PL92427B1 - - Google Patents
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- Publication number
- PL92427B1 PL92427B1 PL17669472A PL17669472A PL92427B1 PL 92427 B1 PL92427 B1 PL 92427B1 PL 17669472 A PL17669472 A PL 17669472A PL 17669472 A PL17669472 A PL 17669472A PL 92427 B1 PL92427 B1 PL 92427B1
- Authority
- PL
- Poland
- Prior art keywords
- nitro
- carbon atoms
- formula
- group
- carboxamide
- Prior art date
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- -1 3-nitro-4- (substituted) pyrazoles Chemical class 0.000 claims description 81
- 125000004432 carbon atom Chemical group C* 0.000 claims description 36
- 150000001875 compounds Chemical class 0.000 claims description 30
- 238000002360 preparation method Methods 0.000 claims description 25
- 150000003857 carboxamides Chemical class 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- MCOJDENHMYYSQV-UHFFFAOYSA-N 5-nitro-1h-pyrazole-4-carboxamide Chemical compound NC(=O)C1=CNN=C1[N+]([O-])=O MCOJDENHMYYSQV-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 229910004039 HBF4 Inorganic materials 0.000 claims description 4
- 125000000304 alkynyl group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 4
- 239000012954 diazonium Substances 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- BHWGVDFLAUBWLA-UHFFFAOYSA-N 5-nitro-1h-pyrazole-4-carbonitrile Chemical compound [O-][N+](=O)C=1NN=CC=1C#N BHWGVDFLAUBWLA-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 150000007942 carboxylates Chemical class 0.000 claims description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 2
- 125000004429 atom Chemical group 0.000 claims 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 2
- 125000004997 halocarbonyl group Chemical group 0.000 claims 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 2
- VSINDDANNGMBLT-UHFFFAOYSA-N 3ah-isoindole-1,3,4-trione Chemical class C1=CC(=O)C2C(=O)NC(=O)C2=C1 VSINDDANNGMBLT-UHFFFAOYSA-N 0.000 claims 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims 1
- 150000008046 alkali metal hydrides Chemical class 0.000 claims 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 claims 1
- 150000004678 hydrides Chemical class 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 125000000335 thiazolyl group Chemical group 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 239000000203 mixture Substances 0.000 description 42
- 125000001424 substituent group Chemical group 0.000 description 26
- 238000002844 melting Methods 0.000 description 25
- 230000008018 melting Effects 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 5
- MZRUFMBFIKGOAL-UHFFFAOYSA-N 5-nitro-1h-pyrazole Chemical group [O-][N+](=O)C1=CC=NN1 MZRUFMBFIKGOAL-UHFFFAOYSA-N 0.000 description 5
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 159000000000 sodium salts Chemical class 0.000 description 5
- NJBDBENRPJEIHN-UHFFFAOYSA-N 1-methyl-3-nitropyrazole-4-carbonitrile Chemical compound CN1C=C(C#N)C([N+]([O-])=O)=N1 NJBDBENRPJEIHN-UHFFFAOYSA-N 0.000 description 4
- NUGZBVBZIDWZAD-UHFFFAOYSA-N 1h-pyrazole-4-carbonitrile Chemical compound N#CC=1C=NNC=1 NUGZBVBZIDWZAD-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- LOIDMDPCSBUPCZ-UHFFFAOYSA-N 1-(2-hydroxyethyl)-3-nitropyrazole-4-carboxamide Chemical compound NC(=O)C1=CN(CCO)N=C1[N+]([O-])=O LOIDMDPCSBUPCZ-UHFFFAOYSA-N 0.000 description 3
- UQRRCAUELNIPJW-UHFFFAOYSA-N 1-(2-hydroxyethyl)-3-nitropyrazole-4-carboxylic acid Chemical compound OCCN1C=C(C(O)=O)C([N+]([O-])=O)=N1 UQRRCAUELNIPJW-UHFFFAOYSA-N 0.000 description 3
- IEWOTEOUUSYKAQ-UHFFFAOYSA-N 1-(2-hydroxyethyl)-n-methyl-3-nitropyrazole-4-carboxamide Chemical compound CNC(=O)C1=CN(CCO)N=C1[N+]([O-])=O IEWOTEOUUSYKAQ-UHFFFAOYSA-N 0.000 description 3
- HZSZGDHAUCLQJY-UHFFFAOYSA-N 1-ethenyl-3-nitropyrazole-4-carboxamide Chemical compound NC(=O)C1=CN(C=C)N=C1[N+]([O-])=O HZSZGDHAUCLQJY-UHFFFAOYSA-N 0.000 description 3
- CYTLOMOEKMHGPM-UHFFFAOYSA-N 1-methyl-3-nitropyrazole-4-carbonyl chloride Chemical compound CN1C=C(C(Cl)=O)C([N+]([O-])=O)=N1 CYTLOMOEKMHGPM-UHFFFAOYSA-N 0.000 description 3
- ZIDNELAAGGUUFP-UHFFFAOYSA-N 1-methyl-3-nitropyrazole-4-carboxamide Chemical compound CN1C=C(C(N)=O)C([N+]([O-])=O)=N1 ZIDNELAAGGUUFP-UHFFFAOYSA-N 0.000 description 3
- BNYCHCAYYYRJSH-UHFFFAOYSA-N 1h-pyrazole-5-carboxamide Chemical compound NC(=O)C1=CC=NN1 BNYCHCAYYYRJSH-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 241000607142 Salmonella Species 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- OSWXMVCQEZDFPI-UHFFFAOYSA-N methyl 1-(2-hydroxyethyl)-3-nitropyrazole-4-carboxylate Chemical compound COC(=O)C1=CN(CCO)N=C1[N+]([O-])=O OSWXMVCQEZDFPI-UHFFFAOYSA-N 0.000 description 3
- 244000045947 parasite Species 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- FGEIVVMHVGMDME-UHFFFAOYSA-N 1-benzyl-3-nitropyrazole-4-carboxamide Chemical compound N1=C([N+]([O-])=O)C(C(=O)N)=CN1CC1=CC=CC=C1 FGEIVVMHVGMDME-UHFFFAOYSA-N 0.000 description 2
- SMXDRRLYXOTORT-UHFFFAOYSA-N 1-methyl-3-nitropyrazole-4-carboxylic acid Chemical compound CN1C=C(C(O)=O)C([N+]([O-])=O)=N1 SMXDRRLYXOTORT-UHFFFAOYSA-N 0.000 description 2
- ZVXKYWHJBYIYNI-UHFFFAOYSA-N 1h-pyrazole-4-carboxamide Chemical compound NC(=O)C=1C=NNC=1 ZVXKYWHJBYIYNI-UHFFFAOYSA-N 0.000 description 2
- 125000005999 2-bromoethyl group Chemical group 0.000 description 2
- MRJYTCKHIMHUMK-UHFFFAOYSA-N 3-nitro-1-nonylpyrazole-4-carboxamide Chemical compound CCCCCCCCCN1C=C(C(N)=O)C([N+]([O-])=O)=N1 MRJYTCKHIMHUMK-UHFFFAOYSA-N 0.000 description 2
- JIRJTQLEIXUBGJ-UHFFFAOYSA-N 3-nitro-1-propylpyrazole-4-carboxamide Chemical compound CCCN1C=C(C(N)=O)C([N+]([O-])=O)=N1 JIRJTQLEIXUBGJ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000589877 Campylobacter coli Species 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000204031 Mycoplasma Species 0.000 description 2
- 241001579016 Nanoa Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000392514 Salmonella enterica subsp. enterica serovar Dublin Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229940023064 escherichia coli Drugs 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000002363 herbicidal effect Effects 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- YJOLQLMJAZKELN-UHFFFAOYSA-N methyl 1-methyl-3-nitropyrazole-4-carboxylate Chemical compound COC(=O)C1=CN(C)N=C1[N+]([O-])=O YJOLQLMJAZKELN-UHFFFAOYSA-N 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 239000013049 sediment Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000007039 two-step reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- UVROAJFELBNMRA-UHFFFAOYSA-N (1-chloro-2-phenylethyl)benzene Chemical compound C=1C=CC=CC=1C(Cl)CC1=CC=CC=C1 UVROAJFELBNMRA-UHFFFAOYSA-N 0.000 description 1
- NDQXKKFRNOPRDW-UHFFFAOYSA-N 1,1,1-triethoxyethane Chemical compound CCOC(C)(OCC)OCC NDQXKKFRNOPRDW-UHFFFAOYSA-N 0.000 description 1
- JDAOVAPWRGYBQR-UHFFFAOYSA-N 1-(2,2-diethoxyethyl)-3-nitropyrazole-4-carboxamide Chemical compound CCOC(OCC)CN1C=C(C(N)=O)C([N+]([O-])=O)=N1 JDAOVAPWRGYBQR-UHFFFAOYSA-N 0.000 description 1
- MLQGOONHCMTHNW-UHFFFAOYSA-N 1-(2-bromoethyl)-3-nitropyrazole-4-carboxamide Chemical compound NC(=O)C1=CN(CCBr)N=C1[N+]([O-])=O MLQGOONHCMTHNW-UHFFFAOYSA-N 0.000 description 1
- HNBISZHHRQNLLY-UHFFFAOYSA-N 1-(2-chloroethyl)-3-nitropyrazole-4-carbonitrile Chemical compound [O-][N+](=O)C1=NN(CCCl)C=C1C#N HNBISZHHRQNLLY-UHFFFAOYSA-N 0.000 description 1
- RKYBOGMRSVFVFN-UHFFFAOYSA-N 1-(2-chloroethyl)-3-nitropyrazole-4-carboxamide Chemical compound NC(=O)C1=CN(CCCl)N=C1[N+]([O-])=O RKYBOGMRSVFVFN-UHFFFAOYSA-N 0.000 description 1
- MZUVBFSJVZYWTC-UHFFFAOYSA-N 1-(2-ethoxyethyl)-3-nitropyrazole-4-carbonitrile Chemical compound CCOCCN1C=C(C#N)C([N+]([O-])=O)=N1 MZUVBFSJVZYWTC-UHFFFAOYSA-N 0.000 description 1
- WECOGUIVFJUKOT-UHFFFAOYSA-N 1-(2-ethoxyethyl)-3-nitropyrazole-4-carboxamide Chemical compound CCOCCN1C=C(C(N)=O)C([N+]([O-])=O)=N1 WECOGUIVFJUKOT-UHFFFAOYSA-N 0.000 description 1
- YLXSGUIBKJNWDR-UHFFFAOYSA-N 1-(2-ethylsulfonylethyl)-3-nitropyrazole-4-carboxamide Chemical compound CCS(=O)(=O)CCN1C=C(C(N)=O)C([N+]([O-])=O)=N1 YLXSGUIBKJNWDR-UHFFFAOYSA-N 0.000 description 1
- CHDFUJJHFZBNFQ-UHFFFAOYSA-N 1-(3-chloro-2-hydroxypropyl)-3-nitropyrazole-4-carbonitrile Chemical compound ClCC(O)CN1C=C(C#N)C([N+]([O-])=O)=N1 CHDFUJJHFZBNFQ-UHFFFAOYSA-N 0.000 description 1
- HSHFZKZJRBPBIZ-UHFFFAOYSA-N 1-(3-chloropropyl)-3-nitropyrazole-4-carbonitrile Chemical compound [O-][N+](=O)C1=NN(CCCCl)C=C1C#N HSHFZKZJRBPBIZ-UHFFFAOYSA-N 0.000 description 1
- ZYEVBSQPKWNECH-UHFFFAOYSA-N 1-(3-methylpentan-2-yl)-3-nitropyrazole-4-carboxamide Chemical compound CCC(C)C(C)N1C=C(C(N)=O)C([N+]([O-])=O)=N1 ZYEVBSQPKWNECH-UHFFFAOYSA-N 0.000 description 1
- NWRLRHHJJOIGFN-UHFFFAOYSA-N 1-[2-(1,3-dioxoisoindol-2-yl)ethyl]-3-nitropyrazole-4-carboxamide Chemical compound N1=C([N+]([O-])=O)C(C(=O)N)=CN1CCN1C(=O)C2=CC=CC=C2C1=O NWRLRHHJJOIGFN-UHFFFAOYSA-N 0.000 description 1
- MKHBODRSULWFMJ-UHFFFAOYSA-N 1-benzyl-3-nitropyrazole-4-carbonitrile Chemical compound C1=C(C#N)C([N+](=O)[O-])=NN1CC1=CC=CC=C1 MKHBODRSULWFMJ-UHFFFAOYSA-N 0.000 description 1
- WKXAEFOKLDCKHX-UHFFFAOYSA-N 1-but-2-enyl-3-nitropyrazole-4-carboxamide Chemical compound CC=CCN1C=C(C(N)=O)C([N+]([O-])=O)=N1 WKXAEFOKLDCKHX-UHFFFAOYSA-N 0.000 description 1
- VDFPLBHYELEAKI-UHFFFAOYSA-N 1-ethyl-3-nitropyrazole-4-carboxylic acid Chemical compound CCN1C=C(C(O)=O)C([N+]([O-])=O)=N1 VDFPLBHYELEAKI-UHFFFAOYSA-N 0.000 description 1
- WFQDTOYDVUWQMS-UHFFFAOYSA-N 1-fluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1 WFQDTOYDVUWQMS-UHFFFAOYSA-N 0.000 description 1
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 1
- YMJLEPMVGQBLHL-UHFFFAOYSA-N 1h-pyrazole-5-carbonitrile Chemical compound N#CC1=CC=NN1 YMJLEPMVGQBLHL-UHFFFAOYSA-N 0.000 description 1
- RQUBFCKHWLKLRV-UHFFFAOYSA-N 2-(1-ethoxybutylidene)propanedinitrile Chemical compound CCCC(OCC)=C(C#N)C#N RQUBFCKHWLKLRV-UHFFFAOYSA-N 0.000 description 1
- GXMOSBIOUZALPM-UHFFFAOYSA-N 2-(1-ethoxypropylidene)propanedinitrile Chemical compound CCOC(CC)=C(C#N)C#N GXMOSBIOUZALPM-UHFFFAOYSA-N 0.000 description 1
- APYUMVPJPKDCKN-UHFFFAOYSA-N 2-(4-carbamoyl-3-nitropyrazol-1-yl)ethyl 4-ethylbenzoate Chemical compound C1=CC(CC)=CC=C1C(=O)OCCN1N=C([N+]([O-])=O)C(C(N)=O)=C1 APYUMVPJPKDCKN-UHFFFAOYSA-N 0.000 description 1
- YLJPIHCSEKMQNU-UHFFFAOYSA-N 2-(4-carbamoyl-3-nitropyrazol-1-yl)ethyl acetate Chemical compound CC(=O)OCCN1C=C(C(N)=O)C([N+]([O-])=O)=N1 YLJPIHCSEKMQNU-UHFFFAOYSA-N 0.000 description 1
- RPDOYSCEKPNPLZ-UHFFFAOYSA-N 2-bromo-1,3,5-triazine Chemical compound BrC1=NC=NC=N1 RPDOYSCEKPNPLZ-UHFFFAOYSA-N 0.000 description 1
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- VGKDKJGNGNLEDI-UHFFFAOYSA-N 3-nitro-1-(2-oxopropyl)pyrazole-4-carboxamide Chemical compound CC(=O)CN1C=C(C(N)=O)C([N+]([O-])=O)=N1 VGKDKJGNGNLEDI-UHFFFAOYSA-N 0.000 description 1
