ITUB20150115A1 - Pyrazole derivatives and their use for the preparation of 1,3,4-thiadiazoles. - Google Patents
Pyrazole derivatives and their use for the preparation of 1,3,4-thiadiazoles. Download PDFInfo
- Publication number
- ITUB20150115A1 ITUB20150115A1 ITUB2015A000115A ITUB20150115A ITUB20150115A1 IT UB20150115 A1 ITUB20150115 A1 IT UB20150115A1 IT UB2015A000115 A ITUB2015A000115 A IT UB2015A000115A IT UB20150115 A ITUB20150115 A IT UB20150115A IT UB20150115 A1 ITUB20150115 A1 IT UB20150115A1
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- IT
- Italy
- Prior art keywords
- group
- general formula
- compound
- halogen atoms
- cycloalkylalkyl
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims description 33
- 150000004869 1,3,4-thiadiazoles Chemical class 0.000 title claims description 6
- 150000003217 pyrazoles Chemical class 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims description 153
- 239000000203 mixture Substances 0.000 claims description 46
- -1 monosubstituted hydrazine Chemical class 0.000 claims description 35
- 238000000034 method Methods 0.000 claims description 31
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 29
- 125000005843 halogen group Chemical group 0.000 claims description 26
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 22
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 13
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 239000000543 intermediate Substances 0.000 claims description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 10
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 10
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 150000007529 inorganic bases Chemical class 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical group CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 239000007800 oxidant agent Substances 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 238000006722 reduction reaction Methods 0.000 claims description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 6
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 5
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000003368 amide group Chemical group 0.000 claims description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- 125000006678 phenoxycarbonyl group Chemical group 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 3
- 239000004343 Calcium peroxide Substances 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- LHJQIRIGXXHNLA-UHFFFAOYSA-N calcium peroxide Chemical compound [Ca+2].[O-][O-] LHJQIRIGXXHNLA-UHFFFAOYSA-N 0.000 claims description 3
- 235000019402 calcium peroxide Nutrition 0.000 claims description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 3
- 150000001451 organic peroxides Chemical class 0.000 claims description 3
- 150000002978 peroxides Chemical class 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- PFUVRDFDKPNGAV-UHFFFAOYSA-N sodium peroxide Chemical compound [Na+].[Na+].[O-][O-] PFUVRDFDKPNGAV-UHFFFAOYSA-N 0.000 claims description 3
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 2
- 239000002168 alkylating agent Substances 0.000 claims description 2
- 229940100198 alkylating agent Drugs 0.000 claims description 2
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000005280 halo alkyl sulfonyloxy group Chemical group 0.000 claims description 2
- 229910052987 metal hydride Inorganic materials 0.000 claims description 2
- 150000004681 metal hydrides Chemical class 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical group C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 claims 4
- 238000004519 manufacturing process Methods 0.000 claims 3
- 125000004441 haloalkylsulfonyl group Chemical group 0.000 claims 2
- 230000001590 oxidative effect Effects 0.000 claims 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims 1
- 150000008046 alkali metal hydrides Chemical class 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
- 239000002904 solvent Substances 0.000 description 24
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 19
- 239000000243 solution Substances 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 238000001704 evaporation Methods 0.000 description 14
- 230000008020 evaporation Effects 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 150000004867 thiadiazoles Chemical group 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 235000011152 sodium sulphate Nutrition 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 11
- 239000008346 aqueous phase Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 238000007363 ring formation reaction Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000003495 polar organic solvent Substances 0.000 description 7
- DQXSULLDIZSRMN-UHFFFAOYSA-N 4-(chloromethyl)-5-fluoro-1-methyl-3-(trifluoromethyl)pyrazole Chemical compound FC1=C(C(=NN1C)C(F)(F)F)CCl DQXSULLDIZSRMN-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000012047 saturated solution Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 238000003760 magnetic stirring Methods 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- 125000003226 pyrazolyl group Chemical group 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- WQRHIGNAKDJJKN-UHFFFAOYSA-N 2-methyl-5-(trifluoromethyl)-1h-pyrazol-3-one Chemical compound CN1NC(C(F)(F)F)=CC1=O WQRHIGNAKDJJKN-UHFFFAOYSA-N 0.000 description 3
- FPVUWZFFEGYCGB-UHFFFAOYSA-N 5-methyl-3h-1,3,4-thiadiazole-2-thione Chemical compound CC1=NN=C(S)S1 FPVUWZFFEGYCGB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 230000002152 alkylating effect Effects 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- OCJKUQIPRNZDTK-UHFFFAOYSA-N ethyl 4,4,4-trifluoro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)C(F)(F)F OCJKUQIPRNZDTK-UHFFFAOYSA-N 0.000 description 3
