dissolved in 50 ml of absolute methylene chloride, are added dropwise. After completion of the dropwise addition, the reaction mixture is heated to 20° and stirred for 30 minutes. It is then cooled to 5° and 100 ml of ice water is added. The methylation chloride phase is separated and washed three times with 100 ml of ice water, dried with sodium sulfate and evaporated in vacuo at 30°.
Metansulfonsyreesteren av 6-fenyl-8-klor-4H-s-triazol/-1,5-a7/_ 1,47benzodiazepin-2-metanol fåes som mørkegul ikke-krystalliserbar olje og omsettes videre uten rensing. Eksempel 2. The methanesulfonic acid ester of 6-phenyl-8-chloro-4H-s-triazole/-1,5-α7/_ 1,47benzodiazepine-2-methanol is obtained as a dark yellow non-crystallizable oil and is reacted further without purification. Example 2.
Metansulfonsyreesteren fremstilt fra 4,9 g (0,015 mol) 6-fenyl-8-klor-4H-s-triazol/~l,5-a77—I,47benzodiazepin-2-metanol og 2,58 g (0,023 mol) metansulfonsyreklorid i henhold til eksempel 1 g) oppløses i 50 ml metanol og man drypper opp-løsningen inn i 100 ml kokende metanol som ved innføring av ammoniakkgass holdes stadig mettet. Man koker i 4 timer ved til-bakeløp og fortsatt innføring av ammoniakkgass og inndamper reaksjonsblandingen i vakuum til tørrhet. Residuet tilsettes 0,1 N natronlut og man ekstraherer med benzen. Benzenekstraktet vaskes en gang med vann og flere ganger med 0,1 N eddiksyre. The methanesulfonic acid ester prepared from 4.9 g (0.015 mol) of 6-phenyl-8-chloro-4H-s-triazole/~1,5-α77-1,47benzodiazepine-2-methanol and 2.58 g (0.023 mol) of methanesulfonic acid chloride in according to example 1 g) is dissolved in 50 ml of methanol and the solution is dripped into 100 ml of boiling methanol which is kept constantly saturated by the introduction of ammonia gas. It is boiled for 4 hours at reflux and continued introduction of ammonia gas and the reaction mixture is evaporated in vacuo to dryness. 0.1 N caustic soda is added to the residue and extracted with benzene. The benzene extract is washed once with water and several times with 0.1 N acetic acid.
De sure ekstrakter slås sammen, innstilles alkalisk med konsentrert ammoniakk og ekstraheres med benzen. De samlede benzenekstrakter vaskes med vann og mettet natriumkloridoppløsning, tørkes over natriumsulfat og inndampes til tørrhet. The acidic extracts are combined, made alkaline with concentrated ammonia and extracted with benzene. The combined benzene extracts are washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness.
Residuet på 1,7 g oppløses i eter-etanol-trietylamin (3". 5:2) og man kromatograferer oppløsningen på en kolonne^ av 170 g kiselgel. Som elueringsmiddel benyttes eter-etanol-trietylamin (3:5:2). Fraksjoner som inneholder de ønskede reaksjonsprodukter slås sammen og inndampes til tørrhet i vakuum. Man får amorft 2-(aminometyl)-6-fenyl-8-klor-4H-s-triazol/—1,5-a7/-l,_47benzodiazepin som blir flytende ved 69 - 75°. The residue of 1.7 g is dissolved in ether-ethanol-triethylamine (3". 5:2) and the solution is chromatographed on a column of 170 g silica gel. Ether-ethanol-triethylamine (3:5:2) is used as eluent. Fractions containing the desired reaction products are combined and evaporated to dryness in vacuo.Amorphous 2-(aminomethyl)-6-phenyl-8-chloro-4H-s-triazole/—1,5-α7/-1,_47benzodiazepine is obtained as becomes liquid at 69 - 75°.
Eksempel 3»Example 3»
Til en.oppløsning av 2,55 g (0,03 mol) piperidin i 30 ml dimetylsulfoksyd dryppes ved 15 - 17° en oppløsning av 6,05 g (0,015 mol) rått metansulfonsyreester av 6-fenyl-8-Ifclor-4H-s-triazol/_~1,5-a7/_~I, 47benzodiazepin-2-metanol (fremstillet etter eksempel lg)) i 50 ml dimetylsulfoksyd, langsomt, og man rører videre i tre timer ved romtemperatur. Reaksjonsblandingen helles opp i isvann og man ekstraherer tre ganger med eter. To a solution of 2.55 g (0.03 mol) of piperidine in 30 ml of dimethylsulfoxide, at 15 - 17°, a solution of 6.05 g (0.015 mol) of crude methanesulfonic acid ester of 6-phenyl-8-Ifchloro-4H- s-triazole/_~1,5-a7/_~I, 47benzodiazepine-2-methanol (prepared according to example 1g)) in 50 ml of dimethylsulfoxide, slowly, and stirring continues for three hours at room temperature. The reaction mixture is poured into ice water and extracted three times with ether.