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Description
Przedmiotem wynalazku jest sposób wytwarzania nowych 3-nitro-4(podstawionych) pirazoli o ogólnym wzorze 1, w*którym R oznacza rodnik epoksyalkilowy o 3—4 atomach wegla, atom wodoru, rodnik alkilowy o 1—10 atomach wegla, alkenylowy o 2—10 atomach wegla, alkinylowy o 3—10 atomach wegla lub cykloalkilo- alkilowy o 4—12 atomach wegla, ewentualnie dowolnie podstawione atomem chlorowca, grupa karboksyamido- wa, keto, wodorotlenowa, ftalimidowa, alkilotio o 1—3 atomach wegla, alkilosulfonylowa o 1—3 atomach wegla, alkanoilowa o 1—3 atomach wegla, alkoksylowa o 1—3 atomach wegla, fenylowa, albo grupa o wzorze 2, w którym R2 oznacza rodnik alkilowy o 1 -3 atomach wegla lub fenylowy, ewentualnie podstawiony rodnikiem alkilowym o 1—3 atomach wegla, albo R oznacza rodnik fenylowy lub tiazolilowy, ewentualnie podstawione grupa nitrowa, R1 oznacza atom wodoru lub rodnik alkilowy o 1—3 atomach wegla, R3 oznacza atom wodoru, grupe aminowa, hydroksylowa lub rodnik alkilowy o 1-6 atomach wegla, a R4 oznacza atom wodoru lub rodnik alkilowy o 1-6 atomach wegla, z wyjatkiem przypadku, ze R4 i R3 nie oznaczaja razem rodnika alkilowego o wiekszej liczbie atomów wegla niz 2 lub R i R1 maja takie znaczenie, ze tworza 1,1 '-(2,5-cykloheksadien-1 ,4-yle- no)-bis-(3-nitro-4-pirazolokarboksyamid).The present invention relates to a process for the preparation of new 3-nitro-4 (substituted) pyrazoles of general the formula I, in which R is an epoxyalkyl radical with 3 to 4 carbon atoms, a hydrogen atom, an alkyl radical with 1-10 carbon atoms, alkenyl with 2-10 carbon atoms, alkynyl with 3-10 carbon atoms or cycloalkyl alkyl with 4 to 12 carbon atoms, optionally optionally substituted with halogen, carboxamide, wa, keto, hydroxyl, phthalimide, alkylthio with 1 to 3 carbon atoms, alkylsulfonyl with 1 to 3 carbon atoms, alkanoyl with 1-3 carbon atoms, alkoxy with 1-3 carbon atoms, phenyl, or the group of formula II, wherein R2 is an alkyl group having 1-3 carbon atoms or a phenyl radical optionally substituted with a radical alkyl of 1-3 carbon atoms, or R is a phenyl or thiazolyl radical, optionally substituted nitro group, R1 is a hydrogen atom or an alkyl radical of 1-3 carbon atoms, R3 is a hydrogen atom, amino, hydroxy or an alkyl radical of 1-6 carbon atoms, and R4 is a hydrogen atom or a radical alkyl of 1-6 carbon atoms, except that R4 and R3 together are not an alkyl radical having more than 2 carbon atoms, or R and R1 have the meaning that they form 1,1 '- (2,5-cyclohexadiene-1,4-yl- no) -bis- (3-nitro-4-pyrazolecarboxamide).
Przykladami rodników alkilowych, alkenylowych, cykloalkiloalkilowych, alkinylowych i alkoksylowych wymienionych w opisie sa rodniki takie jak rodnik etenylowy, 2-butenylowy, 2,3-dwumetylo-3-butenylowy, 3-metylopentylowy, metylowy, Hl-rzed.-butylowy, 3-pentylowy, 2-cyklobutenylowy,2-decenylowy,2-propargi- lowy, 3-heksynylowy, 9-decynylowy, 2,4-heksadienylowy, etoksylowy, izopropoksylowy, 3-pentylowy, heksylo- ksylowy, oktylowy, decylowy, 3-etyloheksylowy, cyklopropylometylowy i cykloheksylopropylowy.Examples of alkyl, alkenyl, cycloalkylalkyl, alkynyl and alkoxy radicals mentioned in the description are radicals such as ethenyl, 2-butenyl, 2,3-dimethyl-3-butenyl radicals, 3-methylpentyl, methyl, Hl-tert-butyl, 3-pentyl, 2-cyclobutenyl, 2-decenyl, 2-propargi lyl, 3-hexynyl, 9-decynyl, 2,4-hexadienyl, ethoxy, isopropoxy, 3-pentyl, hexyl- xyl, octyl, decyl, 3-ethylhexyl, cyclopropylmethyl and cyclohexylpropyl.
Atomami chlorowca sa atomy fluoru, chloru, bromu i jodu.Halogen atoms are fluorine, chlorine, bromine and iodine.
Rodnikami alkilotio o 1-3 atomach wegla sa rodniki metylotio, etylotio lub propylotio. Przykladami grup acyloksylowych o 1 —3 atomach wegla sa grupy formyloksylowa, acetyloksylowa lub propionyloksylowa.The alkylthio radicals having 1-3 carbon atoms are methylthio, ethylthio or propylthio radicals. Examples of groups acyloxy groups with 1-3 carbon atoms have formyloxy, acetyloxy or propionyloxy groups.
Przykladami rodników alkilosulfonylowych o 1-3 atomach wegla sa: metylosulfonylowy, etylosulfonylo- wy lub izopropylosulfonylowy.2 92 427 Przykladami rodników alkanoilowych o 1—3 atomach wegla sa rodniki forrnylowy, acetylowy lub propionylowy.Examples of alkylsulfonyl radicals with 1-3 carbon atoms are: methylsulfonyl, ethylsulfonyl- or isopropylsulfonyl. 2 92 427 Examples of alkanoyl radicals with 1 to 3 carbon atoms are forrnyl, acetyl or propionyl.
Charakterystyczna cecha zwiazków wytwarzanych sposobem wedlug wynalazku jest pierscien 3-nitropira- zolowy.Stwierdzono, ze w praktyce aktywnosc biologiczna pierscienia zalezy od podstawników w pozycjach 1,4 i 5, opisanych w opisie, jak równiez podstawników pokrewnych, których stosowanie bedzie oczywiste dla znawcy* • Nalezy spodziewac sie, ze polaczenie dwóch lub wiecej pierscieni 3-nitropirazolowych da zwiazek biologicznie aktywny, biorac pod uwage aktywnosc zwiazków jednopierscieniowych. Stwierdzono, ze zwiazki skladajace sie z dwóch lub wiecej pierscieni 3-nitropirazolowych, polaczonych poprzez podstawniki w pozycji 1 lub 4, sa aktywne. Typowym przykladem takiego zwiazku jest 1,1'-(2,5-cykloheksadieh-1,4-yleno)-bis- (3-nitro- -4-pirazolokarboksyamid) o wzorze 3.A characteristic feature of the compounds according to the invention is the 3-nitropira ring. It has been found that in practice the biological activity of the ring depends on the substituents in the 1,4 positions and 5 described herein, as well as related substituents the use of which will be apparent to experts * • It should be expected that the combination of two or more 3-nitropyrazole rings will give biologically active, taking into account the activity of monocystic compounds. Found the unions consisting of two or more 3-nitropirazole rings linked via substituents at position 1 or 4 are active. A typical example of such a compound is 1,1 '- (2,5-cyclohexadieh-1,4-ylene) -bis- (3-nitro -4-pyrazole carboxamide) of formula 3.
Korzystnym zwiazkiem przejsciowym do wytwarzania zwiazków o wzorze 1 jest kwas 3(5)-nitro-4-pirazolo- karboksylowy. Korzysc ze stosowania podstawionych kwasów 4-pirazolokarboksylowych jako zwiazków przejs¬ ciowych zilustrowano ponizej oraz w przykladach. Kwas ten jest zwlaszcza dlatego korzystny, ze w pozycji 1 nie ma podstawnika, a w razie potrzeby mozna podstawnik w pozycje 1 wprowadzic.A preferred intermediate for the preparation of compounds of Formula 1 is 3 (5) -nitro-4-pyrazole-acid. carboxylic. The advantage of using substituted 4-pyrazole carboxylic acids as transients are illustrated below and in the examples. This acid is especially advantageous because it is not in position 1 it has a substituent, and you can introduce a substituent in position 1 if necessary.
Wszystkie zwiazki pirazolowe o wzorze 1 bez podstawnika w pozycji 5 wytwarza sie sposobem wedlug wynalazku z 3(5)-amino-4-pirazolokarbonitrylu jako zwiazku wyjsciowego. Zwiazek ten jest dostepny w handlu.All pyrazole compounds of formula I without a substituent in the 5-position are prepared according to the method of the invention with 3 (5) -amino-4-pyrazolecarbonitrile as the starting compound. This compound is commercially available.
Omawiane zwiazki maja te wlasciwosc, ze mozna kolejno wprowadzac podstawniki w pozycje 1,3 i 4 pierscienia pirazolowego w oddzielnych etapach.The discussed compounds also have the property that substituents can be introduced sequentially in positions 1, 3 and 4 of the ring pyrazole in separate steps.
Pierwszym etapem wytwarzania zwiazków o wzorze 1 sposobem wedlug wynalazku jest przeksztalcenie grupy aminowej 3(5)-amino-4-pirazolokarbonitrylu w grupe nitrowa. Etap ten przeprowadza sie dwustopniowo.The first step in the preparation of compounds of formula I by the process of the invention is conversion the amino group of 3 (5) -amino-4-pyrazolecarbonitrile in the nitro group. This stage is carried out in two stages.
Najpierw 3(5)-am(no-4-pirazolokarbonltryl o wzorze 4, w którym R1 ma podane wyzej znaczenie, poddaje sie reakcji zHBF4 w celu wytworzenia soli dwuazoniowofluoroboranowej, która przeksztalca sie dzialaniem azotynu metalu alkalicznego, takiego jak NaN02 w obecnosci miedzi w grupe nitrowa. Warunki reakcji i sposoby oczyszczania produktu opisano ponizej. Wydajnosc dwustopniowej reakcji wynosi 79%, Nastepnie w pozycje 1 pierscienia pirazolowego wprowadza sie podstawniki, takie jak rodnik alkilowy, alkenylowy, cykloalkiloaljdlowy, alkinylowy lub arylowy. Najpierw tworzy sie sól metalu alkalicznego w pozycji 1, np. na drodze reakcji z NaH, a nastepnie utworzona sól poddaje sie reakcji z chlorowcopochodna wprowadzanego podstawnika, w wyniku której powstaje zwiazek pirazolowy o wzorze 5, w którym R ma wyzej podane znaczenie, podstawiony w pozycji 1 i halogenek metalu alkalicznego.First, the 3 (5) -am (no-4-pyrazolecarbonitrile of formula IV, where R1 is as defined above, is subjected to reaction with HBF4 to produce a diazonium fluoroborate salt, which is transformed by the action of an alkali metal nitrite such as NaNO2 in the presence of copper in the nitro group. Reaction conditions and methods purification of the product is described below. The yield of the two-step reaction is 79%, then to items 1 on the pyrazole ring, substituents such as an alkyl, alkenyl, cycloalkylalkyl radical, alkynyl or aryl. First, an alkali metal salt is formed in the 1-position, e.g. by reaction with NaH, and the salt formed is then reacted with the halogen derivative of the substituent introduced, resulting in which gives rise to the pyrazole compound of formula V in which R is as defined above, substituted at position 1 and an alkali metal halide.
Pochodna kwasu 4-karboksylowego tworzy sie przez hydrolize nitrylu o wzorze 5 za pomoca kwasu lub wodorotlenku metalu alkalicznego, a nastepnie pochodna grupy karboksylowej ewentualnie przeksztalca sie w grupe karboktyamidowa poprzez pochodna chlorku karbonylu, lub bezposrednio w pochodna grupy karboksy- lanowej. Karboksylany mozna przeksztalcic albo w podstawione karboksyamidy przez bezposrednia reakcje z amina o wzorze 9, w której R4 i R3 maja wyzej podane znaczenie.The 4-carboxylic acid derivative is formed by hydrolyzing the nitrile of formula V with the acid or the alkali metal hydroxide followed by the derivative of the carboxyl group is optionally transformed in the carboxyamide group via a carbonyl chloride derivative, or directly in a carboxy derivative lanowa. Carboxylates can be converted to either substituted carboxamides by direct reaction with an amine of formula 9, wherein R4 and R3 are as defined above.