- 150000004678 hydrides Chemical class 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 150000003462 sulfoxides Chemical class 0.000 description 3
- 125000006337 tetrafluoro ethyl group Chemical group 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- HZDMNWYSHCWPLK-UHFFFAOYSA-N 2-(trifluoromethyl)-1,3,4-thiadiazole Chemical group FC(F)(F)C1=NN=CS1 HZDMNWYSHCWPLK-UHFFFAOYSA-N 0.000 description 2
- UYUGNEIWEQMKSZ-UHFFFAOYSA-N 2-methyl-5-[1-methyl-5-(2,2,2-trifluoroethoxy)-3-(trifluoromethyl)pyrazol-4-yl]sulfinyl-1,3,4-thiadiazole Chemical compound CN1N=C(C(=C1OCC(F)(F)F)S(=O)C1=NN=C(C)S1)C(F)(F)F UYUGNEIWEQMKSZ-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 101100313649 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) POT1 gene Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 2
- 101100161758 Yarrowia lipolytica (strain CLIB 122 / E 150) POX3 gene Proteins 0.000 description 2
- WIABTIBXPLJUKQ-UHFFFAOYSA-N [5-fluoro-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methanol Chemical compound CN1N=C(C(F)(F)F)C(CO)=C1F WIABTIBXPLJUKQ-UHFFFAOYSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 2
- 125000006003 dichloroethyl group Chemical group 0.000 description 2
- 239000004009 herbicide Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IGKCQDUYZULGBM-UHFFFAOYSA-N 2,2,2-trifluoroethyl 4-methylbenzenesulfonate Chemical compound CC1=CC=C(S(=O)(=O)OCC(F)(F)F)C=C1 IGKCQDUYZULGBM-UHFFFAOYSA-N 0.000 description 1
- NOIXNOMHHWGUTG-UHFFFAOYSA-N 2-[[4-[4-pyridin-4-yl-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenoxy]methyl]quinoline Chemical group C=1C=C(OCC=2N=C3C=CC=CC3=CC=2)C=CC=1C1=NN(CC(F)(F)F)C=C1C1=CC=NC=C1 NOIXNOMHHWGUTG-UHFFFAOYSA-N 0.000 description 1
- CQVKCMMYQYHWLB-UHFFFAOYSA-N 2-[[5-chloro-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methylsulfanyl]-5-methyl-1,3,4-thiadiazole Chemical compound ClC1=C(C(=NN1C)C(F)(F)F)CSC=1SC(=NN=1)C CQVKCMMYQYHWLB-UHFFFAOYSA-N 0.000 description 1
- STABAPSYCQFWOK-UHFFFAOYSA-N 4-chlorobenzenecarboperoxoic acid Chemical compound OOC(=O)C1=CC=C(Cl)C=C1 STABAPSYCQFWOK-UHFFFAOYSA-N 0.000 description 1
- PZOZNOVIRZSNHJ-UHFFFAOYSA-N 5-chloro-1-methyl-3-(trifluoromethyl)pyrazole-4-carbaldehyde Chemical compound CN1N=C(C(F)(F)F)C(C=O)=C1Cl PZOZNOVIRZSNHJ-UHFFFAOYSA-N 0.000 description 1
- OJKIPJVJFWPIJP-UHFFFAOYSA-N 5-fluoro-1-methyl-3-(trifluoromethyl)pyrazole-4-carbaldehyde Chemical compound CN1N=C(C(F)(F)F)C(C=O)=C1F OJKIPJVJFWPIJP-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 238000005874 Vilsmeier-Haack formylation reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QLFNUXTWJGXNLH-UHFFFAOYSA-N bis(2-methoxyethoxy)alumane Chemical compound COCCO[AlH]OCCOC QLFNUXTWJGXNLH-UHFFFAOYSA-N 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 125000004775 chlorodifluoromethyl group Chemical group FC(F)(Cl)* 0.000 description 1
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004998 naphthylethyl group Chemical group C1(=CC=CC2=CC=CC=C12)CC* 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004346 phenylpentyl group Chemical group C1(=CC=CC=C1)CCCCC* 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- PNQBEPDZQUOCNY-UHFFFAOYSA-N trifluoroacetyl chloride Chemical compound FC(F)(F)C(Cl)=O PNQBEPDZQUOCNY-UHFFFAOYSA-N 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Description
Derivati pirazolici e relativo uso per la preparazione di 1,3,4-tiadiazoli Pyrazole derivatives and their use for the preparation of 1,3,4-thiadiazoles
La presente invenzione riguarda derivati pirazolici di formula generale (IV) The present invention relates to pyrazole derivatives of general formula (IV)
e il relativo uso come intermedi per la preparazione di 1,3,4-tiadiazoli di formula generale (I) and its use as intermediates for the preparation of 1,3,4-thiadiazoles of general formula (I)
aventi propriet? erbicide. La presente invenzione riguarda inoltre il processo di preparazione di detti composti di formula generale (IV). having properties herbicide. The present invention also relates to the preparation process of said compounds of general formula (IV).
STATO DELL?ARTE STATE OF THE ART
La presente invenzione riguarda derivati pirazolici di formula generale (IV) The present invention relates to pyrazole derivatives of general formula (IV)
e il relativo uso come composti intermedi per la preparazione dei composti di formula generale (I) and its use as intermediate compounds for the preparation of compounds of general formula (I)
I composti di formula generale (I) recano un anello tiadiazolico ed un anello pirazolico, collegati tra loro da uno spaziatore sulfinile (n = 1) o solfonile (n = 2). The compounds of general formula (I) have a thiadiazole ring and a pyrazole ring, connected together by a sulfinyl (n = 1) or sulfonyl (n = 2) spacer.
Questi composti sono stati descritti di recente dalla Richiedente nella domanda di brevetto in Italia MI2014A001616 per l?impiego come erbicidi per il controllo di erbe infestanti in colture agricole. These compounds have been recently described by the Applicant in the Italian patent application MI2014A001616 for use as herbicides for the control of weeds in agricultural crops.
Ad oggi, ad eccezione di quanto riportato dalla richiedente, nello stato dell?arte non risultano descritti processi per la preparazione dei suddetti composti di formula generale (I). To date, with the exception of what is reported by the applicant, no processes for the preparation of the above compounds of general formula (I) have been described in the state of the art.