Den organiske fasen vaskes to ganger med vann og en gang med mettet natriumoksydoppløsning, tørkes over natriumsulfat og inndampes til tørrhet i vakuum. Residuet oppløses i benzen-metylenklorid (1:1) og man kromatograferer oppløsningen på en kolonne med 100 g basisk aluminiumoksyd, hvorved man eluerer med den samme oppløsningsmiddelblanding. Fraksjonene som inneholder det ønskede reaksjonsproduktet samles og inndampes i vakuum. The organic phase is washed twice with water and once with saturated sodium oxide solution, dried over sodium sulfate and evaporated to dryness in vacuo. The residue is dissolved in benzene-methylene chloride (1:1) and the solution is chromatographed on a column with 100 g of basic aluminum oxide, eluting with the same solvent mixture. The fractions containing the desired reaction product are collected and evaporated in vacuo.
Man får amorft 2-(piperidinometyl)-6-fenyl-8-klor-4H-s-triazol /~1,5-a7/—l,47benzodiazepin som blir flytende ved 55 - 64°. Amorphous 2-(piperidinomethyl)-6-phenyl-8-chloro-4H-s-triazole /~1,5-α7/-1,47benzodiazepine is obtained which becomes liquid at 55 - 64°.
På analog vis får man ut fra 6,05 g (0,015 mol) Analogously, you get from 6.05 g (0.015 mol)
av den samme metansulfonsyre.ester med 5,4 g (0,077 mol) pyrro-lidin, det amorfe produkt 2'-/™(l-pyrrolidinyl)-metyl7-6-fenyl-8-klor-4H-s-triazolW~l,5'-a7/~l, 47benzodiazepin som blir flytende ved 53 - 63°. Likeledes får man med 2,6l g (0,030 mol) morfolin produktet 2-(morfolinometyl)-6-fenyl-8-klor-4H-s-tria-zol/_ l,5-a7/—1,47benzodiazepin, med smeltepunkt 111 - .113° etter krystallisasjon fra eter, med 3,05 g (0,030 mol) 1-metyl- of the same methanesulfonic acid ester with 5.4 g (0.077 mol) of pyrrolidine, the amorphous product 2'-[(l-pyrrolidinyl)-methyl7-6-phenyl-8-chloro-4H-s-triazoleW~l ,5'-a7/~l, 47benzodiazepine which liquefies at 53 - 63°. Likewise, with 2.6l g (0.030 mol) of morpholine, the product 2-(morpholinomethyl)-6-phenyl-8-chloro-4H-s-triazol/_1,5-α7/—1,47benzodiazepine is obtained, with melting point 111 - .113° after crystallization from ether, with 3.05 g (0.030 mol) of 1-methyl-
piperazin får man produktet 2-/_-(.^-aBtyi-l-piperazi'nylJ-mét'yl7-6-fenyl-8-klor-4H-s-triazol/ 1, 5-& 7f~ 1,4/benzodiazepin med smeltepunkt 162 -.163° etter krystallisasjon fra eter, og med 2>4 g (0,080 mol) metylamin får man det amorfe produkt 2-/_~(me-tylamino)-metyl7-6-fenyl-8-klor-4H-s-triazol/__l,5-a7/_~l,_47benzo-diazepin som blir flytende ved 5.6 - 67°C. piperazine, the product 2-/_-(.^-aBtyi-l-piperazi'nylJ-met'yl7-6-phenyl-8-chloro-4H-s-triazole/ 1, 5-& 7f~ 1,4/ benzodiazepine with melting point 162 -.163° after crystallization from ether, and with 2>4 g (0.080 mol) methylamine, the amorphous product 2-/_~(methylamino)-methyl7-6-phenyl-8-chloro- 4H-s-triazole/__l,5-a7/_~l,_47benzo-diazepine which liquefies at 5.6 - 67°C.