Mozna równiez stosowac Inna kolejnosc reakcji. Na przyklad najpierw poddaje sie reakcji hydrolizy 3(5)-nitro-4-plrazolokarbonitryl do kwasu 3(6)-nitro4-pirazolokarboksylowego, a nastepnie wprowadza w pozy¬ cje 1 odpowiedni podstawnik.You can also use a different order of reactions. For example, it is first subjected to a hydrolysis reaction 3 (5) -nitro-4-plrazolecarbonitrile to 3 (6) -nitro-4-pyrazolecarboxylic acid and then to 1 suitable substituent.
Jesli wytwarza sie zwiazek podstawiony w pozycji 5 rodnikiem alkilowym, wtedy pierwszym etapem reakcji jest wytworzenie 3(5)alkilo-3(5)-amino-4-pirazolokarbonitrylu przez zamkniecie pierscienia w reakcji wodzianu hydrazyny z nitrylem kwasu alkilidenomalonowego. Dalsze wprowadzanie podstawników w pozycje 1 i 4 prowadzi sie w sposób wyzej opisany. - Przykladami zwiazków wytwarzanych sposobem wedlug wynalazku, sa nastepujace zwiazki: N,N,1 -trófmetylo-3-nitro^-pfrazolokarboksyamid o temperaturze topnienia 135—137°C, 1-metylo-3-nltro-4-plra2olokarboksyamid o temperaturze topnienia 190-193° C, 3-nltro-1-/4-nitrofenyloA4-pirazok)karbok$yamid o temperaturze topnienia265—268°C, v N-heksylo*1-(5-rtitrcK2-tiazolilo)-3-nitro-4-pirazolokarboksyamid, 1*(2-ketopropylo)-3-nitro-4-plrazolokarboksyamid o temperaturze topnienia 173-175°C, 1-(2-ftallmidoetylo)-3-nitro-4l)irazolokarbok8yamid o temperaturze topnienia 263-265°C, 1 '8llHo*3-nItro-4-pirazolokarbok8yamid o temperaturze topnienia 111—113°C, 1 -fenyloetylo^-nitro-4i)lrazolokarbok8yamid o temperaturze topnienia 121 -123°C, 1-benzylo-3-nitro-4-pirazolokarboksyamid o temperaturze topnienia 132-134°C, 1-[2-(4-etyiobenzoiioksy)etylo]-3-nitro-4-pirazolokarboksyamidf 1-(2-benzolloksyetylo)-3*nitro-4-pirazolokarbo ksyamld, 1 -allilo-5-metylo-3-nitro-4-pirazolokarboksyamid, 1 -(2-etoksyetylo)-5^metylo-3-nitro-4-pirazolokarboksyamid, -izopropylo«3-nitro-1 -winylo-4-plrazolokarboksyamid, 1 -(2-hydrok8ycyklopropylometylo)-3-nitro-4-pirazolokarbok3yamid, 1 -<2-cyklooktyloetylo)-3-nitro-4-pirazolokarboksyamid, 1-(2-hydroksyetylo)-3-nltro-4i3irazolokarboksyamid o temperaturze topnienia 148-150°C, 1-(2-chloroetylo)-N,N-dwumetylo-3-nitro-4H3lrazolokarbok8yamld o temperaturze topnienia 110-112°C,92 427 1-(2-etoksyetylo)-3-nitro-4-pirazolokarboksyamid o temperaturze topnienia 78-80°C, 1-(2-etylosulfonyloetylo)-3-nitro-4-pirazolokarboksyamid o temperaturze topnienia 147—149°C, 1-(2-etoksyetylo)-N-mety!o-3-nitro-4-pirazolokarboksyamid, 1-(2-etylosulfonyloetylo)-N-hydroksy-3-nitro-4-pirazolokarboksyamid, 3-nitro-1-propylo-4-pirazolokarboksyamld o temperaturze topnienia 125—127°C, 1-(2-etoksyetylo)-N-hydroksy-3-nitro-4iDirazolokarboksyamid, 1-(2-ety!osuifonyloetylo)-N-metylo-3-nitro-4-pirazolokarboksyamid# 1*(2-etylosulfonyloetylo)-N,N-dwumetylo-3-nitro4-pirazolokarboksyamid, 1-(2-«toksyetylo)-N,N-dwumetylo-3-nitro-4-pirazolokarboksyamid, 1-(2-bromopentylo)-N-hydroksy-3-nitro-4-pirazoiokarboksyamid, N-metylo-3-nitro-1-(lll-rzed.-biitylo)-4iDirazolpkarboksyamid, 1-(3-metylo-2-pentylo)-3-nitro-4-pirazolokarboksyamid, 1 -(4-hydroksybutylo)-N-metylo-3-nitro4'Pirazo!okarboksyamid, N43utylo-1-(2-butenylo)-3-nitro-4-pirazolokarboksyamid/ 1-(3-hydrok8ycykloheksylo)-3-nitró-N-pentylo-4HDirazolokarboksyamJd, 3-nitro-1 -nonylo-4-pirazolokarboksyamid o temperaturze topnienia 60—62°C, 1-(2-hydroksyetylo)-N,N-dwumefylo-3-nitro-4iDirazolokarboksyamid o temperaturze topnienia 118—120°C, 1-winylo-N,N -dwumetylo-3-nitro-4-pirazolokarboksyamid, 1-(2-chloroetylo)-3-nitro-4-pirazolokarboksyamid o temperaturze topnienia 128—130°C, 1 -(2-chloroetylo)-N-metylo-3-nitroH3irazolokarboksyamid, 1-(2-chloroetylo)-N-hydroksy-3-nitro-4i3frazolokarboksyamid, 1-(2-hydroksyetylo)-N-hydroksy-3-nitro-4-pirazolokarboksyamid o temperaturze topnienia 143—145°C, 1 *(3,4-epoksybutylo)-N-metylo-3-nitro-4-pirazolokarboksyamid, 1-(2,3-epoksypropylo)-3-nitro-4-pirazolokarboksyamid, 1-(2-hydroksyetylo)-N-metylo-3-nitro-4-pirazolokarboksyamid o temperaturze topnienia 138—140°C, 1.1 '-(2,5-cykloheksadieno-1,4-yleno)-bIs-(3-nitro-4-pirazolokarboksyamid) o temperaturze topnienia 128—130°Cr 3{5)-nitro-4-pira*olokarboksyamid o temperaturze topnienia 224-225°C, 1,5«dwumetylo-3-nitro«4-pirazolokarboksyamId o temperaturze topnienia 217—220°C, 1-(2-hydroksyetylo)-3-nItro*6-metylo-4-pirazolookarbonitryl o temperaturze topnienia 86—B8°C, 1-metylo-3-nltro-4-(N-metylo)karbok8yamid o temperaturze topnienia 163—165°C, ester etylowy kwasu 3(6)-nltro-6(3)-metylo-4-pirazolokarbok9ylowego o temperaturze topnienia 121 —123°C, 1-winylo-3-nitro-5-metylo^4-pirazolokarbonitryl o temperaturze topnienia 130-133°C, 3(5)-nitro-4-pirazolokarbonitryl o temperaturze topnienia 153-156°C, 1 -(2,3^oksypropylo)-3-nitro-4-pirazolokarbonitryl o temperaturze topnienia 78-80°C. kwas 3(5)-nltro-4-pirazolokarboksylowy o temperaturze topnienia 221 —224°C, 1 -metylo-3-nitro-4~pirazolokarbonitryl o temperaturze topnienia 85-87°C, 3(5)-nitro-5(3)-metyfo-4-pirazolokarbonitryl o temperaturze topnienia 168—170°C, IjB-dwumetyló-S-nitro^pirazolokarbonitryl o temperaturze topnienia 107—109°C, 1-(3-bydroksypropylo)-3-nitro-4-plrazolokarboksyamid o temperaturze topnienia 105—108°C, 1-(3-chlóropropy!o)'3-nltro-4-pirazolokarboksyamid o temperaturze topnienia 117—119°C, 1«Jzopropylo«3-nitro*4-pirazolokarbok8yamid o temperaturze topnienia 133—135°C, 1-(2-meto-ksyetylo)-3-nitro-4-pira2olokarboksyamid o temperaturze topnienia 95-97°C, 1-(2-metylosulfonyletylo)-3«^itro-4-pirazolokarboksyamrd o temperaturze topnienia 184—1B6°C, 3Hiltro-1«trójfenyloetylo-4-pirazolokarboksyamid o temperaturze topnienia 214—216°C, 1-(2-ehloroetylo)-3»nitro-4-pirazolo-NrN-dwumetylo-karboksyamid o temperaturze topnienia 110—112°C, 3-nltro*4-(1 H-tetrazol-6-ylo)-pirazoloetanol-1, o temperaturze topnienia 178—13p°C, 3(5)-nftro-4-pirazolokarboksyamid o temperaturze topnienia 220—223°C, 1-(22-dwuetoksyetylo)-3-nitro-4-pirazolokarbonitryl o temperaturze topnienia 73-75°C, 3-nltro-1-(5-nitro-2-tIazolilo)^4-pirazolokarbonitryl o temperaturze topnienia 207-209°C, 1-(2-hydroksypropylo)-3-nitro-4HDirazolokarboksyamid o temperaturze topnienia 136—138°C, ester metylowy kwasu 1-metylo^3-nitro-4-pirazolokarboksylowego o temperaturze topnienia 88-90°C, v 1-metylc«\3-nitro-4HDirazolo-N,N-dwumetylokarboksyamid o temperaturze topnienia 135—137°C, 1-metylo-3-nitro-4-pirazolokarboksyamid o temperaturze topnienia 190—192°C, 1-etylo-3-nitro-4-plrazolokarbonitryl o temperaturze topnienia 62-64°C, 1-benzylo-3-nitro-4-pirazolokarbonItryl o temperaturze topnienia 135—137°C, kwas 1 -etylo«3-nitro-4-pirazolokarboksylowy o temperaturze topnienia 160—163°C, 1-(2-hydroksyetylo)-3-nitro-4HDirazolokarbonitryl o temperaturze topnienia 84-86°C, 1-hydroksymetylo-3-nitro-4-pirazolokarbonitryl o temperaturze topnienia 89—91°C, 1 -winylo-3-nitro-4i3irazolo-N,N-dwumetylokarboksyamId o temperaturze topnienia 149-151°C, m ester metylowy kwasu 1-(2-hydroksyetylo)-3-nitro-4-plrazolokarboksylowegó o temperaturze topnienia 93-95°C, 1-(2-hydroksyetylo)-3-nitro-4-pirazolo-N-metylokarboksyamid o temperaturze topnienia 138-140°C, 1-(2-etylotioetylo)-3-nitro-4HDirazolokarbonitryl o temperaturze topnienia 79-80°C, 1-(2-hydroksyetylo)-3-nitro-4-pirazolo-N,N-dwumetylokarboksyamid o temperaturze topnienia 118-120°C, 1-(2-chloroetylo)-3-nitro-4-pirazolokarbonitryl o temperaturze topnienia 117—120°C, -nitro-furfurylidenohydrazyd kwasu 1-metylo-3-nitro-4-pirazolokarboksylowego o temperaturze topnienia 225—227°C, 3(5)-nitro-4-pirazolo-N,N-dwumetylokarboksyamid o temperaturze topnienia 192—195°C, 1-benzylo-3-nitro-4-pirazolokarboksyamid o temperaturze topnienia 132—134°C. 1-hydroksymetylo-3-nitro-4-pirazolokarboksyamid o temperaturze topnienia 1S1-163°C, 3-nltro-1 -fenetylo-4-pirazolokarboksyamid o temperaturze topnienia 121 —12ocCf4 92 427 1 -(2-butenylo)-3-nitro-4-pirazolokarboksyamid o temperaturze topnienia 88—90°C, 1-propylo-3-nitro-4-pirazolokarboksyamid o temperaturze topnienia 125,—i27°C,~ 3-nitro-1-(2-ftalimidoetylo)-4-pirazolokarboksyamid o temperaturze topnienia 263—265°C, 1-winylo-3-nitro-4-pirazolokarboksyamid o temperaturze topnienia 153—155°C, 1-(2,2-dwuetoksyetylo)-3-nitro-4-pirazolokarboksyamid o temperaturze topnienia 119—121°C, 1-(2-hydroksyetylo)-3-nitro4i3irazolokarboksyamid o temperaturze topnienia 148—150°C, 1-(3-chloropropylo)-3-nitro-4-pirazolokarbonitryl o temperaturze topnienia 75—77°C, 1-(2-etoksyetylo)-3-nitro-4-pirazolokarbonitryl o temperaturze topnienia 58—60°C, N-(n-butylo)-1-(2-hydroksyetylo)-3-nitro-4-pirazolokarboksyamid o temperaturze topnienia 77—80°C, 1-(etylosulfonyloetylo)-3-nitro-4iDirazolokarbonitryl o temperaturze topnienia 105-108°C, 1-(cyklopropylometylo)-3-nitn>4-pirazolokarbonitryl o temperaturze topnienia 66—70°C, 1-(2-hydroksyetylo)-3-nitro-N-izopropylo-4i3irazolokarboksyamid o temperaturze topnienia 128—130°C, 1-nonylo-3-nItro-4-pirazolokarbonitry! o temperaturze topnienia 35—37°C, 3-nltro-1-(2-propylo)-4iDlrazolokarbonitryl o temperaturze topnienia 95-97°C, 1-nonylo-3-nitro-4-pirazolokarboksyamid o temperaturze topnienia 60-62°C, 1-(2-etylosuifonyloetylo)-3-nitro-4iDirazolokarbok8yamid o temperaturze topnienia 147—149°C, 1-cyklopropylometylo-3-nitro-4i3irazolokarboksyamid o temperaturze topnienia 130—131°C, 1-(2-etoksyetylo)-3-liitro-4-pirazolokarboksyamld o temperaturze topnienia 78—80°C, 1-(2-bromoetylo)-3-nltro-4-pirazolokarbonitryl