Il brevetto US4097669 riporta diversi processi per la preparazione di 1,3,4-tiadiazoli sostituiti in posizione 2 con un residuo solfonato, aventi la seguente struttura chimica: US patent 4097669 reports various processes for the preparation of 1,3,4-thiadiazoles substituted in position 2 with a sulfonate residue, having the following chemical structure:
Una prima strategia di sintesi riportata nel brevetto US4097669 prevede la reazione tra un 5-trifluorometil-1,3,4-tiadiazolo recante un gruppo X in posizione 2 e un mercaptano di formula R-SH in condizioni basiche, in cui X ? un atomo di cloro o di bromo, come riportato nello schema 1. A first synthesis strategy reported in US patent 4097669 provides for the reaction between a 5-trifluoromethyl-1,3,4-thiadiazole bearing a group X in position 2 and a mercaptan of the formula R-SH under basic conditions, in which X? an atom of chlorine or bromine, as shown in diagram 1.
Schema 1 Scheme 1
Una via alternativa per preparare i tiadiazoli desiderati descritta in US4097669 consiste nel far reagire un 5-trifluorometil-1,3,4-tiadiazolo recante un gruppo SH in posizione 2 con un composto di formula LG-R in condizioni basiche, in cui LG rappresenta un gruppo uscente, quale alogeno, mesile o tosile, come riportato nello schema 2. An alternative way to prepare the desired thiadiazoles described in US4097669 consists in reacting a 5-trifluoromethyl-1,3,4-thiadiazole bearing an SH group in position 2 with a compound of formula LG-R under basic conditions, in which LG represents a leaving group, such as halogen, mesyl or tosyl, as reported in diagram 2.
Schema 2 Scheme 2
I tiadiazoli cos? ottenuti vengono successivamente sottoposti ad ossidazione per fornire il corrispondente derivato solfonato desiderato. The thiadiazoles cos? obtained are subsequently subjected to oxidation to provide the corresponding desired sulfonate derivative.
In US4097669 non viene mai menzionato che il gruppo R pu? rappresentare un anello pirazolico opzionalmente sostituito, come nella presente invenzione. D?altra parte, derivati pirazolici recanti un gruppo alcossilico in posizione 5 dell?eterociclo possono essere preparati ad esempio, secondo le metodiche riportate nelle domande di brevetto US2005/215797 e US2007/249844. In US4097669 it is never mentioned that the R group can? representing an optionally substituted pyrazole ring, as in the present invention. On the other hand, pyrazole derivatives bearing an alkoxy group in position 5 of the heterocycle can be prepared for example, according to the methods reported in patent applications US2005 / 215797 and US2007 / 249844.
Tali metodiche prevedono un primo passaggio di ciclizzazione mediante reazione tra un?idrazina monosostituita ed un beta-chetoestere in cui R3 rappresenta un gruppo alchilico, e successiva alchilazione del gruppo idrossilico in presenza di un reagente alchilante, in cui LG ? un gruppo uscente quale ad esempio un atomo di alogeno, come riportato nello schema 3. These methods involve a first cyclization step by reaction between a monosubstituted hydrazine and a beta-ketoester in which R3 represents an alkyl group, and subsequent alkylation of the hydroxyl group in the presence of an alkylating reagent, in which LG? a leaving group such as a halogen atom, as shown in diagram 3.
Schema 3 Scheme 3
Tuttavia, i suddetti derivati pirazolici vengono ottenuti con basse rese e purezze, rendendo pertanto difficile l?impiego a livello industriale di tali processi. Inoltre, non risulta presente alcun suggerimento in merito all?applicazione degli stessi per la preparazione di derivati tiadiazolici recanti un anello pirazolico. However, the aforesaid pyrazole derivatives are obtained with low yields and purities, thus making it difficult to use these processes at an industrial level. Furthermore, there is no suggestion regarding their application for the preparation of thiadiazole derivatives bearing a pyrazole ring.
E? quindi sentita la necessit? di fornire nuovi intermedi per la preparazione dei composti di formula generale (I) nonch? di fornire un processo migliorato per la preparazione di composti recanti sia un anello tiadiazolico che pirazolico in elevate rese e purezze, facente uso di reagenti non tossici e condizioni di reazione blande. AND? then felt the need? to provide new intermediates for the preparation of compounds of general formula (I) as well as? to provide an improved process for the preparation of compounds bearing both a thiadiazole and pyrazole ring in high yields and purities, using non-toxic reagents and mild reaction conditions.
DESCRIZIONE DESCRIPTION
La richiedente ha ora sorprendentemente trovato che ? possibile ottenere i composti di formula generale (I) Has the applicant now surprisingly found that? it is possible to obtain the compounds of general formula (I)
a partire da composti di formula generale (IV) starting from compounds of general formula (IV)
con elevate rese e purezze. Risultati particolarmente vantaggiosi si raggiungono quando i composti di formula generale (IV) sono ottenuti facendo reagire un?idrazina monosostituita di formula generale R2NH-NH2 o un suo sale fisiologicamente accettabile ed un beta-chetoestere di formula generale (II) with high yields and purities. Particularly advantageous results are achieved when the compounds of general formula (IV) are obtained by reacting a monosubstituted hydrazine of general formula R2NH-NH2 or its physiologically acceptable salt and a beta-ketoester of general formula (II)
in cui R1, R2, R4 e R5 hanno i significati sotto riportati. in which R1, R2, R4 and R5 have the meanings reported below.