Eksempel 4. Example 4.
a) I analogi med eksempel 3 får man ut fra 2,4 g (0,080 mol) metylamin og 6,32 g (0,015 mol) rå metansulfonsyreester av 6- (o-f luorfenyl)-6'-klor-4H-.s-triazol_/—1,5-aT/-1,47 benzodiazepin-2-metanol produktet 2- £~(metylamino)-metyl7-6-(o-f luorf enyl)-8-klor-4H-s-triazo'l/_—l,5-a7/_~1,4_7benzodiazepin. Forbindelsen blir i 330 ml etylacetat tilsatt eterisk saltsyre til en prøve tilsatt vann for en pH-verdi på ca. 2. Etter lengre tids avkjøling frafiltreres de utfelte krystaller og om-krystalliseres to ganger fra etanol. Hydrokloridet som fåes etter tørking inneholder'den dobbelte molare mengde krystall-vann og smelter ved 247 - 249°. a) In analogy with example 3, one obtains from 2.4 g (0.080 mol) methylamine and 6.32 g (0.015 mol) crude methanesulfonic acid ester of 6-(o-fluorophenyl)-6'-chloro-4H-.s-triazole_ /—1,5-aT/-1,47 benzodiazepine-2-methanol the product 2- £~(methylamino)-methyl7-6-(o-fluorophenyl)-8-chloro-4H-s-triazo'l/_— 1,5-a7/_~1,4_7 benzodiazepine. The compound is added to 330 ml of ethyl acetate with ethereal hydrochloric acid to a sample with added water for a pH value of approx. 2. After a longer period of cooling, the precipitated crystals are filtered off and recrystallized twice from ethanol. The hydrochloride obtained after drying contains twice the molar amount of crystal water and melts at 247 - 249°.
Analogt får man ut fra 2,4g(0,08 mol) metylamin Analogously, 2.4g (0.08 mol) methylamine is obtained
og 6,57 g (0,015 mol) rå metansulfoirsyreester av 6-(o-klor-fenyl)-8-klor-4H-s-triazo'l/<_>1,5-a7/<_>— 1,47benzodiazepin-2-metanol produktet 2-/~(<m>et<y>.lamino)-met<y>17-6- (klorfen<y>l) -8-klor-4H-s-triazol/~l,5-a7/<_> 1,47benzodiazepin. Forbindelsen oppløses i 130 ml etanol og tilsettes en mettet^etanolisk fumarsyreoppløs-'ning til pH-verdien for en prøve tilsatt vann ligger på 6. and 6.57 g (0.015 mol) crude methanesulfoic acid ester of 6-(o-chloro-phenyl)-8-chloro-4H-s-triazo'l/<_>1,5-a7/<_>— 1,47 benzodiazepine -2-methanol the product 2-/~(<m>et<y>.lamino)-met<y>17-6-(chlorophen<y>l)-8-chloro-4H-s-triazole/~l, 5-a7/<_> 1,47benzodiazepine. The compound is dissolved in 130 ml of ethanol and a saturated ethanolic fumaric acid solution is added until the pH value for a sample with added water is 6.
Etter avkjøling frafiltreres de utfelte krystaller og omkrystal-liseres en gang fra metanol.. Etter tørking smelter det fremstilte 2-/~ (metylamino)-met'yl7-6- (o-klorf enyl)-8-klor-4H-s-triazol_/_l,5-a7/_-l,4_7benzodiazepinfumarat-(2:1) ved 199 - 201°. After cooling, the precipitated crystals are filtered off and recrystallized once from methanol. After drying, the produced 2-(methylamino)-methyl7-6-(o-chlorophenyl)-8-chloro-4H-s- triazole_/_1,5-α7/_-1,4_7benzodiazepine fumarate-(2:1) at 199 - 201°.