o temperaturze topnienia 125—127°C, M2-hydroksyetylo)-3-nitrp-5-metylo-4-pirazolokarboksyamid o temperaturze topnienia 161—163°C, 3-nitro-1-(4-nitrofenylo)-4-pirazoloksrbonitryl o temperaturze topnienia 172—175°C, 3-nitro-1 -(4-nitrofenylo)-4-pirazolokarboksyamld o temperaturze topnienia 265—268°C, 1 -acetonylo-3-nitropirazolo-4-karboksyamid o temperaturze topnienia 173-175°C, 1-(2-chloroetylo)-3-nltro-4H3irazolokarboksyamid o temperaturze topnienia 128-130°C, 1-allHo-3-n1tro-4-plrazolokarboksyamid o temperaturze topnienia 111 —113°C, 3-nitro-1*(5-nitro-2-tiazolyio)pirazolo-4-karboksyamid o temperaturze topnienia 251 —253°C, 1-(2-bromoetylo)-3-nitropirazolo-4-karbok8yamid o temperaturze topnienia 135—137°C, H2-(metylotio)etylo]-3-nitropirazolo-4-karboksyamid o temperaturze topnienia 131—133°C.If a compound substituted at the 5-position with an alkyl radical is produced, then the first step the reaction is to form 3 (5) alkyl-3 (5) -amino-4-pyrazolecarbonitrile by closing the ring by reaction of hydrazine hydrate with alkylidenemalonic acid nitrile. Further introducing substituents at position 1 and 4 is carried out as described above. - Examples of compounds according to the invention are the following: N, N, 1-triethyl-3-nitro-4-pphrazole carboxamide, m.p. 135-137 ° C, 1-methyl-3-nltro-4-plra2ol carboxamide with a melting point of 190-193 ° C, 3-nltro-1- (4-nitrophenyl? 4-pyrazo) carboxylamide, mp 265-268 ° C, v N-hexyl * 1- (5-rtitrcK2-thiazolyl) -3-nitro-4-pyrazole carboxamide, 1 * (2-ketopropyl) -3-nitro-4-plrazolecarboxamide, m.p. 173-175 ° C, 1- (2-phthalmidoethyl) -3-nitro-4l) irazole carboxamide, m.p. 263-265 ° C, 1,811Ho * 3-nItro-4-pyrazolecarboxamide, m.p. 111-113 ° C, 1-phenylethyl Nitro-4i) lrazolocarboxyamide, m.p. 121-123 ° C, 1-benzyl-3-nitro-4-pyrazolecarboxamide, m.p. 132-134 ° C, 1- [2- (4-ethylbenzoyloxy) ethyl] -3-nitro-4-pyrazole carboxamide 1- (2-benzolloxyethyl) -3 * nitro-4-pyrazolocarboxyamld, 1-allyl-5-methyl-3-nitro-4-pyrazole carboxamide, 1- (2-ethoxyethyl) -5-methyl-3-nitro-4-pyrazole carboxamide, -isopropyl-3-nitro-1-vinyl-4-plrazole carboxamide, 1- (2-hydrocyclopropylmethyl) -3-nitro-4-pyrazolecarboxyamide, 1- <2-cyclooctylethyl) -3-nitro-4-pyrazolecarboxamide, 1- (2-hydroxyethyl) -3-nltro-4 and 3-pyrazole carboxamide, m.p. 148-150 ° C, 1- (2-chloroethyl) -N, N-dimethyl-3-nitro-4H3lrazole carboxyamld with a melting point of 110-112 ° C, 92 427 1- (2-ethoxyethyl) -3-nitro-4-pyrazole carboxamide, m.p. 78-80 ° C, 1- (2-ethylsulfonylethyl) -3-nitro-4-pyrazolecarboxamide, m.p. 147-149 ° C, 1- (2-ethoxyethyl) -N-methyl! O-3-nitro-4-pyrazolecarboxamide, 1- (2-ethylsulfonylethyl) -N-hydroxy-3-nitro-4-pyrazole carboxamide, 3-nitro-1-propyl-4-pyrazolecarboxamide, mp 125-127 ° C, 1- (2-ethoxyethyl) -N-hydroxy-3-nitro-4iDirazole carboxamide, 1- (2-ethyl! Osuifonylethyl) -N-methyl-3-nitro-4-pyrazolecarboxamide # 1 * (2-ethylsulfonylethyl) -N, N-dimethyl-3-nitro-4-pyrazole carboxamide, 1- (2 -toxyethyl) -N, N-dimethyl-3-nitro-4-pyrazolecarboxamide, 1- (2-bromopentyl) -N-hydroxy-3-nitro-4-pyrazo carboxamide, N-methyl-3-nitro-1- (III-order-biityl) -4iDirazolepcarboxamide, 1- (3-methyl-2-pentyl) -3-nitro-4-pyrazole carboxamide, 1- (4-hydroxybutyl) -N-methyl-3-nitro-4'Pirazo! Carboxamide, N43utyl-1- (2-butenyl) -3-nitro-4-pyrazole carboxamide / 1- (3-Hydrocyclohexyl) -3-nitro-N-pentyl-4HDirazolcarboxyamJd, 3-nitro-1-nonyl-4-pyrazolecarboxamide, mp 60-62 ° C, 1- (2-hydroxyethyl) -N, N-dimephyl-3-nitro-4iDirazole carboxamide, m.p. 118-120 ° C, 1-vinyl-N, N-dimethyl-3-nitro-4-pyrazole carboxamide, 1- (2-chloroethyl) -3-nitro-4-pyrazolecarboxamide, m.p. 128-130 ° C, 1- (2-chloroethyl) -N-methyl-3-nitroH3-pyrazole carboxamide, 1- (2-chloroethyl) -N-hydroxy-3-nitro-4 and 3-phrazole carboxamide, 1- (2-hydroxyethyl) -N-hydroxy-3-nitro-4-pyrazole carboxamide, m.p. 143-145 ° C, 1 * (3,4-epoxybutyl) -N-methyl-3-nitro-4-pyrazole carboxamide, 1- (2,3-epoxypropyl) -3-nitro-4-pyrazole carboxamide, 1- (2-hydroxyethyl) -N-methyl-3-nitro-4-pyrazole carboxamide, mp 138-140 ° C, 1.1 '- (2,5-cyclohexadiene-1,4-ylene) -bIs- (3-nitro-4-pyrazole carboxamide), mp 128-130 ° Cr 3 {5) -nitro-4-pyra * olecarboxamide, m.p. 224-225 ° C, 1,5-dimethyl-3-nitro-4-pyrazolecarboxamide, mp 217-220 ° C, 1- (2-hydroxyethyl) -3-nItro * 6-methyl-4-pyrazolecarbonitrile with a melting point of 86-B8 ° C, 1-methyl-3-ntro-4- (N-methyl) carboxamide, m.p. 163-165 ° C, 3 (6) -nltro-6 (3) -methyl-4-pyrazolecarboxylic acid ethyl ester, mp 121-123 ° C, 1-vinyl-3-nitro-5-methyl ^ 4-pyrazolecarbonitrile with a melting point of 130-133 ° C, 3 (5) -nitro-4-pyrazolecarbonitrile with a melting point of 153-156 ° C, 1- (2,3-oxypropyl) -3-nitro-4-pyrazolecarbonitrile, m.p. 78-80 ° C. 3 (5) -nltro-4-pyrazolecarboxylic acid, mp 221-224 ° C, 1-methyl-3-nitro-4-pyrazolecarbonitrile with a melting point of 85-87 ° C, 3 (5) -nitro-5 (3) -methfo-4-pyrazolecarbonitrile with a melting point of 168-170 ° C, IjB-dimethyl-S-nitro-pyrazolecarbonitrile, melting point 107-109 ° C, 1- (3-by-hydroxypropyl) -3-nitro-4-plrazolecarboxamide, m.p. 105-108 ° C, 1- (3-chloropropy! O) '3-nltro-4-pyrazolecarboxamide, mp 117-119 ° C, 1 "Isopropyl" 3-nitro * 4-pyrazolecarboxamide, m.p. 133-135 ° C, 1- (2-methoxyethyl) -3-nitro-4-pyra2ol carboxamide, m.p. 95-97 ° C, 1- (2-methylsulphonylethyl) -3'thro-4-pyrazolecarboxyamide, m.p. 184-1B6 ° C, 3Hiltro-1-triphenylethyl-4-pyrazolecarboxamide, mp 214-216 ° C, 1- (2-chloroethyl) -3 ”nitro-4-pyrazole-NR N-dimethyl carboxamide, mp 110-112 ° C, 3-nltro * 4- (1H-tetrazol-6-yl) -pyrazole-ethanol-1, m.p. 178-13 ° C, 3 (5) -nftro-4-pyrazolecarboxamide, m.p. 220-223 ° C, 1- (22-diethoxyethyl) -3-nitro-4-pyrazolecarbonitrile with a melting point of 73-75 ° C, 3-nltro-1- (5-nitro-2-thIazolyl) ^ 4-pyrazolecarbonitrile with a melting point of 207-209 ° C, 1- (2-hydroxypropyl) -3-nitro-4HDirazole carboxamide, mp 136-138 ° C, 1-Methyl-3-nitro-4-pyrazole carboxylic acid methyl ester, m.p. 88-90 ° C, v 1-methylc [beta], 3-nitro-4HDirazole-N, N-dimethylcarboxamide, mp 135-137 ° C, 1-methyl-3-nitro-4-pyrazolecarboxamide, mp 190-192 ° C, 1-ethyl-3-nitro-4-plrazolecarbonitrile with a melting point of 62-64 ° C, 1-benzyl-3-nitro-4-pyrazolecarbonitrile, mp 135-137 ° C, 1-ethyl-3-nitro-4-pyrazole carboxylic acid, m.p. 160 ° -163 ° C, 1- (2-hydroxyethyl) -3-nitro-4HDirazolecarbonitrile with a melting point of 84-86 ° C, 1-hydroxymethyl-3-nitro-4-pyrazolecarbonitrile, mp 89-91 ° C, 1-vinyl-3-nitro-4i3irazole-N, N-dimethylcarboxamide with mp 149-151 ° C, m 1- (2-hydroxyethyl) -3-nitro-4-plrazole carboxylic acid methyl ester, mp 93-95 ° C, 1- (2-hydroxyethyl) -3-nitro-4-pyrazole-N-methyl carboxamide, m.p. 138-140 ° C, 1- (2-ethylthioethyl) -3-nitro-4HDirazolecarbonitrile with a melting point of 79-80 ° C, 1- (2-hydroxyethyl) -3-nitro-4-pyrazole-N, N-dimethylcarboxamide, m.p. 118-120 ° C, 1- (2-chloroethyl) -3-nitro-4-pyrazolecarbonitrile, melting point 117-120 ° C, 1-methyl-3-nitro-4-pyrazolecarboxylic acid nitro-furfurylidene hydrazide, m.p. 225 ° -227 ° C, 3 (5) -nitro-4-pyrazole-N, N-dimethyl carboxamide, m.p. 192-195 ° C, 1-benzyl-3-nitro-4-pyrazolecarboxamide, m.p. 132-134 ° C. 1-hydroxymethyl-3-nitro-4-pyrazolecarboxamide, melting point 1S1-163 ° C, 3-nltro-1-phenethyl-4-pyrazolecarboxamide, mp 121-12ocCf4 92 427 1- (2-butenyl) -3-nitro-4-pyrazolecarboxamide, m.p. 88-90 ° C, 1-propyl-3-nitro-4-pyrazolecarboxamide, m.p. 125, -27 ° C, ~ 3-nitro-1- (2-phthalimidoethyl) -4-pyrazole carboxamide, m.p. 263 ° -265 ° C, 1-vinyl-3-nitro-4-pyrazolecarboxamide, m.p. 153-155 ° C, 1- (2,2-diethoxyethyl) -3-nitro-4-pyrazole carboxamide, m.p. 119-121 ° C, 1- (2-hydroxyethyl) -3-nitro413irazole carboxamide, m.p. 148-150 ° C, 1- (3-chloropropyl) -3-nitro-4-pyrazolecarbonitrile, mp 75-77 ° C, 1- (2-ethoxyethyl) -3-nitro-4-pyrazolecarbonitrile, mp 58-60 ° C, N- (n-butyl) -1- (2-hydroxyethyl) -3-nitro-4-pyrazolecarboxamide, mp 77-80 ° C, 1- (ethylsulfonylethyl) -3-nitro-4iDirazolecarbonitrile with a melting point of 105-108 ° C, 1- (cyclopropylmethyl) -3-nitrile 4-pyrazolecarbonitrile, mp 66-70 ° C, 1- (2-hydroxyethyl) -3-nitro-N-isopropyl-4 and 3-pyrazole carboxamide, m.p. 128-130 ° C, 1-nonyl-3-nItro-4-pyrazolecarbonitr! melting point 35-37 ° C, 3-nltro-1- (2-propyl) -4iDlrazolecarbonitrile with a melting point of 95-97 ° C, 1-nonyl-3-nitro-4-pyrazolecarboxamide, melting point 60-62 ° C, 1- (2-ethylsiphonylethyl) -3-nitro-4iDirazole carboxamide, m.p. 147-149 ° C, 1-cyclopropylmethyl-3-nitro-4 and 3-pyrazole carboxamide, m.p. 130-131 ° C, 1- (2-ethoxyethyl) -3-liitro-4-pyrazolecarboxamide, mp 78-80 ° C, 1- (2-bromoethyl) -3-nltro-4-pyrazolecarbonitrile, m.p. 125-127 ° C, M2-hydroxyethyl) -3-nitrp-5-methyl-4-pyrazole carboxamide, mp 161-163 ° C, 3-nitro-1- (4-nitrophenyl) -4-pyrazoloxyrbonitrile, m.p. 172-175 ° C, 3-nitro-1- (4-nitrophenyl) -4-pyrazolecarboxamide, mp 265-268 ° C, 1-acetonyl-3-nitropyrazole-4-carboxamide, m.p. 173-175 ° C, 1- (2-chloroethyl) -3-nltro-4H3-pyrazole carboxamide, m.p. 128-130 ° C, 1-allHo-3-n-1-trro-4-plrazolecarboxamide, melting point 111-113 ° C, 3-nitro-1 * (5-nitro-2-thiazolyio) pyrazole-4-carboxamide, mp 251-253 ° C, 1- (2-bromoethyl) -3-nitropyrazole-4-carboxamide, m.p. 135-137 ° C, H 2 - (methylthio) ethyl] -3-nitropyrazole-4-carboxamide, m.p. 131-133 ° C.