Costituiscono pertanto un primo oggetto della presente invenzione i composti di formula generale (IV) Therefore, the compounds of general formula (IV) constitute a first object of the present invention
in cui: in which:
- R1 rappresenta un gruppo alchilico C1-C4, un gruppo aloalchilico C1-C4, un gruppo cicloalchilico C3-C6, un gruppo cicloalchilalchilico C4-C7, un gruppo arilico C6-C10 o un gruppo arilalchilico C7-C12, tutti questi gruppi opzionalmente sostituiti da uno o pi? gruppi scelti tra atomi di alogeno, un gruppo alchilico C1-C4, un gruppo aloalchilico C1-C4, un gruppo alcossilico C1-C4, un gruppo aloalcossilico C1-C4, un gruppo cicloalcossilico C1-C4, un gruppo alchilsulfinilico C1-C4, un gruppo alchilsulfonilico C1-C4, un gruppo arilsulfonilico C6-C10, un gruppo NO2, un gruppo CN, un gruppo NH2, un gruppo alchilammino C1-C4, un gruppo alcossicarbonilico C2-C5, un gruppo ammidico, un gruppo benzilossicarbonilico o un gruppo fenossicarbonilico; - R2 rappresenta un gruppo alchilico C1-C4, un gruppo cicloalchilico C3-C6, un gruppo cicloalchilalchilico C4-C7, un gruppo arilico C6-C10 o un gruppo arilalchilico C7-C12, tutti questi gruppi opzionalmente sostituiti da uno o pi? atomi di alogeno; - R1 represents a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C3-C6 cycloalkyl group, a C4-C7 cycloalkylalkyl group, a C6-C10 aryl group or a C7-C12 arylalkyl group, all of these optionally substituted groups from one or more? groups selected from halogen atoms, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxyl group, a C1-C4 haloalkoxyl group, a C1-C4 cycloalkoxyl group, a C1-C4 alkylsulfinyl group, a C1-C4 alkylsulfonyl group, C6-C10 arylsulfonyl group, NO2 group, CN group, NH2 group, C1-C4 alkylamino group, C2-C5 alkoxycarbonyl group, amide group, benzyloxycarbonyl group, or phenoxycarbonyl group ; - R2 represents a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a C4-C7 cycloalkylalkyl group, a C6-C10 aryl group or a C7-C12 arylalkyl group, all of these groups optionally replaced by one or more? halogen atoms;
- R5 rappresenta un atomo di idrogeno oppure un radicale tiadiazolo di formula generale (III) - R5 represents a hydrogen atom or a thiadiazole radical of general formula (III)
in cui R rappresenta un atomo di idrogeno, un gruppo alchilico C1-C4, un gruppo cicloalchilico C3-C6 o un gruppo cicloalchilalchilico C4-C7, tutti questi gruppi opzionalmente sostituiti da uno o pi? atomi di alogeno. wherein R represents a hydrogen atom, a C1-C4 alkyl group, a C3-C6 cycloalkyl group or a C4-C7 cycloalkylalkyl group, all of these groups optionally replaced by one or more? halogen atoms.
Esempi di gruppo alchilico C1-C4 sono metile, etile, propile, butile. Examples of C1-C4 alkyl group are methyl, ethyl, propyl, butyl.
Esempi di gruppo aloalchilico C1-C4 sono diclorometile, difluorometile, triclorometile, trifluorometile, clorodifluorometile, dicloroetile, trifluoroetile, tetrafluoroetile, pentafluoroetile, tetrafluoroetile, pentafluoroetile, tetrafluoropropile, pentafluoropropile, diclorobutile, difluorobutile. Examples of the C1-C4 haloalkyl group are dichloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, chlorodifluoromethyl, dichloroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, tetrafluoroethyl, pentafluoroethyl, tetrafluoroethyl, dichloroethyl, pentafluoroethyl, tetrafutyl, difluoropluoroethyl.
Esempi di gruppo cicloalchilico C3-C6 sono ciclopropile, ciclobutile, ciclopentile, cicloesile. Examples of C3-C6 cycloalkyl group are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
Esempi di gruppo cicloalchilalchilico C4-C7 sono ciclopropilmetile, ciclobutilmetile, ciclopentilmetile, ciclobutilmetile. Examples of C4-C7 cycloalkylalkyl group are cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclobutylmethyl.
Esempi di gruppo arilico C6-C10 sono fenile, naftile. Examples of C6-C10 aryl group are phenyl, naphthyl.
Esempi di gruppo arilalchilico C7-C12 sono benzile, feniletile, fenilpropile, fenilbutile, fenilpentile, fenilesile, naftil-metile, naftiletile. Examples of C7-C12 arylalkyl group are benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, naphthyl-methyl, naphthylethyl.
Esempi di alogeno sono fluoro, cloro, bromo, iodio. Examples of halogen are fluorine, chlorine, bromine, iodine.
Tra i composti di formula generale (I) che possono essere preparati a partire dai composti intermedi di formula generale (IV) della presente invenzione, sono preferiti quelli in cui: Among the compounds of general formula (I) which can be prepared starting from the intermediate compounds of general formula (IV) of the present invention, those in which:
- R rappresenta metile, etile, propile, isopropile, ciclopropile, ciclopropilmetile o trifluorometile; - R represents methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl or trifluoromethyl;
- R1 rappresenta metile, etile, propile, isopropile, ciclopropile, ciclopropilmetile, difluorometile, trifluorometile, metossimetile, arile o benzile; - R2 rappresenta metile, etile, ciclopropile, ciclopropilmetile, arile o benzile; - R3 rappresenta metile, etile, isopropile, difluorometile, trifluorometile, 2,2,2-trifluoroetile, 1,1-2,2-tetrafluoroetile, 1,1,1-2,2,2-esafluoroetile, 1,1,1-trifluoropropile, metansolfonico, p-toluensolfonico, trifluorometansolfonico, arile o benzile. - R1 represents methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, difluoromethyl, trifluoromethyl, methoxymethyl, aryl or benzyl; - R2 represents methyl, ethyl, cyclopropyl, cyclopropylmethyl, aryl or benzyl; - R3 represents methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1,1-2,2-tetrafluoroethyl, 1,1,1-2,2,2-hexafluoroethyl, 1,1,1 -trifluoropropyl, methanesulfonic, p-toluenesulfonic, trifluoromethanesulfonic, aryl or benzyl.