Den metansulfonsyreester som brukes som utgangsstoff fremstilles slik: b) I analogi med eksempel lb) får man under anvendelse av 62,5 g (0,25 mol) 2-amino-5_klor-2'-fluorbenzofenon produktet f~ 2-(o-fluorbenzoyl)-4-klorfenylazo7-(2-kloracetamido)-malonsyre-dietyleste<p>; The methanesulfonic acid ester used as starting material is prepared as follows: b) By analogy with example lb), using 62.5 g (0.25 mol) of 2-amino-5_chloro-2'-fluorobenzophenone, the product f~ 2-(o- fluorobenzoyl)-4-chlorophenylazo7-(2-chloroacetamido)-malonic acid diethyl ester<p>;
med 66,5 g (0,25 mol) 2-amino-2',5-diklorbenzofenon produktet l_ 2- (o-klorbenzoyl)-4-klorfenylazo7- (2-kloracetamido)-malonsyredietylester; with 66.5 g (0.25 mol) of the 2-amino-2',5-dichlorobenzophenone product 1_ 2-(o-chlorobenzoyl)-4-chlorophenylazo7-(2-chloroacetamido)-malonic acid diethyl ester;
c) Til en oppløsning av 51,2 g (0,10 mol) /~2-(o-fluorbenzoyl)-4-klorfenylazo7-(2-kloracetamido)-malonsyre-dietyl-ester i 600 ml dioksan tildryppes i løpet av to timer en opp-løsning av 8,0 g (0,20 mol) natriumhydroksyd i 400 ml vann. Herved stiger reaksjonsblandingens temperatur fra til å begynne med 20° til høyst 30° og pH-verdien når slutten 8,5 til 9,0. Blandingen røres i 45 minutter videre ved romtemperatur og c) To a solution of 51.2 g (0.10 mol) /~2-(o-fluorobenzoyl)-4-chlorophenylazo7-(2-chloroacetamido)-malonic acid diethyl ester in 600 ml dioxane is added dropwise over the course of two hours a solution of 8.0 g (0.20 mol) of sodium hydroxide in 400 ml of water. Hereby, the temperature of the reaction mixture rises from 20° to a maximum of 30° and the pH finally reaches 8.5 to 9.0. The mixture is stirred for a further 45 minutes at room temperature and
man nøytraliserer deretter ved tilsetning av iseddik og inndamper i vakuum. Residuet tilsettes is og 5%- ig natriumbikar-bonatoppløsning, man rister blandingen to ganger med eter og oppbevarer vannfasen. De organiske faser slås sammen, vaskes med iskald 5%- ig natriumbikarbonatoppløsning og vann, tørkes over natriumsulfat og inndampes i vakuum. Residuet krystalli-seres om fra isopropanol. Etter tørking smelter hovedproduktet l-/~2-(o-fluorbenzoyl)-4-klorfenyl7-5-(klormetyl)-lH-l,2,4-triazol-3-karboksylsyre-etylester ved 97 - 98°. it is then neutralized by adding glacial acetic acid and evaporated in a vacuum. Ice and 5% sodium bicarbonate solution are added to the residue, the mixture is shaken twice with ether and the aqueous phase is kept. The organic phases are combined, washed with ice-cold 5% sodium bicarbonate solution and water, dried over sodium sulfate and evaporated in vacuo. The residue is recrystallized from isopropanol. After drying, the main product 1-(o-fluorobenzoyl)-4-chlorophenyl-7-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid ethyl ester melts at 97-98°.
Ovenstående vandige natriumbikarbonatoppløshinger (opprinnelige og vaskeoppløsninger) slås sammen, tilsettes 1055-ig saltsyre til kongosur reaksjon og ekstraheres tre ganger med metylenklorid. De samlede organiske ekstrakter vaskes med The above aqueous sodium bicarbonate solutions (original and washing solutions) are combined, 1055 mg hydrochloric acid is added to the congo acid reaction and extracted three times with methylene chloride. The combined organic extracts are washed with
vann og mettet natriumkloridoppløsning, tørkes over natriumsulfat og inndampes i vakuum. Man får som biprodukt det rå amorfe l-/_~2-(o-fluorbenzoyl)-4-klorfeiryl7-5-(klormetyl)-lH-l,2,4-tria-zol-3-karboksylsyre. Denne rå syre kan brukes direkte til ring-slutningsreaksjonen i henhold til eksempel 1 c) eller 1 d). water and saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The crude amorphous 1-(o-fluorobenzoyl)-4-chlorophenyl-7-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid is obtained as a by-product. This crude acid can be used directly for the ring-closing reaction according to example 1 c) or 1 d).
Analogt får man Analogously you get
med 52,9 g (0,10 mol) /~2-(o-klorbenzoyl)-4-klorf.enylazo7-(2-kloracetamido)-malonsyre-dietylester produktet l-/<->2-(o-klor-benzoyl )-4-klorfeny_l7-5- (klormetyl)-lH-l, 2,4-triazol-3-karbokr sylsyre-etylester og den tilsvarende syre med smeltepunkt 170 - 175°. with 52.9 g (0.10 mol) of 2-(o-chlorobenzoyl)-4-chlorophenylazo7-(2-chloroacetamido)-malonic acid diethyl ester the product 1-(o-chloro- benzoyl)-4-chlorophenyl-17-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid ethyl ester and the corresponding acid with a melting point of 170 - 175°.