Skutecznosc dzialania 3-nitropirazoli wytworzonych sposobem wedlug wynalazku badano in vitro i in vlvo. Przykladami organizmów, które zwalczano za pomoca badanych zwiazków sa: Histomonas melesgridis, Trichomonas vaginalisr Staphylococcus aureus, bakteryjna rdza ziarna, Vibrio coli, Salmonella typhosa, Mycopla- sma gallisepticum, Pseudomonas solanaceanum, Escherichia coli, Erwinia amylovora, Salmonella dublin, Botrytis cinerea, Mycoplasma synouige, Verticillium alboatrium, Salmonella typhimuricum, Trypanosoma cruzi.The effectiveness of the 3-nitropyrazoles according to the invention was tested in vitro and in others vlvo. Examples of organisms that were combated with the test compounds are: Histomonas melesgridis, Trichomonas vaginalisr Staphylococcus aureus, bacterial grain rust, Vibrio coli, Salmonella typhosa, Mycopla- sma gallisepticum, Pseudomonas solanaceanum, Escherichia coli, Erwinia amylovora, Salmonella dublin, Botrytis cinerea, Mycoplasma synouige, Verticillium lubatrium, Salmonella typhimuricum, Trypanosoma cruzi.
Z wymienionej listy mozna zorientowac sie, ze zwiazki wytwarzane sposobem wedlug wynalazku sa uzyteczne do zwalczania mikroorganizmów infekujacych zarówno zwierzeta jak i rosliny. Badania in vivo dotyczyly obydwu rodzajów dzialania.From this list it can be seen that the compounds according to the invention are useful for combating microorganisms infecting both animals and plants. In vivo studies they concerned both types of action.
Na przyklad, 1-(2-hydroksyetylo)-3-nitro-4-pirazolokarboksyamid calkowicie zwalcza rozwój nastepuja¬ cych mikroorganizmów w podanych stezeniach zwiazku przeciwbakteryjnego: Mg/ml Staphylococcus 3,1 Vibriocoli 6,2 Mycoplasma galliseptieum 0,8 Escherichiacoli 3,1 Salmonelladublin 3,1 Stwierdzono, ze zwiazki wytworzone sposobem wedlug wynalazku charakteryzuja sie niska toksycznoscia dla zwierzat. Np. 1-(2-hydroksyetylo)-3-nitro4-pirazolokarboksyamid zwalcza Salmonella typhimuricum u pis¬ klat w dawkach 60 mg/kg. U myszy nie stwierdzono toksycznosci przy dawkach 500 mg/kg.For example, 1- (2-hydroxyethyl) -3-nitro-4-pyrazolecarboxamide completely combats the development of the following of the following microorganisms at the stated concentrations of the antimicrobial compound: Mg / ml Staphylococcus 3.1 Vibriocoli 6.2 Mycoplasma galliseptieum 0.8 Escherichiacoli 3.1 Salmonelladublin 3.1 It has been found that the compounds according to the invention have low toxicity for animals. For example, 1- (2-hydroxyethyl) -3-nitro-4-pyrazole carboxamide fights Salmonella typhimuricum in pis¬ cages at doses of 60 mg / kg. In mice, no toxicity was observed at doses of 500 mg / kg.
Zwiazki o dzialaniu chwastobójczym wykazuja zdolnosc niszczenia chwastów przy podawaniu w dawkach nizszych niz 1,12 kg/ha. Dzialanie chwastobójcze uzyskuje sie przy stosowaniu zwiazków 3-nitropirazolowych w sposób ogólnie znany, przez bezposrednie dzialanie srodkiem do opryskiwania lub srodkiem w postaci stalej na rosliny lub glebe na której rosliny rosna.The herbicidal compounds show a weed-killing ability when applied at doses less than 1.12 kg / ha. The herbicidal action is obtained with the use of 3-nitropyrazole compounds in a manner known per se, by direct treatment with a spray or solid product on plants or the soil in which plants grow.
Niektóre zwiazki 3-nitropirazolowe sa zdolne do zwalczania pasozytów organów wewnetrznych. Niektóre z tych zwiazków stosowano do zwalczania Tryponosoma cruzi u gryzoni. 3-nitro-1-winylo4-pirazolokarboksy- amid niszczy 91% Triponosoma cruzi szczepu BHC/10 przy podawaniu dawek 123 mg/kg, w ciagu 10 dni.Some 3-nitropyrazole compounds are able to fight parasites in internal organs. Some of these compounds have been used to control Tryponosoma cruzi in rodents. 3-nitro-1-vinyl-4-pyrazole carboxy- the amide destroys 91% of Triponosoma cruzi strain BHC / 10 at doses of 123 mg / kg within 10 days.
Badanie aktywnosci przeciwko pasozytowi ptasiemu Histomonas meleagridis badano przez podawanie zwiazków zainfekowanym kurczetom. W wyniku testu stwierdzono, ze 3-nitro-1-fenyloetylo«4-pirazolokarboksy- amid zwalcza pasozyty przy dawce 0,007% w odniesieniu do pokarmu.The test for activity against the avian parasite Histomonas meleagridis was tested by administration compounds to infected chickens. The test showed that 3-nitro-1-phenylethyl-4-pyrazolecarboxy- amide combats parasites at a dose of 0.007% in relation to food.
Ponizsze przyklady ilustruja szczególowo warunki reakcji prowadzonych sposobem wedlug wynalazku.The following examples illustrate in detail the conditions of the reactions carried out according to the invention.
Przyklad I. Wytwarzanie 3(5)-amino-5(3)-metylo-4-pirazolokarbonitrylu.Example I. Preparation of 3 (5) -amino-5 (3) -methyl-4-pyrazolecarbonitrile.
Mieszanine 243 g ortooctanu trójetylu, 68 g nitrylu kwasu malonowego i250g bezwodnika octowego ogrzewa sie w temperaturze 85-90°C wciagu 4 godzin. Nastepnie mieszanine ogrzewa sie w temperaturze92 427 5 145-150°C w celu oddestylowania lotnych produktów. Po oziebieniu do temperatury pokojowej mieszanina zestala sie. Surowy produkt rekrystalizuje sie z mieszaniny octanu i benzenu. Otrzymuje sie 124,5 g 1-etoksyety- lidenomalononitrylu o temperaturze topnienia 90-92°C. 403 g tego produktu dodaje sie porcjami do 35,4 g 85% wodzianu hydrazyny. Nastepnie mieszanine reakcyjna ogrzewa sie na lazni parowej w ciagu 1 godziny, a po oziebieniu do temperatury pokojowej dodaje do niej wody, co powoduje wytracenie osadu. Osad odsacza sie, przemywa niewielka iloscia zimnej wody i krystalizuje z wody. Otrzymuje sie 31 g 3(5)*amino-5(3)-metylo-4-pira- zolokarbonitrylu o temperaturze topnienia 160-163°C.Mixture of 243 g of triethyl orthoacetate, 68 g of malonic acid nitrile and 250 g of acetic anhydride heated at 85-90 ° C for 4 hours. Then the mixture is heated to 92 427 5 145-150 ° C to distill off volatile products. After cooling to room temperature the mixture it solidified. The crude product is recrystallized from a mixture of acetate and benzene. 124.5 g of 1-ethoxyethyl lidenemalononitrile, mp 90-92 ° C. 403 g of this product are added in portions to 35.4 g 85% hydrazine hydrate. The reaction mixture is then heated on the steam bath for 1 hour and after that when cooled to room temperature, water was added to it, causing the precipitate to be precipitated. The sediment drains away, it is washed with a small amount of cold water and crystallizes from the water. 31 g of 3 (5) * amino-5 (3) -methyl-4-pyra are obtained. zolocarbonitrile with a melting point of 160-163 ° C.
Inne zwiazki podstawione w pozycji 5 rodnikami alkilowymi otrzymuje sie w sposób analogiczny.Other compounds substituted at the 5-position with alkyl radicals are prepared analogously.
Zwiazek wyjsciowy Podstawnik w pozycji 5 1-etoksybutylidenomalononitryl rodnik propylowy 1-etoksypropylidenomalononitryl rodnik etylowy Przyklad II.Wytwarzanie3(5)-nitro-4-pirazolokarbonitrylu.Starting compound Substituent in position 5 1-ethoxybutylidenemalononitrile propyl radical 1-ethoxypropylidenemalononitrile ethyl radical Example II. Preparation of 3 (5) -nitro-4-pyrazolecarbonitrile.
Wytwarza tle zawiesine 643 g 3(5)-amino4-pirazolokarbonitrylu w 300 ml 48% HBF4 w temperaturze pokojowej. Zawiesine miesza sie w temperaturze -5°C i wkrapla do niej 42 g NaNOa w 84 ml wody w ciagu pól godziny, przy czym temperature mieszaniny utrzymuje sie ciagle w granicach -5 do 0°C. Po zakonczeniu dodawania mieszanine miesza sie w ciagu pól godziny w temperaturze —5°C, sól dwuazoniowa odsacza sie, przemywa najpierw 125 ml zimnego etanolu, a nastepnie wielokrotnie bezwodnym eterem i suszy pod obnizo¬ nym cisnieniem nad P*Óg. Otrzymuje sie 124 g soli 3(5)-dwuazoniowo-fluoroboranowej 4-pirazolokarbonitrylu o temperaturze topnienia 104°C (z rozkladem). Sól te dodaje sie porcjami w ciagu 2 godzin, w trakcie mieszania, do mieszaniny 300 g NaNOa, 500 ml wody 125 g dokladnie rozdrobnionej miedzi, w temperaturze 20-25°C.Produces a suspension of 643 g 3 (5) -amino4-pyrazolecarbonitrile in 300 ml of 48% HBF4 at room. The suspension is stirred at -5 ° C and 42 g of NaNOa in 84 ml of water are added dropwise over half a time. hours, while the temperature of the mixture is kept constantly between -5 to 0 ° C. After the addition, the mixture is stirred for half an hour at -5 ° C, the diazonium salt is filtered off, it is washed first with 125 ml of cold ethanol and then several times with anhydrous ether and dried under reduced pressure. pressure over P * Óg. 124 g of the 3 (5) -diazonium-fluoroborate salt of 4-pyrazolecarbonitrile are obtained. mp 104 ° C (decomposition). These salt are added in portions over 2 hours, while stirring, for a mixture of 300 g NaNOa, 500 ml of water 125 g of finely ground copper, at a temperature of 20-25 ° C.
Nastepnie mieszanine miesza sie w temperaturze 25°C wciagu 2 godzin, oziebia do temperatury 0°C i saczy.Then the mixture was stirred at 25 ° C for 2 hours, cooled to 0 ° C and filtered.
Placek filtracyjny odciska sie jak tytko mozliwe do sucha i przemywa sie 200 ml lodowatej wody. Nastepnie osad zawiesza sie w 300 ml wody, oziebia na lazni lodowej i w trakcie mieszania dodaje 60 ml 6 n kwasu solnego.The filter cake is pressed dry as much as possible and washed with 200 ml of ice water. Then the sediment The mixture is suspended in 300 ml of water, cooled in an ice bath, and 60 ml of 6N hydrochloric acid are added while stirring.
Nastepnie do otrzymanej mieszaniny dodaje sie 1 litr octanu etylu i po dokladnym wymieszaniu emulsje przesacza sie przez warstwe materialu filtracyjnego. Warstwe organiczna oddziela sie, suszy nad siarczanem magnezu i odparowuje do sucha. Pozostalosc odbarwia sie, przekrystalizowuje z mieszaniny metanolu i wody i suszy. Otrzymuje sie 87,5 g3(5)-nltro-4-pirazolokarbonitryl o temperaturze topnienia 154—156°C.Then 1 liter of ethyl acetate is added to the resulting mixture and, after thoroughly mixing, the emulsions seeps through the layer of filter material. The organic layer was separated, dried over sulfate magnesium and evaporates to dryness. The residue becomes discolored and recrystallizes from a mixture of methanol and water and dries. 87.5 g of 3 (5) -nltro-4-pyrazolecarbonitrile are obtained, mp 154-156 ° C.
Przyklad III.Wytwarzanie M2*hydroksyetylo)-3-nitro4-pirazolokarbonitrylu.Example III. Preparation of M2 * hydroxyethyl) -3-nitro-4-pyrazolecarbonitrile.
Roztwór 32 g 3(5)-nltro-4-pirazolokarbonitrylu w 25 ml 1,2-dwumetoksyetanu wkrapla sie, w trakcie mieszania, wydzielania sie wodoru odsacza sie produkt, który suszy sie pod obnizonym cisnieniem w temperaturze 120°C.A solution of 32 g of 3 (5) -nltro-4-pyrazolecarbonitrile in 25 ml of 1,2-dimethoxyethane was added dropwise while mixing, through the evolution of hydrogen, the product is filtered off, which is dried under reduced pressure at a temperature of 120 ° C.