I suddetti composti preferiti di formula generale (I) sono ottenuti a partire da composti di formula generale (IV) in cui: The above preferred compounds of general formula (I) are obtained starting from compounds of general formula (IV) in which:
- R5 ? H oppure un gruppo tiadiazolico di formula generale (III) in cui R ? scelto fra: metile, etile, propile, isopropile, ciclopropile, ciclopropilmetile e trifluorometile; - R5? H or a thiadiazole group of general formula (III) in which R? selected from: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl and trifluoromethyl;
- R1 ? scelto fra: metile, etile, propile, isopropile, ciclopropile, ciclopropilmetile, difluorometile, trifluorometile, metossimetile, arile e benzile; - R2 ? scelto fra: metile, etile, ciclopropile, ciclopropilmetile, arile, benzile. Particolarmente preferiti sono i composti di formula generale (I) in cui: - R1? selected from: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethyl, difluoromethyl, trifluoromethyl, methoxymethyl, aryl and benzyl; - R2? selected from: methyl, ethyl, cyclopropyl, cyclopropylmethyl, aryl, benzyl. Particularly preferred are the compounds of general formula (I) in which:
- R rappresenta metile o etile; - R represents methyl or ethyl;
- R1 rappresenta difluorometile o trifluorometile; - R1 represents difluoromethyl or trifluoromethyl;
- R2 rappresenta metile; - R2 represents methyl;
- R3 rappresenta etile, difluorometile o 2,2,2-trifluoroetile. - R3 represents ethyl, difluoromethyl or 2,2,2-trifluoroethyl.
Questi ultimi composti pi? preferiti di formula generale (I) sono ottenuti a partire da composti di formula generale (IV) in cui: The latter compounds pi? favorites of general formula (I) are obtained starting from compounds of general formula (IV) in which:
- R5 ? H oppure un gruppo tiadiazolico di formula generale (III) in cui R ? scelto fra: metile ed etile; - R5? H or a thiadiazole group of general formula (III) in which R? selected from: methyl and ethyl;
- R1 ? scelto fra: difluorometile e trifluorometile; - R1? selected from: difluoromethyl and trifluoromethyl;
- R2 rappresenta metile. - R2 represents methyl.
In accordo con un altro aspetto, la presente invenzione concerne un processo per la preparazione dei composti di formula generale (IV) che comprende una reazione di ciclizzazione tra un?idrazina monosostituita di formula generale R2NH-NH2 o un suo sale fisiologicamente accettabile ed un beta-chetoestere di formula generale (II), in ambiente acido, per dare il composto di formula generale (IV), come riportato nello schema 4, dove R1, R2 e R5 hanno i significati sopra definiti e R4 rappresenta un gruppo alchilico C1-C4, opzionalmente sostituito da uno o pi? atomi di alogeno. In accordance with another aspect, the present invention relates to a process for the preparation of compounds of general formula (IV) which comprises a cyclization reaction between a monosubstituted hydrazine of general formula R2NH-NH2 or a physiologically acceptable salt thereof and a beta -ketoester of general formula (II), in an acid medium, to give the compound of general formula (IV), as reported in scheme 4, where R1, R2 and R5 have the meanings defined above and R4 represents a C1-C4 alkyl group , optionally replaced by one or more? halogen atoms.
Schema 4 Scheme 4
L?ambiente acido che permette la formazione del composto di formula generale (IV) pu? essere ottenuto mediante aggiunta di un acido organico od inorganico, oppure mediante l?impiego di un?idrazina monosostituita salificata con un acido organico od inorganico. The acidic environment that allows the formation of the compound of general formula (IV) can? be obtained by adding an organic or inorganic acid, or by using a monosubstituted hydrazine salified with an organic or inorganic acid.
Detta idrazina pu? essere disponibile in commercio oppure pu? essere preparata secondo metodiche riportate in letteratura. Said hydrazine can? be commercially available or can? be prepared according to methods reported in the literature.
Secondo una forma di realizzazione preferita, l?idrazina monosostituita di formula generale R2NH-NH2 viene impiegata in forma non salificata e sciolta in almeno un solvente organico polare, pi? preferibilmente in un solvente alcolico scelto tra metanolo, etanolo, propanolo, butanolo, o loro miscele. According to a preferred embodiment, the monosubstituted hydrazine of general formula R2NH-NH2 is used in an unsalified form and dissolved in at least one polar organic solvent, plus? preferably in an alcoholic solvent selected from methanol, ethanol, propanol, butanol, or their mixtures.
La miscela di reazione cos? formata viene portata ad una temperatura compresa tra -10?C e temperatura ambiente, preferibilmente compresa tra 0?C e 10?C, alla quale si aggiunge il beta-chetoestere di formula generale (II). The reaction mixture so? formed is brought to a temperature between -10 ° C and room temperature, preferably between 0 ° C and 10 ° C, to which the beta-ketoester of general formula (II) is added.
Il beta-chetoestere di formula generale (II) pu? essere disponibile in commercio, oppure viene preparato mediante tecniche note all?esperto del settore. The beta-ketoester of general formula (II) can? be commercially available, or is prepared by means of techniques known to those skilled in the art.
Preferibilmente, il beta-chetoestere di formula generale (II) viene aggiunto alla suddetta miscela di reazione in un rapporto molare compreso tra 0,6 e 2, pi? preferibilmente tra 0,8 e 1,5, ancora pi? preferibilmente di circa 1 rispetto alla quantit? di idrazina. Preferably, the beta-ketoester of general formula (II) is added to the aforementioned reaction mixture in a molar ratio comprised between 0.6 and 2, plus. preferably between 0.8 and 1.5, even more? preferably of about 1 with respect to the quantity? of hydrazine.