d) En oppløsning av 16,88 g (0,04 mol) l-/~2-(o-fluor-benzoyl)-4-klorfenyl7-5-(klormetyl)-lH-l,2,4-triazol-3_karboksylsyre-etylester og 11,2 g (0,08 mol) heksametylentetramin i 250 ml absolutt etanol kokes i 6 timer ved tilbakeløp. Derpå inndampes oppløsningen ved 40° i vakuum, residuet tilsettes 800 ml isvann d) A solution of 16.88 g (0.04 mol) of 1-(o-fluoro-benzoyl)-4-chlorophenyl-7-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid -ethyl ester and 11.2 g (0.08 mol) of hexamethylenetetramine in 250 ml of absolute ethanol are boiled for 6 hours at reflux. The solution is then evaporated at 40° in a vacuum, the residue is added to 800 ml of ice water
og ekstraheres to ganger med metylenklorid. Den organiske fasen vaskes to ganger med iskald 1 N saltsyre og tre ganger med vann, tørkes over natriumsulfat og inndampes i vakuum. Residuet kry-stalliseres om fra isopropanol. Etter tørking smelter det fremstilte 6- (o-f luorf enyl)-8-klor-4H-s-triazol^-l,5-a7/_-l,47benzodiazepin-2-karboksylsyre-etylester ved 177 - 179°- and extracted twice with methylene chloride. The organic phase is washed twice with ice-cold 1 N hydrochloric acid and three times with water, dried over sodium sulfate and evaporated in vacuo. The residue is recrystallized from isopropanol. After drying, the prepared 6-(o-fluorophenyl)-8-chloro-4H-s-triazol-1,5-α7/_-1,47benzodiazepine-2-carboxylic acid ethyl ester melts at 177 - 179°-
På analog måte får man Analogously, you get
ut fra 17,54 g (0,04 mol) l-/~2-(o-klorbenzoyl)-4-klorfenyl7-5- (klormetyl)-lH-l,2,4-triazol-3-karboksylsyre-etylester pro-duktet 6-(o-klorfenyl)-8-klor-4H-s-triazol/_~l,5-a7/_~l,_47benzodiazepin-2-karboksylsyreetylester; utbytte 86$. e) og f) I analogi med eksempel lf) og g) får man ut fra 11,54 g (0,03 mol) 6-(o-fluorfenyl)-8-klor-4H-s-triazol^~l,5-a7-/~l,4/benzodiazepin-2-karboksylsyre-ety.lester produktet 6- (o-f luorf enyl)-8-klor-4H-s-triazol_/_l,5-a.7/_-l,4_7benzodiazepin-2-metanol med smeltepunkt 138"- 145° (fra isopropanol) og dens metansulfonsyreester (råprodukt); from 17.54 g (0.04 mol) 1-(o-chlorobenzoyl)-4-chlorophenyl7-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid ethyl ester pro -duct 6-(o-chlorophenyl)-8-chloro-4H-s-triazole/_~1,5-α7/_~1,_47benzodiazepine-2-carboxylic acid ethyl ester; dividend 86$. e) and f) In analogy with examples lf) and g), one obtains from 11.54 g (0.03 mol) 6-(o-fluorophenyl)-8-chloro-4H-s-triazole^~1.5 -α7-/~1,4/benzodiazepine-2-carboxylic acid-ethyl ester product 6-(o-fluorophenyl)-8-chloro-4H-s-triazol_/_1,5-α.7/_-1,4_7benzodiazepine -2-methanol with melting point 138"- 145° (from isopropanol) and its methanesulfonic acid ester (crude product);
ut fra 12,04 g (0,03 mol) 6-(o-klorfenyl)-8-klor-4H-s-triazol l_ 1,5 - a7/~l, 4_7benz odiazepin-2-karboksylsyre-ety.le st er produktet 6- (o-klorfenyl)-8-klor-4H-s-triazol/—1,5-a7/~1,47benzodiazepin-2-metanol og dens metansulfonsyreester. from 12.04 g (0.03 mol) 6-(o-chlorophenyl)-8-chloro-4H-s-triazole 1,5-α7/~1,4-7benz odiazepine-2-carboxylic acid-ethyl st is the product 6-(o-chlorophenyl)-8-chloro-4H-s-triazole/—1,5-α7/~1,47benzodiazepine-2-methanol and its methanesulfonic acid ester.
Eksempel 5- Example 5-
I analogi med eksempel 1 får man By analogy with example 1, one obtains
ved anvendelse av 8,41 g metansulfonsyreester av 6-(o-fluorfenyl)-8-klor-4H-s-triazol Æ^5-a77 I, 47benzodiazepin-2-metanol produktet 2-/~(dimetylamino)-metyl7-6-(o-fluorfenyl)-8-klor-4H-s-triazol _/~l,5-a7/_~l,_47benzodiazepin, som etter omkrystallisasjon fra eter-petroleter smelter ved 114 - 116°. by using 8.41 g of methanesulfonic acid ester of 6-(o-fluorophenyl)-8-chloro-4H-s-triazole Æ^5-a77 I,47benzodiazepine-2-methanol the product 2-/~(dimethylamino)-methyl7-6 -(o-fluorophenyl)-8-chloro-4H-s-triazole _/~1,5-a7/_~1,_47benzodiazepine, which after recrystallization from ether-petroleum ether melts at 114 - 116°.