Otrzymuje sie 36 g soli sodowej 3(5)-nitro4-pirazolokarbonitrylu o temperaturze topnienia 260-262°C (z roz¬ kladem). 32 g tego zwiazku rozpuszcza sie w 200 ml acetonitrylu i 25 g 2-bromoetanolu. Mieszanine miesza sie w temperaturze 56-60°C wciagu 15 godzin, nastepnie oziebia sie do temperatury pokojowej, wylewa do lodowatej wody i ekstrahuja octanem etylu. Warstwe organiczna przemywa sie zimnym, nasyconym roztworem NaOI, suszy MgSO* i odparowuje pod obnizonym cisnieniem. Pozostalosc w postaci oleju krystalizuje sie po oziebieniu i zadrapywaniu. Otrzymane krysztaly przekrystalizowuje sie z mieszaniny metanolu i wody i otrzy¬ muje 20 g 1-(2*hydroksyetylo)-3-nitro-4-pirazolokarbonitrylu o temperaturze topnienia 79-81 °C.36 g of sodium salt of 3 (5) -nitro-4-pyrazolecarbonitrile with a melting point of 260-262 ° C (with a solution of clade). 32 g of this compound are dissolved in 200 ml of acetonitrile and 25 g of 2-bromoethanol. The mixture is stirred at a temperature of 56-60 ° C for 15 hours, then cooled to room temperature, poured to ice water and extraction with ethyl acetate. The organic layer is washed with cold saturated solution NaOI, dried with MgSO * and evaporated under reduced pressure. The residual oil crystallizes after cooling and scratching. The obtained crystals are recrystallized from a mixture of methanol and water and obtained 20 g of 1- (2 * hydroxyethyl) -3-nitro-4-pyrazolecarbonitrile, mp 79-81 ° C.
Podstawniki w pozycje 1 pierscienia pirazolowego, takie jak rodnik alkilowy, alkenylowy, alkinylowy i cykloalkiloalkilowy wprowadza sie w sposób analogiczny do wyzej opisanego. Reagentami sa zwiazki, które skladaja sie z grupy podstawionej w pozycji 1 i atomu chlorowca lub zawieraja inny odpowiedni podstawnik, np. rodnik tolueno-4-sulfonowy. Niewielkie zmiany w warunkach prowadzenia poszczególnych reakcji moga byc wprowadzane przez znawce bez wiekszych trudnosci. Ponizej podano przyklady podstawników w pozycji 1 i odpowiednich substancji wyjsciowych.Substituents on the 1-position of the pyrazole ring, such as an alkyl, alkenyl, alkynyl radical and cycloalkylalkyl is introduced analogously to that described above. The reactants are the compounds that they consist of a 1-substituted group and a halogen atom or carry another suitable substituent, e.g. toluene-4-sulfonic radical. There may be slight changes in the conditions of conducting individual reactions introduced by experts without major difficulties. Examples of substituents at position 1 are given below and suitable starting materials.
Reagent Podstawnikw pozycji 1 1-bromo-2-chloroetan 2-chloroetyl bromocykloheksan cykloheksyl bromocyklopropylometan cyklopropylometyl 1 -chloro-2-etylosulfonyloetan 2-etylosulfonyloetyl 1-bromo-2-«tylotiopropan 2-etylotiopropyl 1-chloro-3-acetyloheksan 3-acetyloheksyl 1 -bromo-4-propionylobutan 4-propionylobutyl 1 -chloropropionamid propionamid6 92 427 1-bromo-3-chloro-2-pentan 3-chloro-2-pentenyl jodeketylu etyl chlorek benzylu benzyl Sposób postepowania w celu wytworzenia pirazoli podstawionych w pozycji 1 ilustruje nastepujacy przyklad.Substituent Reagent in position 1 1-bromo-2-chloroethane 2-chloroethyl cyclohexyl bromocyclohexane bromocyclopropylmethane cyclopropylmethyl 1-chloro-2-ethylsulfonylethane 2-ethylsulfonylethyl 2-ethylthiopropyl 1-bromo-2-ylthiopropane 1-chloro-3-acetylhexane 3-acetylhexyl 4-propionylbutyl 1-bromo-4-propionyl butane 1-chloropropionamide propionamide 6 92 427 1-bromo-3-chloro-2-pentane 3-chloro-2-pentenyl ethyl iodeketyl benzyl benzyl chloride The procedure for preparing 1-substituted pyrazoles is illustrated as follows example.
Przyklad IV.Wytwarzanie 1-metylo-3-nitro-4-pirazolokarbonitrylu.Example IV. Preparation of 1-methyl-3-nitro-4-pyrazolecarbonitrile.
Do roztworu 20 g 3(5)-nitro4-pirazolokarbonitrylu w 150 ml 1,2-dwumetoksyetanu dodaje sie 54 g jodku metylu i 21 r4 g bezwodnego K2 C03. Mieszanine utrzymuje sie w stanie wrzenia pod chlodnica zwrotna w ciagu godzin, mieszajac. Nastepnie mieszanine po ochlodzeniu saczy sie i przemywa osad 1,2-dwumetoksyetanem.54 g of iodide are added to a solution of 20 g of 3 (5) -nitro-4-pyrazolecarbonitrile in 150 ml of 1,2-dimethoxyethane methyl and 21 R4 g of anhydrous K 2 CO 3. The mixture is kept under reflux during the course of the process hours, stirring. After cooling, the mixture is filtered and washed with 1,2-dimethoxyethane.
Przesacz i ciecz z przemycia odparowuje sie pod obnizonym cisnieniem. Otrzymany olej rozpuszcza sie w octanie etylu i kolejno przemywa roztworem K2C03, nasyconym roztworem Na2S303 i woda. Nastepnie roztwór suszy sie nad MgSCU, odpedza rozpuszczalnik pod obnizonym cisnieniem, a stala pozostalosc przekrystalizowuje z benzenu. Otrzymuje sie 18,7 g 1-metylo-3-nitro4-pirazolokarbonitrylu o temperaturze topnienia 85-B7°C.The filtrate and washings are evaporated under reduced pressure. The resulting oil is dissolved in acetate ethyl acetate and sequentially washed with K2CO3 solution, saturated Na2S303 solution and water. The solution is then dried over MgSCU, evacuates the solvent under reduced pressure, and the solid residue recrystallizes from benzene. 18.7 g of 1-methyl-3-nitro-4-pyrazolecarbonitrile are obtained, m.p. 85-B7 ° C.
Przyklad V.Wytwarzanie 1-(2,3-epoksypropylo)-3-nitro-4-pirazolokarbonitrylu.Example V. Preparation of 1- (2,3-epoxypropyl) -3-nitro-4-pyrazolecarbonitrile.
Mieszanine 2,76 g 3(5)-nitro*4-pirazoJókarbonitryiu, 14 ml epichlorohydryny i 230 mg bezwodnego K3C03 utrzymuje sie wstanie wrzenia pod chlodnica zwrotna w ciagu 10 minut. Goraca mieszanine saczy sie i nieorganiczna stala substancje przemywa sie goracym etanolem. Przesacz i ciecz z przemywania odparowuje sie pod obnizonym cisnieniem w celu wyodrebnienia 1-(2-hydroksy-3-chloropropylo)-3-nitro4-pirazolokarbonitrylu w postaci oleju barwy pomaranczowej. Olej rozpuszcza sie w 100 ml octanu etylu, dodaje 10 ml 10% NaOH i mieszanine miesza sie wciagu 30 minut. Warstwe organiczna oddziela sie, przemywa zimna woda i suszy nad MgS04. Po odparowaniu rozpuszczalnika pod obnizonym cisnieniem otrzymuje sie olej, który po oziebieniu krystalizuje. Surowy produkt odbarwia sie I przekrystalizowuje z mieszaniny octanu etylu i benzenu. Otrzymuje sie 2 g 1-(2,3-epoksypropylo)-3*nitro-4-pirazolokarbonitrylu o temperaturze topnienia 78-80°C.A mixture of 2.76 g of 3 (5) -nitro * 4-pyrazo-carbonitrile, 14 ml of epichlorohydrin and 230 mg of anhydrous K3C03 boils under reflux for 10 minutes. The hot mixture is sipping and the inorganic solid is washed with hot ethanol. The filtrate and washings are evaporated under reduced pressure to isolate 1- (2-hydroxy-3-chloropropyl) -3-nitro-4-pyrazolecarbonitrile in the form of an orange oil. The oil is dissolved in 100 ml of ethyl acetate, 10 ml of 10% NaOH are added and the mixture is stirred for 30 minutes. The organic layer is separated, washed with cold water, and dried over MgSO 4. After evaporating off the solvent under reduced pressure, an oil is obtained, which after cooling crystallizes. The crude product is discolored and recrystallized from a mixture of ethyl acetate and benzene. Receives 2 g of 1- (2,3-epoxypropyl) -3 * nitro-4-pyrazolecarbonitrile, mp 78-80 ° C.
W analogiczny sposób otrzymuje sie zwiazki podstawione w pozycji 1 rodnikami arylowymi. Niektóre podstawniki arylowe musza miec w pierscieniu grupe aktywujaca, taka jak grupa nitrowa, aby atom chlorowca stal sie reaktywny.Compounds substituted in the 1-position with aryl radicals are prepared in an analogous manner. Some Aryl substituents must have an activating group such as a nitro ring in the ring in order for the halogen atom to he became reactive.
Przyklad VI. Wytwarzanie 1-(4-nitrofenylo)-3-nitro-4-pirazolokarbonitrylu. do roztworu 8g soli sodowej 3(5)-nitro-4-pirazolokarbonitfylu (wytworzonej sposobem opisanym w przykladzie III) w 40 ml bezwodnego dwumetyloformamidu dodaje sie 8,4 g 4-fluoronitrobenzenu i otrzyma¬ na mieszanine ogrzewa sie w temperaturze 120—125°C, wciagu 5 godzin, mieszajac. Mieszanine oziebiona do temperatury pokojowej wylewa sie do 150 ml zimnej wody i otrzymana dwufazowa mieszanine ekstrahuje sie octanem etylu. Warstwe organiczna przemywa sie zimna woda, suszy nad MgS04 i odparowuje rozpuszczalnik.Example VI. Preparation of 1- (4-nitrophenyl) -3-nitro-4-pyrazolecarbonitrile. to a solution of 8 g of 3 (5) -nitro-4-pyrazolecarbonitphyl sodium salt (prepared by the method described in in Example III), 8.4 g of 4-fluoronitrobenzene are added in 40 ml of dry dimethylformamide to give the mixture is heated at 120 ° -125 ° C for 5 hours with stirring. Chilled mixture to at room temperature, it is poured into 150 ml of cold water and the resulting biphasic mixture is extracted ethyl acetate. The organic layer is washed with cold water, dried over MgSO 4 and the solvent is evaporated.
Otrzymuje sie 10 g H4-nitrofenylo)-3-nitro4-pirazolokarbonitrylu o temperaturze topnienia 172-175°C.10 g of H4-nitrophenyl) -3-nitro4-pyrazolecarbonitrile are obtained, m.p. 172-175 ° C.
Przyklady innych podstawników arylowych i substancje wyjsciowe podano ponizej.Examples of other aryl substituents and starting materials are given below.
Reagent Podstawnik w pozycji 1 2-bromo-(1,3,5-triazyna) 2-0,3,5-triazynyl) 3-bromo-4-nitropirydyna 4-nitro-3-pirydyl 2-bromo-4-etylopirymidyna 4-etylo-2-pirymidynyl Zwiazki zawierajace w podstawniku w pozycji 1 grupe acyloksylowa wytwarza sie w kilku etapach. Do pierscienia wprowadza sie w pozycje 1 podstawnik zawierajacy w polozeniu, w którym ma byc grupa acylowa, grupe hydroksylowa, a nastepnie postepuje sie w sposób nastepujacy.Reagent Substituent in position 1 2-bromo (1,3,5-triazine) 2-0,3,5-triazinyl) 3-bromo-4-nitropyridine 4-nitro-3-pyridyl 2-bromo-4-ethylpyrimidine 4-ethyl-2-pyrimidinyl Compounds with an acyloxy group in the 1-position are prepared in several steps. Down the rings are introduced into position 1 of the containing substituent in the position where the acyl group is to be, a hydroxyl group, and then proceeds as follows.
Przyklad VII. Wytwarzanie octanu 2-(4-karbamoilo-3-nitropirazolo-1-ylo)etylu.Example VII. Preparation of 2- (4-carbamoyl-3-nitropyrazol-1-yl) ethyl acetate.
Do zawiesiny 5g 1-(2-hydroksyetylo)-3-nitro4-pirazolokarboksyamidu w 25 ml bezwodnika octowego dodaje sie w temperaturze pokojowej 5 kropli pirydyny. Mieszanine ogrzewa sie na lazni parowej wciagu 1 godziny, chlodzi do temperatury pokojowej i wylewa do 150 ml zimnej wody. Wytracony bialy osad odsacza sie, przemywa woda i suszy. Po rekrystalizacji z metanolu otrzymuje sie 4 g octanu 2-(4-karbomilo-3-nitropirazo- lo-1 -ylo)etylu o temperaturze topnienia 139-141 °C.For a suspension of 5 g of 1- (2-hydroxyethyl) -3-nitro-4-pyrazole carboxamide in 25 ml of acetic anhydride 5 drops of pyridine are added at room temperature. The mixture is heated in a steam bath 1 hour, cooled to room temperature and poured into 150 ml of cold water. The precipitated white sludge precipitate it is washed with water and dried. After recrystallization from methanol, 4 g of 2- (4-carbomyl-3-nitropyrazo-acetate) are obtained. 1-1-yl) ethyl, m.p. 139-141 ° C.
Przyklad VIII. Wytwarzanie kwasu 1-metylo-3-nitro-4-pirazolokarboksylowego.Example VIII. Preparation of 1-methyl-3-nitro-4-pyrazole carboxylic acid.