Preferibilmente, si lascia reagire per un periodo di tempo compreso tra 1 ora e 2 ore a temperatura ambiente, e si aggiunge almeno un acido organico od inorganico. Preferably, it is left to react for a period of time comprised between 1 hour and 2 hours at room temperature, and at least one organic or inorganic acid is added.
Acidi adatti allo scopo della presente invenzione sono ad esempio HCl, HBr, H2SO4, CF3COOH, CH3SO3H, CF3SO3H, acido p-toluensolfonico, pi? preferibilmente HCl, HBr e H2SO4. Acids suitable for the purpose of the present invention are for example HCl, HBr, H2SO4, CF3COOH, CH3SO3H, CF3SO3H, p-toluenesulfonic acid, pi? preferably HCl, HBr and H2SO4.
Detto acido viene preferibilmente aggiunto in un rapporto molare compreso tra 0,7 e 1,5, pi? preferibilmente di circa 1 rispetto alla quantit? di beta-chetoestere di formula generale (II). Said acid is preferably added in a molar ratio comprised between 0.7 and 1.5, plus. preferably of about 1 with respect to the quantity? of beta-ketoester of general formula (II).
La miscela di reazione viene successivamente portata ad una temperatura compresa tra temperatura ambiente e temperatura di ebollizione del solvente, preferibilmente ad una temperatura compresa tra 60?C e 120?C. The reaction mixture is subsequently brought to a temperature comprised between room temperature and the boiling temperature of the solvent, preferably at a temperature comprised between 60 ° C and 120 ° C.
A completamento della reazione, il composto di formula generale (IV) pu? essere isolato e purificato secondo metodologie ben note all?esperto del settore. Ad esempio, la miscela di reazione pu? essere concentrata sotto vuoto, diluita con acqua, ed estratta con un solvente immiscibile con l?acqua. Il composto di formula generale (IV) pu? essere successivamente recuperato per evaporazione del solvente organico e purificato mediante tecniche classiche, quali ad esempio cristallizzazione, precipitazione o cromatografia. Upon completion of the reaction, the compound of general formula (IV) can? be isolated and purified according to methods well known to the expert in the field. For example, the reaction mixture can? be concentrated under vacuum, diluted with water, and extracted with a solvent immiscible with water. The compound of general formula (IV) can? be subsequently recovered by evaporation of the organic solvent and purified by classical techniques, such as for example crystallization, precipitation or chromatography.
Preferibilmente, il suddetto composto di formula generale (IV) non viene sottoposto ad ulteriori purificazioni e viene utilizzato tal quale nei successivi passaggi sintetici. Preferably, the aforesaid compound of general formula (IV) is not subjected to further purifications and is used as it is in the subsequent synthetic steps.
La Richiedente ha scoperto che, quando la reazione di ciclizzazione ? condotta come sopra descritto, ovvero in presenza di specifici reagenti e condizioni sperimentali, ? possibile ottenere direttamente, senza dover ricorrere ad ulteriori purificazioni, il composto di formula generale (IV) in rese e purezze significativamente pi? elevate rispetto ai derivati tiadiazolici descritti nell?arte. Di conseguenza, tali condizioni consentono di preparare anche i composti di formula generale (I) con elevate rese e purezze. The Applicant has found that when the cyclization reaction? conducted as described above, or in the presence of specific reagents and experimental conditions,? It is possible to obtain directly, without having to resort to further purifications, the compound of general formula (IV) in significantly higher yields and purities? high compared to the thiadiazole derivatives described in the art. Consequently, these conditions allow to prepare also the compounds of general formula (I) with high yields and purities.
Pertanto, un ulteriore oggetto della presente invenzione ? l?uso dei composti di formula generale (IV) Therefore, a further object of the present invention? the use of compounds of general formula (IV)
in cui R1, R2 e R5 hanno i significati di cui sopra, where R1, R2 and R5 have the above meanings,
come intermedi nella preparazione dei composti di formula generale (I). as intermediates in the preparation of compounds of general formula (I).
Secondo un aspetto particolarmente preferito, vengono utilizzati i composti di formula generale (IVa) e (IVb), come intermedi nella preparazione dei composti di formula generale (I) According to a particularly preferred aspect, the compounds of general formula (IVa) and (IVb) are used, as intermediates in the preparation of the compounds of general formula (I)
Tali composti corrispondono ai composti di formula generale (IV), in cui R5 assume il significato di, rispettivamente, un atomo di idrogeno oppure un tiadiazolo sostituito di formula generale (III) come sopra menzionato. These compounds correspond to the compounds of general formula (IV), in which R5 assumes the meaning of, respectively, a hydrogen atom or a substituted thiadiazole of general formula (III) as mentioned above.
In accordo con un ulteriore aspetto, la presente invenzione riguarda pertanto un processo per la preparazione dei composti di formula generale (I) a partire dai composti intermedi di formula generale (IV) secondo lo Schema 5 seguente. In accordo con tale schema di reazione, il composto intermedio di partenza ? il composto di formula generale (IVa) corrispondente al composto di formula generale (IV) in cui R5 ? idrogeno. In accordance with a further aspect, the present invention therefore relates to a process for the preparation of compounds of general formula (I) starting from intermediate compounds of general formula (IV) according to the following Scheme 5. According to this reaction scheme, the starting intermediate compound? the compound of general formula (IVa) corresponding to the compound of general formula (IV) wherein R5? hydrogen.