Eksempel 6. Example 6.
a) Til en oppløsning av 1,75 g (0,00S mol) 2-(azido-' metyl )-6-fenyl-8-klor-4H-s-triazol/~ 1,5-a7A~ 47benzodiazepin i a) To a solution of 1.75 g (0.00 mol) 2-(azido-' methyl )-6-phenyl-8-chloro-4H-s-triazole/~ 1,5-α7A~ 47benzodiazepine in
175 ml 95$-ig vandig etanol dryppes ved 0-5° langsomt en opp-løsning av 1,69 g (0,0075 mol) tinn(lI)-klorid-dihydrat i 24 ml 2 N natronlut. Reaksjonsblandingen blir straks uklar. Etter avsluttet tildrypping røres videre i 30 minutter ved 5 - 10°. Derpå nøytraliseres reaksjonsblandingen med 2 N saltsyre og man inndamper til tørrhet i vakuum. Residuet tilsettes 2 N natronlut og is og ekstraheres med en blanding av eter og metylenklorid (5:1). De organiske fasene ekstraheres med kald 1 N saltsyre. A solution of 1.69 g (0.0075 mol) stannous chloride dihydrate in 24 ml of 2 N caustic soda is added slowly at 0-5° to 175 ml of 95% aqueous ethanol. The reaction mixture immediately becomes cloudy. After the addition has finished, stir for 30 minutes at 5 - 10°. The reaction mixture is then neutralized with 2 N hydrochloric acid and evaporated to dryness in vacuo. The residue is added to 2 N caustic soda and ice and extracted with a mixture of ether and methylene chloride (5:1). The organic phases are extracted with cold 1 N hydrochloric acid.
De sure ekstrakter slås sammen, tilsettes 5 N natronlut til pH-verdi 10 og ekstraheres med eter. De samlede eterekstraktene vaskes med vann og mettet natriumkloridoppløsning, tørkes over natriumsulfat og inndampes til tørrhet. Man får amorft 2-(amino-metyl)-6-fenyl-8-klor-4H-s-triazol/~l ,5-a7/~l, 4_7benzodiazepin som blir flytende ved 69 - 75°- The acidic extracts are combined, 5 N caustic soda is added to a pH value of 10 and extracted with ether. The combined ether extracts are washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. Amorphous 2-(amino-methyl)-6-phenyl-8-chloro-4H-s-triazol/~1,5-α7/~1,4_7benzodiazepine is obtained which becomes liquid at 69 - 75°-
På analog måte får man Analogously, you get
ut fra 1,84 g (0,005 mol). 2-(,azidometyl)-6-(o-f luorfenyl)-8-klor-4H-s-triazol/ l,5-a7</>—l',<4>7benzodiazepin produktet 2-(amino-metyl)-6-(o-fluorfenyl)-8-klor-4H-s-triazol/~l,5-a7/_<_>l,47 benzodiazepin. b) Azidometyl-forbindelsene som brukes som utgangsstoffer fremstilles på følgende måte: Den rå metansulfonsyreester som er fremstilt i henhold til eksempel 1 g). ut fra 3,25 g (0,05 mol) 6-fenyl-8-klor-4H-s-triazol/ 1,5-a7/~1,47benzodiazepin-2-metanol og 1,71 g (0,015 mol) metansulfonsyreklorid oppløses i 50 ml aceton og man tilsetter en oppløsning av 3,25 g (0,15 mol) natriumazid i 25 ml vann. Reaksjonsblandingen røres i en time ved 30° og inndampes i vakuum. Den dannede rå azidometylforbindelse oppløses i benzen og vaskes med kald 5%- ig natriumbikarbonatopp-løsning og to ganger med vann. Den organiske oppløsning tørkes over natriumsulfat og inndampes i vakuum. Man oppløser residuet i benzen og kromatograferer oppløsningen på kolonnene inneholdende 30 g kiselgel samt eluerer med benzen. Fraksjonene som inneholder det ønskede reaksjonsprodukt slås sammen og inndampes i vakuum. Man får 2-(azidometyl)-6-fenyl-8-klor-4H-s-triazol/<_>—l,5-a7/_ 1,47benzodiazepin som en gul olje som kan omsettes direkte videre. from 1.84 g (0.005 mol). 