Roztwór 32 g 1-metylo-3-nitro4-pirazolokarbonitrylu i 35 g NaOH w 350 ml wody utrzymuje sie w stanie wrzenia pod chlodnica zwrotna wciagu 18 godzin, oziebia na lazni lodowej i zakwasza stezonym kwasem solnym do wartosci pH 2. Wytracony osad odsacza sie, przemywa zimna woda i rekrystalizuje z mieszaniny metanolu i wody. Otrzymuje sie 32,5 g kwasu 1 -metylo-3-nitro4-pirazolokarboksylowego o temperaturze topnie¬ nia 185-187°C.92 427 7 Przyklad IX. Wytwarzanie kwasu 1-(2-hydroksyetylo)-3-nitro-4-pirazolokarboksylowego. g 1-(2-hydroksyetylo)-3-nitro-4*pirazolokarbonitrylu dodaje sie do 150 ml stezonego kwasu solnego i miesza w temperaturze 70—75°C wciagu 10 godzin. Otrzymany roztwór odparowuje sie do sucha pod obnizonym cisnieniem. Ze stalej pozostalosci wytwarza sie zawiesine w 200 ml izopropanolu, ogrzewa ja do wrzenia, oziebia na lazni lodowej i saczy w celu oddzielenia NH4CI. Przesacz odparowuje sie pod obnizonym cisnieniem, pozostaly olej po oziebieniu krystalizuje. Surowy produkt rekrystalizuje sie z mieszaniny benzenu i octanu etylu. Otrzymuje sie 13,4 g kwasu 1-(2-hydroksyetylo)-3-nitro-4-pirazolokarboksylowego o temperatu¬ rze topnienia 147-149°G.Maintain a solution of 32 g 1-methyl-3-nitro-4-pyrazolecarbonitrile and 35 g NaOH in 350 ml water. boiling under a reflux condenser within 18 hours, cooled in an ice bath and acidified with concentrated acid salt to pH 2. The precipitate is filtered off, washed with cold water and recrystallized from the mixture methanol and water. 32.5 g of 1-methyl-3-nitro-4-pyrazole carboxylic acid are obtained, m.p. n. 185-187 ° C. 92 427 7 Example IX. Preparation of 1- (2-hydroxyethyl) -3-nitro-4-pyrazole carboxylic acid. g of 1- (2-hydroxyethyl) -3-nitro-4 * pyrazolecarbonitrile are added to 150 ml of concentrated hydrochloric acid and stirred at 70-75 ° C for 10 hours. The resulting solution was evaporated to dryness under reduced pressure. The solid residue is suspended in 200 ml isopropanol and heated to boiling, chilled in an ice bath and filtered to separate NH4Cl. The filtrate evaporates under the lowered pressure, the remaining oil crystallizes upon cooling. The crude product is recrystallized from a mixture of benzene and ethyl acetate. 13.4 g of 1- (2-hydroxyethyl) -3-nitro-4-pyrazolecarboxylic acid at a temperature of mp 147-149 ° G.
Cennymi zwiazkami przeciwbakteryjnymi sa zwiazki podstawione w pozycji 4 grupa karboksyamido.Valuable antibacterial compounds are those substituted in the 4-position by the carboxamido group.
Ponlie] podano przyklady ilustrujace sposób wytwarzania takich zwiazków.Ponlie], examples are given that illustrate the method of making such compounds.
Przyklad X. Wytwarzanie chlorku 1 -metylo-3-nitro-4-pirazolokarbonylu.Example X. Preparation of 1-methyl-3-nitro-4-pyrazolcarbonyl chloride.
Do zawiesiny 20 g kwasu 1-metylo-3-nitro4-pirazclokarboksylowego w 250 ml CHCI3 dodaje sie 65 g chlorku tionylu i mieszanine utrzymuje sie w stanie wrzenia w ciagu 3 godzin. Nastepnie mieszanine odparowuje sie pod obnizonym cisnieniem. Pozostaly olej krystalizuje po oziebieniu. Surowy produkt uciera sie na proszek z mieszanina eteru naftowego i eteru etylowego. Otrzymuje sie 22,5 g chlorku 1-metylo-3-nitro-4-pirazolokarbo- nylu o temperaturze topnienia 68-70°C.65 g are added to a suspension of 20 g of 1-methyl-3-nitro-4-pyrazclecarboxylic acid in 250 ml of CHCl3 of thionyl chloride and the mixture is boiled for 3 hours. Then the mixture is evaporated under reduced pressure. The residual oil crystallizes upon cooling. The crude product is pulverized with a mixture of petroleum ether and diethyl ether. 22.5 g of 1-methyl-3-nitro-4-pyrazole carbohydrate chloride are obtained. nylon with a melting point of 68-70 ° C.
Przyklad XI.Wytwarzanie 1 -metylo-3-nitro-4-pirazolokarboksyamidu. 7fl chlorku 1-metylo-3-nitro-4-pirazolokarbonylu dodaje sie porcjami do 50 ml stezonego NH4OH.Example XI. Preparation of 1-methyl-3-nitro-4-pyrazole carboxamide. 7 µl of 1-methyl-3-nitro-4-pyrazolcarbonyl chloride is added in portions to 50 ml of concentrated NH 4 OH.
Mieszanine utrzymuje sie wstanie wrzenia pod chlodnica zwrotna wciagu 15—20 minut, odparowuje do sucha I oziebia. Otrzymany krystaliczny produkt zidentyfikowano jako 1-metylo-3-nitro-4-pirazolokarboksyamid o temperaturze topnienia 190-192°C.The mixture is refluxed for 15-20 minutes and evaporated to dryness And it freezes. The obtained crystalline product was identified as 1-methyl-3-nitro-4-pyrazole carboxamide mp 190-192 ° C.
Przyklad XII. Wytwarzanie N,1-dwumetylo-3-nitro-4-pirazolokarboksyamidu. 6 ml oziebionej na lazni lodowej wody nasyca sie monometyloamina. Do otrzymanego roztworu dodaje sie porcjami 2 g chlorku 1-metylo-3-nitro-4-pirazolokarbonylu i mieszanine ogrzewa do momentu rozpuszczenia substancji stalych. Nastepnie roztwór oziebia sie a wytracony produkt rekrystalizuje zwody. Otrzymuje sie '1,3 g N>1 Te sama reakcje stosuje sie do wytwarzania innych zwiazków karboksyamidowych. Przyklady substancji wyjsciowych i podstawników w pozycji 4 podano ponizej Reagent Podstawnik dwumetyloaminadwumetylokarboksyamid heksyloamina heksylokarboksyamid 3-pentyloamina 3-pentylokarboksyamid etyloamina etylokarboksyamid Przyklad XIIL Wytwarzanie estru metylowego kwasu 1-(2-hydroksyetylo)-3-nitro-4-pirazolokarbok- sylowego.Example XII. Preparation of N, 1-dimethyl-3-nitro-4-pyrazole carboxamide. 6 ml of water cooled in an ice bath is saturated with monomethylamine. Add to the obtained solution 2 g of 1-methyl-3-nitro-4-pyrazolcarbonyl chloride are mixed in portions and the mixture is heated until it dissolves. solids. The solution is then cooled and the product that is precipitated out recrystallizes the waters. I get '1.3 g N> 1 The same reactions are used to prepare other carboxamide compounds. Examples of substances the starting and substituents at position 4 are given below Substituent reagent dimethylaminadimethylcarboxamide hexylamine hexyl carboxamide 3-pentylamine 3-pentylcarboxamide ethylamine ethyl carboxamide Example XIIL Preparation of 1- (2-hydroxyethyl) -3-nitro-4-pyrazolecarboxylic acid methyl ester the style.
Do roztworu 13 g kwasu H2*hydroksyetylo)-3-nitro-4-pirazolokarboksylowego w 200 ml czterowodorofu- ranu oziebionego na lazni lodowej wkrapla sie niewielki nadmiar eterowego roztworu dwuazometanu. Po zakonczeniu wydzielania sie azotu usuwa sie pod obnizonym cisnieniem rozpuszczalnik. Pozostaly olej krystalizuje po oziebieniu. Surowy produkt rekrystalizuje sie z mieszaniny eteru i acetonu. Otrzymuje sie 12 g estru metylowego kwasu 1-(2-hydroksyetylo)-3-nitro-4-pirazolokarboksylowego o temperaturze topnienia 93-95°C.For a solution of 13 g of H 2 * hydroxyethyl) -3-nitro-4-pyrazole carboxylic acid in 200 ml of tetrahydrofuran a slight excess of an ethereal diazomethane solution is dripped into the cold wound in an ice bath. After on completion of nitrogen evolution, the solvent is removed under reduced pressure. Residual oil crystallizes on cooling. The crude product is recrystallized from a mixture of ether and acetone. You get 12 g 1- (2-Hydroxyethyl) -3-nitro-4-pyrazole carboxylic acid methyl ester, melting point 93-95 ° C.
Do wytwarzania estrów mozna stosowac równiez inne metody estryfikacji.Other esterification methods can also be used to produce esters.
Przyklad XIV. Wytwarzanie estru. metylowego kwasu 1-(2-hydroksyetylo)-3-nltro4-pirazolokarbo- ksylowego.Example XIV. Manufacture of ester. 1- (2-hydroxyethyl) -3-nltro4-pyrazole carbohydrate methyl xylowe.
Metanolowy roztwór 21,6 g kwasu 1-(2-hydroksyetylo)-3-nitro-4-pirazolokarboksylowego nasyca sie chlo¬ rowodorem i odstawia na kilka godzin w temperaturze pokojowej, a nastepnie odparowuje. Pozostalosc rozpusz¬ cza sie w estrze, przemywa roztworem Na^CO* i odparowuje do sucha. Otrzymuje sie 18 g estru metylowego kwasu 1-(2"hydroksyetylo)-3mitro-4-pirazolokarboksylowego o temperaturze topnienia 93-95°C.A methanolic solution of 21.6 g of 1- (2-hydroxyethyl) -3-nitro-4-pyrazolecarboxylic acid is saturated with chlorine hydrogen and left to stand for a few hours at room temperature, then evaporated. Dissolve the residue quenched in the ester, washed with Na 2 CO * solution, and evaporated to dryness. 18 g of methyl ester are obtained 1- (2 "hydroxyethyl) -3-mitro-4-pyrazole carboxylic acid, m.p. 93-95 ° C.
Inne estry wytwarza sie w sposób analogiczny.Other esters are prepared analogously.
Reagent etanol butanol heksanol Podstawnik ester etylowy ester butylowy ester heksylowy8 92 427 Estry nioga sluzyc do wytwarzania zwiazków z grupa karboksyamidowa w pozycji 4, a niektóre równiez wykazuja aktywnoscbiologiczna. ¦¦' Przyklad XV. Wytwarzanie 1-(2-hydroksyetylo)-N-metylo-3-nitro4-pirazolokarboksyamidu. 4g estru metylowego kwasu 1-(2-hydroksyetylo)-3-nitro4-pirazolokarboksylowego rozpuszcza sie w zim¬ nej mieszaninie 25 ml absolutnego metanolu i 25 ml skroplonej metyloaminy. Roztwór przetrzymuje sie w zamknietym zbiorniku w ciagu 48 godzin w temperaturze pokojowej. Nastepnie odpedza sie lotne ciecze pod obnizonym cisnieniem, a pozostale cialo stale odbarwia sie i rekrystalizuje z mieszaniny metanolu i izopropano- lu. Otrzymuje sie 2,3 g 1-(2-hydroksyetylo)-N-metylo-3-nitro4-pirazolokarboksyamidu o temperaturze topnienia 138-140°C.Reagent ethanol butanol hexanol Substituent ethyl ester butyl ester hexyl ester 8 92 427 Nogi esters serve to form compounds with the carboxamide group in the 4-position and some also show biological activity. ¦¦ ' Example XV. Preparation of 1- (2-hydroxyethyl) -N-methyl-3-nitro-4-pyrazole carboxamide. 4 g of 1- (2-hydroxyethyl) -3-nitro-4-pyrazole carboxylic acid methyl ester is dissolved in the cold a mixture of 25 ml of absolute methanol and 25 ml of condensed methylamine. The solution is kept in a closed container within 48 hours at room temperature. The volatile liquids underneath are then stripped off reduced pressure, and the rest of the body constantly discolored and recrystallized from a mixture of methanol and isopropane lu. 2.3 g of 1- (2-hydroxyethyl) -N-methyl-3-nitro-4-pyrazole carboxamide are obtained, m.p. 138-140 ° C.
W powyzszy sposób otrzymuje sie inne zwiazki 4-aminowe, przyklady substancji wyjsciowej i podstawni¬ ków podano ponizej.Other 4-amino compounds are prepared in the above manner, examples of starting material and substituting see below.
Reagent Podstawnik dwumetyloamina dwumetylokarboksyamid n-butyloamina n-butylokarboksyamid izopropyloamina izopropylokarboksyamid Przyklad XVI. Wytwarzanie N-hydroksy-1 -metylo-3-nitro4-pirazolokarboksyarnidu.Substituent reagent dimethylamine dimethyl carboxamide n-butylamine n-butyl carboxamide isopropylamine isopropyl carboxamide Example XVI. Preparation of N-hydroxy-1-methyl-3-nitro-4-pyrazole carboxamide.