Schema 5 Scheme 5
In accordo con lo Schema 5, il composto di formula generale (IVa) viene trattato con un reagente di aloformilazione per dare il composto di formula generale (V) In accordance with Scheme 5, the compound of general formula (IVa) is treated with a haloformylation reagent to give the compound of general formula (V)
Tale reazione, nota come aloformilazione di Vilsmeier-Haack, viene condotta in almeno un solvente organico polare, preferibilmente in un solvente organico polare scelto tra dimetilformammide, xilene, dimetilsolfossido o loro miscele, pi? preferibilmente in dimetilformammide. This reaction, known as Vilsmeier-Haack haloformylation, is carried out in at least one polar organic solvent, preferably in a polar organic solvent selected from dimethylformamide, xylene, dimethylsulfoxide or their mixtures, plus? preferably in dimethylformamide.
Ad una temperatura compresa tra 0?C e 10?C, si prepara il reagente di Vilsmeier sciogliendo nel suddetto solvente polare almeno un composto di formula generale POX3, in cui X ? un atomo di cloro o un atomo di bromo. Si lascia preferibilmente rinvenire la miscela a temperatura ambiente, e si aggiunge il composto di formula generale (IVa). At a temperature between 0 ° C and 10 ° C, the Vilsmeier reagent is prepared by dissolving in the aforementioned polar solvent at least one compound of general formula POX3, in which X? a chlorine atom or a bromine atom. The mixture is preferably left to temper at room temperature, and the compound of general formula (IVa) is added.
Secondo la presente invenzione, il rapporto molare tra la quantit? di reagente di aloformilazione di formula generale POX3 e la quantit? di composto di formula generale (IVa) ? compreso tra 2 e 20, preferibilmente tra 4 e 10, pi? preferibilmente di circa 6. According to the present invention, the molar ratio between the quantity? of haloformylation reagent of general formula POX3 and the quantity? of compound of general formula (IVa)? between 2 and 20, preferably between 4 and 10, plus? preferably about 6.
Secondo una forma di realizzazione dell?invenzione, l?atomo di alogeno X presente nel composto di formula generale (V) pu? essere sostituito in modo da introdurre diversi gruppi funzionali sull?anello pirazolico, secondo metodiche ben note nell?arte. According to an embodiment of the invention, the halogen atom X present in the compound of general formula (V) can? be substituted in order to introduce different functional groups on the pyrazole ring, according to methods well known in the art.
Ad esempio, detto composto pu? essere sottoposto a nitrazione, come descritto nella domanda di brevetto US2013/324547, oppure a fluorurazione come riportato in US2004/259734. For example, said compound pu? be subjected to nitration, as described in patent application US2013 / 324547, or to fluorination as reported in US2004 / 259734.
Preferibilmente, l?atomo di alogeno X viene sostituito attraverso una reazione di sostituzione nucleofila con un gruppo R? per dare il composto di formula generale (VI) e il carbonile in posizione 4 del pirazolo viene successivamente ridotto ad alcol, fornendo il composto di formula generale (VII) Preferably, the halogen atom X is replaced through a nucleophilic substitution reaction with an R? Group? to give the compound of general formula (VI) and the carbonyl in position 4 of the pyrazole is subsequently reduced to alcohol, giving the compound of general formula (VII)
in cui R? rappresenta un atomo di fluoro, un gruppo nitro, un gruppo metansolfonico, un gruppo para-toluensolfonico, un gruppo trifluorometansolfonico. where R? represents a fluorine atom, a nitro group, a methanesulfonic group, a para-toluenesulfonic group, a trifluoromethanesulfonic group.
Secondo un?altra forma di realizzazione, il composto di formula generale (V) pu? essere sottoposto direttamente ad una reazione di riduzione, per portare alla formazione del composto di formula generale (VII), in cui R? assume gli stessi significati di X, ovvero rappresenta un atomo di cloro o di bromo. According to another embodiment, the compound of general formula (V) can? be subjected directly to a reduction reaction, to lead to the formation of the compound of general formula (VII), in which R? assumes the same meanings as X, ie it represents a chlorine or bromine atom.
La reazione di riduzione da aldeide ad alcol viene condotta in almeno un solvente organico, preferibilmente in almeno un solvente aprotico, pi? preferibilmente un solvente etereo quale tetraidrofurano, diossano, etere etilico, tert-butil-metiletere o loro miscele. The reduction reaction from aldehyde to alcohol is carried out in at least one organic solvent, preferably in at least one aprotic solvent, plus preferably an ethereal solvent such as tetrahydrofuran, dioxane, ethyl ether, tert-butyl-methyl ether or their mixtures.
A tal fine, ad esempio, si riscalda la miscela di reazione ad una temperatura compresa tra 0?C e 10?C e si aggiunge a porzioni un idruro metallico, preferibilmente un idruro scelto tra sodio boroidruro, calcio boroidruro, litio alluminio idruro, diisobutil alluminio idruro, bis-metossietossi alluminio idruro, pi? preferibilmente sodio boroidruro. To this end, for example, the reaction mixture is heated to a temperature between 0 ° C and 10 ° C and a metal hydride is added in portions, preferably a hydride selected from sodium borohydride, calcium borohydride, lithium aluminum hydride, diisobutyl aluminum hydride, bis-methoxyethoxy aluminum hydride, pi? preferably sodium borohydride.
Secondo la presente invenzione, la conversione completa da aldeide ad alcol avviene introducendo preferibilmente detto idruro in un rapporto molare compreso tra 1 e 1,5, rispetto alla quantit? dell?aldeide di partenza. According to the present invention, the complete conversion from aldehyde to alcohol occurs by preferably introducing said hydride in a molar ratio of between 1 and 1.5, with respect to the quantity? of the starting aldehyde.