2-(,azidomethyl)-6-(o-fluorophenyl)-8-chloro-4H-s-triazole/l,5-a7</>—l',<4>7benzodiazepine product 2-(amino-methyl)-6 -(o-fluorophenyl)-8-chloro-4H-s-triazole/~1,5-α7/_<_>1,47 benzodiazepine. b) The azidomethyl compounds used as starting materials are prepared in the following way: The crude methanesulphonic acid ester which is prepared according to example 1 g). from 3.25 g (0.05 mol) 6-phenyl-8-chloro-4H-s-triazole/1,5-α7/~1.47benzodiazepine-2-methanol and 1.71 g (0.015 mol) methanesulfonic acid chloride is dissolved in 50 ml of acetone and a solution of 3.25 g (0.15 mol) of sodium azide in 25 ml of water is added. The reaction mixture is stirred for one hour at 30° and evaporated in vacuo. The crude azidomethyl compound formed is dissolved in benzene and washed with cold 5% sodium bicarbonate solution and twice with water. The organic solution is dried over sodium sulfate and evaporated in vacuo. The residue is dissolved in benzene and the solution is chromatographed on columns containing 30 g of silica gel and eluted with benzene. The fractions containing the desired reaction product are combined and evaporated in vacuo. 2-(azidomethyl)-6-phenyl-8-chloro-4H-s-triazole/<_>—1,5-α7/_ 1,47benzodiazepine is obtained as a yellow oil which can be reacted directly further.
I analogi får man By analogy you get
2- (azidometyl)-6- (o-f luorf enyl)-@-klor-4H-s-triazol_/_l,5-a7/._l,i7-benzodiazepin ved å anvende de tilsvarende rå metansulfonsyreestere som i analogi med eksempel 1 g) er fremstillet med 1,71 g (0,015 mol) metansulfonklorid ut fra 2-(azidomethyl)-6-(o-fluorophenyl)-@-chloro-4H-s-triazol_/_l,5-a7/._1,i7-benzodiazepine by using the corresponding crude methanesulfonic acid esters as in analogy with example 1 g ) is prepared with 1.71 g (0.015 mol) of methanesulphonic chloride from
3,43 g (0,01 mol). 6-(o-fluorfenyl)-8-klor-4H-s-triazol/~l,5-a7 L 1, 4_/t>enzodiazepin-2-metanol. 3.43 g (0.01 mol). 6-(o-Fluorophenyl)-8-chloro-4H-s-triazole/~1,5-α7 L 1, 4_/t>enzodiazepine-2-methanol.
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CH1088571A CH553801A (en) | 1971-07-23 | 1971-07-23 | PROCESS FOR THE PRODUCTION OF NEW DIAZEPIN DERIVATIVES. |
Publications (2)
Publication Number | Publication Date |
---|---|
NO134868B true NO134868B (en) | 1976-09-20 |
NO134868C NO134868C (en) | 1976-12-29 |
Family
ID=4367854
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO2588/72A NO134868C (en) | 1971-07-23 | 1972-07-19 |
Country Status (23)
Country | Link |
---|---|
US (1) | US3878205A (en) |
JP (1) | JPS561316B1 (en) |
AR (2) | AR194603A1 (en) |
AT (2) | AT319956B (en) |
AU (1) | AU472145B2 (en) |
BE (1) | BE786530A (en) |
CA (1) | CA967956A (en) |
CH (1) | CH553801A (en) |
CS (2) | CS178411B2 (en) |
DD (1) | DD99578A5 (en) |
DE (1) | DE2234652A1 (en) |
FI (1) | FI52729C (en) |
FR (1) | FR2147092B1 (en) |
GB (1) | GB1395416A (en) |
HU (1) | HU165319B (en) |
IE (1) | IE36563B1 (en) |
IL (1) | IL39883A (en) |
NL (1) | NL7209809A (en) |
NO (1) | NO134868C (en) |
PL (1) | PL85681B1 (en) |
SE (1) | SE380804B (en) |
SU (2) | SU472505A3 (en) |
ZA (1) | ZA724839B (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4209516A (en) * | 1974-01-14 | 1980-06-24 | Ciba-Geigy Corporation | Triazole derivatives |
JPS5747915B2 (en) * | 1974-04-17 | 1982-10-13 | ||
US4209515A (en) * | 1974-06-14 | 1980-06-24 | Ciba-Geigy Corporation | Triazole derivatives |