Do roztworu 1,4 g chlorowodorku hydroksyloaminy w jak najmniejszej ilosci metanolu dodaje sie roztwór 1,6 g NaOH w metanolu. Wytracony NaCI odsacza sie, a przesacz natychmiast wkrapla, w trakcie mieszania, do roztworu 4,3 g estru metylowego kwasu 1-metylo-3-nitro-4-pirazolokarboksylowego w metanolu w temperaturze pokojowej i w atmosferze azotu. Po 15 minutach mieszanine ogrzewa sie do wrzenia i utrzymuje w stanie wrzenia pod chlodnica zwrotna w ciagu 1 godziny. Nastepnie mieszanine reakcyjna odparowuje sie pod obnizonym cisnieniem. ' Stala pozostalosc rozpuszcza sie w niewielkiej ilosci wody, zakwasza do wartosci pH = 2 stezonym kwasem solnym i roztwór odparowuje do sucha pod obnizonym cisnieniem. Pozostalosc rozpuszcza sie w metanolu I powstaly NaCI odsacza sie. Przesacz odparowuje sie znów do sucha pod obnizonym cisnieniem.The solution is added to a solution of 1.4 g of hydroxylamine hydrochloride in as little methanol as possible 1.6 g of NaOH in methanol. The precipitated NaCl is drained off, and the percolate is immediately dropped into the stirred mixture a solution of 4.3 g of 1-methyl-3-nitro-4-pyrazole carboxylic acid methyl ester in methanol at a temperature room under nitrogen atmosphere. After 15 minutes, the mixture is boiled and kept under boiling to reflux condenser within 1 hour. The reaction mixture was then evaporated under reduced pressure pressure. 'The solid residue dissolves in a little water, acidifies to a pH value of 2 with the concentrated hydrochloric acid and the solution is evaporated to dryness under reduced pressure. The remainder dissolves in methanol and the formed NaCl is filtered off. The slurry is again evaporated to dryness under reduced pressure.
Pozostaly olej rozpuszcza sie w mieszaninie benzenu i acetonu i oziebia w celu wykrystalizowania produktu.The residual oil is dissolved in a mixture of benzene and acetone and cooled to crystallize the product.
Produkt rekrystalizuje sie z izopropanolu i otrzymuje 2g N-hydroksy-1 -metylo-3-nitro4-pirazolokarboksyamid 0 temperaturze topnienia 143-145°C (z rozkladem).The product is recrystallized from isopropanol to give 2 g of N-hydroxy-1-methyl-3-nitro-4-pyrazole carboxamide Mp 143-145 ° C (decomposition).
Przyklad XVII.Wytwarzanie 1 -(2-hydroksyetylo)^-nitro4-pirazo1okarboksyamidu. g H2-hydrokiyetyló)-3-nitro4^irazolokarbonitrylu rozpuszcza sie w 200 ml metanolu i dodaje 110 ml % H30,. Nastepnie, w trakcie mieszania, dodaje sie malymi porcjami 8,5 ml 6 n NaOH w ciagu 30 minut.Example XVII. Preparation of 1- (2-hydroxyethyl) -1-nitro-4-pyrazole-1 carboxamide. g of H2-hydroxyethyl) -3-nitro4-irazolecarbonitrile are dissolved in 200 ml of methanol and 110 ml of % H30 ,. Then, while stirring, 8.5 ml of 6N NaOH are added in small portions over 30 minutes.
Mieszanine reakcyjna utrzymuje sie w tym czasie w temperaturze ponizej 50°C, chlodzac na zewnatrz. Nastepnie mieszanine miesza sie wciagu 1 godziny w temperaturze 45—50°C, chlodzi do temperatury pokojowej, pH doprowadza do wartosci 8 za pomoca stezonego kwasu solnego (odpedza rozpuszczalnik pod obnizonym cisnieniem. Produkt wykrystalizowany podczas odparowania odsacza sie, przemywa zimna woda, rozpuszcza w metanolu, odbarwia za pomoca wegla i rekrystalizuje. Otrzymuje sie 20 g 1 -(2-hydroksyetylo)-3-nitro-4-pirazo- lokarboksyamid o temperaturze topnienia 148-150°C.During this time, the reaction mixture is kept at a temperature below 50 ° C while cooling outside. Next the mixture is stirred for 1 hour at 45-50 ° C, cooled to room temperature, pH is brought to the value of 8 with concentrated hydrochloric acid (it evacuates the solvent under reduced pressure. The product crystallized during evaporation is filtered off, washed with cold water and dissolved in methanol, decolorizes with carbon and recrystallizes. 20 g of 1- (2-hydroxyethyl) -3-nitro-4-pyrazo are obtained. locarboxamide, m.p. 148-150 ° C.
Przyklad XVIII.Wytwarzanie 1 -(2-bromometylo)-3-nitro-4-pIrazolokarboksyamidu.Example XVIII. Preparation of 1- (2-bromomethyl) -3-nitro-4-pyrazole carboxamide.
Do zawiesiny 10 g 1-(2"hydroksyetylo)-3-nitro-4-pirazolokarboksyarnidu w 150 ml 1,2-dwumetoksyetanu wkrapla sie w trakcie mieszania, w ciagu 1 godziny 14 g PBr3. Otrzymana mieszanine miesza sie w temperaturze 45—50°C wciagu 10 godzin. Nastepnie pod obnizonym cisnieniem, usuwa sie rozpuszcalnik, a pozostalosc wymywa octanem etylu. Warstwe organiczna przemywa sie wodnym roztworem NaHC03, nastepnie solanka 1 suszy nad bezwodnym MgS04. Po odparowaniu rozpuszczalnika pod obnizonym cisnieniem uzyskuje sie cialo stale barwy bialej, które rekrystalizuje sie z metanolu. Otrzymuje sie 6 g 1-(2-bromoetylo)-3-nitro-4-pirazolokar- boksyamidu o temperaturze topnienia 135—137°C.For a suspension of 10 g of 1- (2 "hydroxyethyl) -3-nitro-4-pyrazolecarboxamide in 150 ml of 1,2-dimethoxyethane it is instilled while stirring 14 g PBr3 within 1 hour. The resulting mixture was stirred at temperature 45-50 ° C within 10 hours. Then, under reduced pressure, the solvent is removed and the remainder was washed with ethyl acetate. The organic layer is washed with aq. NaHCO 3, then with brine 1 is dried over anhydrous MgSO 4. After evaporating off the solvent under reduced pressure, a body is obtained white steels which are recrystallized from methanol. 6 g of 1- (2-bromoethyl) -3-nitro-4-pyrazolocar are obtained. boxamide, mp 135-137 ° C.
Przyklad XIX.Wytwarzanie3-nitro-1-winylo-4-pirazolokarboksyamidu.Example XIX. Preparation of 3-nitro-1-vinyl-4-pyrazole carboxamide.
Zawiesine 6 g 1-(24>romoetylo)-3-nitro4-pirazolokarboksyamidu w 100 ml 5% roztworu Na? C03 utrzymu¬ je sie w stanie wrzenia pod chlodnica zwrotna, mieszajac, w ciagu 5 godzin. Nastepnie mieszanine oziebia sie na lazni lodowej I zakwasza stezonym HCI do wartosci pH = 2. Wytracony produkt odsacza sie, przemywa zimna woda i rekrystalizuje z mieszaniny metanolu i wody. Otrzymuje sie 2 g 3-nitro-1-winylo-4-pirazolokarboksyamid o temperaturze topnienia 150—152°C.Suspension of 6 g of 1- (24> romoethyl) -3-nitro-4-pyrazolecarboxamide in 100 ml of 5% Na? C03 retained they are boiled under reflux and stirred for 5 hours. The mixture is then cooled down on Ice bath I acidifies with concentrated HCl to the value of pH = 2. The precipitated product is filtered off, washed with cold water and recrystallizes from a mixture of methanol and water. 2 g of 3-nitro-1-vinyl-4-pyrazole carboxamide are obtained mp 150-152 ° C.
W analogiczny sposób otrzymuje sie inne, podstawione w pozycji 1 rodnikiem alkenylowym, zwiazki.92 427 9 Podstawnik w pozycji 1 Podstawnik w pozycji 1 substancji wyjsciowej produktu 3-bromopropyl allil 4-bromobutyl kroty I Ponizej podano przyklad reakcji dwuetapowej, w której wytwarza sie zwiazki majace 2 pierscienie 3-nitropirazolowe polaczone poprzez podstawnik w pozycji 1. Czesto prowadzi sie reakcje z podstawnikiem pozycji 4 przed przylaczeniem podstawnika w pozycji 1, korzystna jest np. nastepujaca reakcja.The other compounds substituted in the 1-position with alkenyl radicals were prepared analogously. 92 427 9 Substituent in position 1 Substituent in position 1 product starting material 3-bromopropyl allyl 4-bromobutyl fold I. An example of a two-step reaction which produces compounds having 2 rings is given below 3-nitropyrazole compounds linked via a substituent at the 1-position. Reactions are frequently carried out with a substituent in the 4 position prior to attachment of the 1 substituent, the following reaction is, for example, preferable.
Przyklad XX. Wytwarzanie solt sodowej 3-nitro4-pirazolokarboksyamidu.Example XX. Preparation of the sodium salt of 3-nitro-4-pyrazole carboxamide.
Do roztworu 8 g soli sodowej 3-nitro4-pirazolokarbonitrylu w metanolu dodaje sie 75 ml 15% H202, a nastepnie 5 ml 6 n NaOH. Mieszanine reakcyjna ogrzewa sie do temperatury 45°C, po czym chlodzi od zewnatrz tak, aby utrzymac temperature 45—50°C. Po zakonczeniu reakcji egzotermicznej mieszanine miesza sie w temperaturze 45—50°C wciagu 4 godzin, oziebia i odpedza metanol pod obnizonym cisnieniem- Pozostala ciecz oziebia sie na lazni lodowej, wytworzony produkt odsacza i suszy pod obnizonym cisnieniem. Otrzymuje sie 8 g soli sodowej 3-nitro-4-pirazolokarboksyamidu o temperaturze topnienia powyzej 300°C.75 ml of 15% H 2 O 2 are added to a solution of 8 g of 3-nitro-4-pyrazolecarbonitrile sodium in methanol, followed by 5 ml of 6 N NaOH. The reaction mixture is heated to 45 ° C, then cooled to outdoors to maintain a temperature of 45-50 ° C. After the exothermic reaction has ended, the mixture is stirred at a temperature of 45-50 ° C for 4 hours, it cools and expels methanol under reduced pressure - Remaining the liquid is cooled in an ice bath, the product produced is filtered off and dried under reduced pressure. Receives 8 g of sodium salt of 3-nitro-4-pyrazolecarboxamide with a melting point above 300 ° C.
Przyklad XXI. Wytwarzanie 1,1 '-(2,5-cykloheksadieno-1,4-yleno)-bis-(3-nitro4-pirazolokarboksyami- du.Example XXI. Preparation of 1,1 '- (2,5-cyclohexadiene-1,4-ylene) -bis- (3-nitro-4-pyrazolecarboxamides- du.
Do zawiesiny 5,34 g soli sodowej 3(5)-nitro4-pirazolokarboksyamidu, wytworzonej w sposób opisany w przykladzie XX, w 100 ml acetonitrylu dodaje sie 4g bromku propargilu i 2,5 g bezwodnego NanC03.To a suspension of 5.34 g of sodium salt of 3 (5) -nitro-4-pyrazole carboxamide, prepared as described in Example XX, 4 g of propargyl bromide and 2.5 g of anhydrous NanCO 3 are added in 100 ml of acetonitrile.
Nastepnie do mieszaniny dodaje sie niewielka ilosc wody i calosc miesza sie w temperaturze pokojowej w ciagu 24 godzin. Nastepnie mieszanine reakcyjna wylewa sie do 500 ml wody i ekstrahuje octanem etylu. Warstwe organiczna przemywa sie zimna woda z sola i suszy nad MgS04. Rozpuszczalnik odpedza sie pod obnizonym cisnieniem, surowy produkt odbarwia sie i rekrystalizuje z mieszaniny izopropanolu i metanolu. Otrzymuje sie 1,6 g produktu o temperaturze topnienia 128-130°C (z rozkladem).A little water is then added to the mixture and the mixture is stirred at room temperature continuously 24 hours. The reaction mixture is then poured into 500 ml of water and extracted with ethyl acetate. Layer the organic is washed with cold salt water and dried over MgSO 4. The solvent flattens out under the lowered pressure, the crude product decolorizes and recrystallises from a mixture of isopropanol and methanol. I get 1.6 g of the product, m.p. 128-130 ° C (with decomposition).
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US12446371A | 1971-03-15 | 1971-03-15 | |
| US21179171A | 1971-12-23 | 1971-12-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| PL92427B1 true PL92427B1 (en) | 1977-04-30 |
Family
ID=26822622
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PL17669472A PL92427B1 (en) | 1971-03-15 | 1972-03-15 |
Country Status (8)
| Country | Link |
|---|---|
| AR (2) | AR208267A1 (en) |
| DD (1) | DD97200A5 (en) |
| DK (1) | DK134285B (en) |
| ES (1) | ES400714A1 (en) |
| IE (1) | IE36144B1 (en) |
| IL (1) | IL38950A (en) |
| PL (1) | PL92427B1 (en) |
| RO (1) | RO64927A (en) |
-
1972
- 1972-01-01 AR AR24094672A patent/AR208267A1/en active
- 1972-03-08 IE IE29772A patent/IE36144B1/en unknown
- 1972-03-10 IL IL38950A patent/IL38950A/en unknown
- 1972-03-13 ES ES400714A patent/ES400714A1/en not_active Expired
- 1972-03-15 PL PL17669472A patent/PL92427B1/pl unknown
- 1972-03-15 RO RO7777772A patent/RO64927A/en unknown
- 1972-03-15 DD DD16153772A patent/DD97200A5/xx unknown
- 1972-03-15 DK DK120672A patent/DK134285B/en unknown
-
1973
- 1973-11-15 AR AR25101173A patent/AR209267A1/en active
Also Published As
| Publication number | Publication date |
|---|---|
| DK134285B (en) | 1976-10-11 |
| IL38950A0 (en) | 1972-05-30 |
| IE36144L (en) | 1972-09-15 |
| IE36144B1 (en) | 1976-09-01 |
| DK134285C (en) | 1977-03-21 |
| AR208267A1 (en) | 1976-12-20 |
| AR209267A1 (en) | 1977-04-15 |
| IL38950A (en) | 1976-07-30 |
| ES400714A1 (en) | 1975-01-16 |
| RO64927A (en) | 1979-03-15 |
| DD97200A5 (en) | 1973-04-20 |
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