US3996230A (en) * | 1975-03-28 | 1976-12-07 | The Upjohn Company | 1-Piperazino-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepines |
US4510141A (en) * | 1982-09-13 | 1985-04-09 | Ciba-Geigy Corporation | Tricyclic polyazaheterocycles for treating depression or anxiety |
WO2023052312A1 (en) | 2021-09-29 | 2023-04-06 | F. Hoffmann-La Roche Ag | New benzodiazepine derivatives as gaba a gamma1 pam |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE758921A (en) * | 1969-11-15 | 1971-04-16 | Takeda Chemical Industries Ltd | BENZODIAZEPINE DERIVATIVES |
-
0
- BE BE786530D patent/BE786530A/en unknown
-
1971
- 1971-07-23 CH CH1088571A patent/CH553801A/en not_active IP Right Cessation
-
1972
- 1972-06-28 FI FI721828A patent/FI52729C/en active
- 1972-07-11 IL IL39883A patent/IL39883A/en unknown
- 1972-07-12 IE IE982/72A patent/IE36563B1/en unknown
- 1972-07-13 SE SE7209242A patent/SE380804B/en unknown
- 1972-07-13 ZA ZA724839A patent/ZA724839B/en unknown
- 1972-07-14 US US272088A patent/US3878205A/en not_active Expired - Lifetime
- 1972-07-14 DE DE2234652A patent/DE2234652A1/en active Pending
- 1972-07-14 NL NL7209809A patent/NL7209809A/xx not_active Application Discontinuation
- 1972-07-17 CA CA147,245A patent/CA967956A/en not_active Expired
- 1972-07-19 NO NO2588/72A patent/NO134868C/no unknown
- 1972-07-20 CS CS5172A patent/CS178411B2/cs unknown
- 1972-07-20 CS CS489A patent/CS178450B2/cs unknown
- 1972-07-21 HU HUCI1256A patent/HU165319B/hu unknown
- 1972-07-21 DD DD164605A patent/DD99578A5/xx unknown
- 1972-07-21 SU SU1813891A patent/SU472505A3/en active
- 1972-07-21 PL PL1972156882A patent/PL85681B1/pl unknown
- 1972-07-21 AU AU44837/72A patent/AU472145B2/en not_active Expired
- 1972-07-21 AT AT1013073A patent/AT319956B/en not_active IP Right Cessation
- 1972-07-21 FR FR7226331A patent/FR2147092B1/fr not_active Expired
- 1972-07-21 GB GB3421672A patent/GB1395416A/en not_active Expired
- 1972-07-21 AT AT631372A patent/AT318625B/en not_active IP Right Cessation
- 1972-07-22 JP JP7305972A patent/JPS561316B1/ja active Pending
- 1972-07-24 AR AR243233A patent/AR194603A1/en active
-
1973
- 1973-05-29 AR AR248269A patent/AR197989A1/en active
-
1974
- 1974-01-30 SU SU1993157A patent/SU497776A3/en active
Also Published As
Publication number | Publication date |
---|---|
AU4483772A (en) | 1974-01-24 |
IE36563L (en) | 1973-01-23 |
IL39883A0 (en) | 1972-09-28 |
NO134868C (en) | 1976-12-29 |
US3878205A (en) | 1975-04-15 |
CA967956A (en) | 1975-05-20 |
DD99578A5 (en) | 1973-08-12 |
PL85681B1 (en) | 1976-04-30 |
AT319956B (en) | 1975-01-27 |
FI52729B (en) | 1977-08-01 |
AR194603A1 (en) | 1973-07-31 |
AR197989A1 (en) | 1974-05-24 |
DE2234652A1 (en) | 1973-02-01 |
CS178450B2 (en) | 1977-09-15 |
BE786530A (en) | 1973-01-22 |
FR2147092A1 (en) | 1973-03-09 |
JPS561316B1 (en) | 1981-01-13 |
SU497776A3 (en) | 1975-12-30 |
SU472505A3 (en) | 1975-05-30 |
HU165319B (en) | 1974-08-28 |
CS178411B2 (en) | 1977-09-15 |
CH553801A (en) | 1974-09-13 |
SE380804B (en) | 1975-11-17 |
AT318625B (en) | 1974-11-11 |
NL7209809A (en) | 1973-01-25 |
IE36563B1 (en) | 1976-12-08 |
GB1395416A (en) | 1975-05-29 |
ZA724839B (en) | 1973-04-25 |
FI52729C (en) | 1977-11-10 |
FR2147092B1 (en) | 1975-08-08 |
IL39883A (en) | 1976-06-30 |
AU472145B2 (en) | 1976-05-20 |
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