In alternativa, il composto di formula generale (VII) pu? essere ottenuto sottoponendo detto composto di formula generale (VI) a una reazione di idrogenazione catalitica in presenza di un catalizzatore metallico quale ad esempio Pd/C, Ni Raney. Alternatively, the compound of general formula (VII) can? be obtained by subjecting said compound of general formula (VI) to a catalytic hydrogenation reaction in the presence of a metal catalyst such as for example Pd / C, Ni Raney.
Detta reazione di idrogenazione catalitica avviene preferibilmente in almeno un solvente organico polare, quale un solvente alcolico come ad esempio metanolo, etanolo oppure in acetato di etile. Said catalytic hydrogenation reaction preferably takes place in at least one polar organic solvent, such as an alcoholic solvent such as methanol, ethanol or in ethyl acetate.
Opzionalmente, i parametri delle suddette reazioni di riduzione, quali temperatura e pressione, possono essere scelti dall?esperto del settore in modo da massimizzare la resa e la purezza del composto desiderato. Optionally, the parameters of the aforesaid reduction reactions, such as temperature and pressure, can be chosen by the expert in the field in order to maximize the yield and purity of the desired compound.
Successivamente, il gruppo idrossilico dell?alcol di formula generale (VII) cos? ottenuto viene sostituito con un gruppo X1 in condizioni ben note all?esperto del settore, per formare il corrispondente composto di formula generale (VIII) Subsequently, the hydroxyl group of the alcohol of general formula (VII) is so? obtained is substituted with a group X1 under conditions well known to those skilled in the art, to form the corresponding compound of general formula (VIII)
in cui: in which:
R1, R2 e R? hanno i significati di cui sopra; R1, R2 and R? have the above meanings;
X1 rappresenta un atomo di cloro, un atomo di bromo, un gruppo alchilsulfonilossilico, un gruppo aloalchilsulfonilossilico, un gruppo arilsulfonilossilico. X1 represents a chlorine atom, a bromine atom, an alkylsulfonyloxy group, a haloalkylsulfonyloxy group, an arylsulfonyloxy group.
Preferibilmente, X1 rappresenta un atomo di cloro, un atomo di bromo, un gruppo metansolfonico, un gruppo para-toluensolfonico, un gruppo trifluorometansolfonico. Preferably, X1 represents a chlorine atom, a bromine atom, a methanesulfonic group, a para-toluenesulfonic group, a trifluoromethanesulfonic group.
Pi? preferibilmente, X1 rappresenta un atomo di cloro, un gruppo metansolfonico, un gruppo para-toluensolfonico. Pi? preferably, X1 represents a chlorine atom, a methanesulfonic group, a para-toluenesulfonic group.
Secondo una forma di realizzazione particolarmente preferita, un reagente alogenante viene aggiunto al composto di formula generale (VII), pi? preferibilmente cloruro di tionile o cloruro di ossalile, per fornire un composto di formula generale (VIII) in cui X1 rappresenta un atomo di cloro. According to a particularly preferred embodiment, a halogenating reagent is added to the compound of general formula (VII), plus? preferably thionyl chloride or oxalyl chloride, to provide a compound of general formula (VIII) in which X1 represents a chlorine atom.
Detta reazione di sostituzione del gruppo OH con il gruppo X1 pu? essere condotta in presenza o in assenza di una base organica od inorganica, in modo da neutralizzare l?acido liberato durante tale reazione. Said substitution reaction of the OH group with the X1 group can? be carried out in the presence or absence of an organic or inorganic base, in order to neutralize the acid released during this reaction.
Preferibilmente, la suddetta reazione di sostituzione viene effettuata in assenza di base. A completamento della stessa, la miscela di reazione viene concentrata sotto vuoto e il composto di formula generale (VIII) viene utilizzato nel passaggio successivo senza ulteriore purificazione. Preferably, the aforementioned substitution reaction is carried out in the absence of base. Upon completion of the same, the reaction mixture is concentrated under vacuum and the compound of general formula (VIII) is used in the next step without further purification.
Secondo la presente invenzione, detto composto di formula generale (VIII) viene poi condensato con un derivato tiadiazolico di formula generale (IX) in presenza di una base organica quale trietilammina, dietilammina, diisopropiletilammina, piridina od inorganica quale carbonato di sodio, carbonato di potassio, tert-butilato di potassio. According to the present invention, said compound of general formula (VIII) is then condensed with a thiadiazole derivative of general formula (IX) in the presence of an organic base such as triethylamine, diethylamine, diisopropylethylamine, pyridine or inorganic such as sodium carbonate, potassium carbonate , potassium tert-butylate.
Una base adatta per la suddetta reazione di condensazione ? una base organica scelta tra trietilammina, dietilammina, diisopropiletilammina, piridina, preferibilmente ? la trietilammina, per dare il composto di formula generale A suitable basis for the aforementioned condensation reaction? an organic base selected from triethylamine, diethylamine, diisopropylethylamine, pyridine, preferably? triethylamine, to give the compound of general formula
in cui R, R1, R2, R? e X1 hanno i significati di cui sopra. where R, R1, R2, R? and X1 have the above meanings.
La reazione di condensazione viene preferibilmente condotta in almeno un solvente organico apolare, pi? preferibilmente in almeno un solvente clorurato, ancora pi? preferibilmente in cloroformio, diclorometano, dicloroetano o loro miscele. The condensation reaction is preferably carried out in at least one non-polar organic solvent, pi? preferably in at least one chlorinated solvent, even more? preferably in chloroform, dichloromethane, dichloroethane or their mixtures.
Il passaggio successivo del processo della presente invenzione prevede di far reagire il composto di formula generale (X) con un reagente di formula generale R3-OH mediante sostituzione nucleofila, per fornire il composto di formula generale (XI) The next step of the process of the present invention provides for the reaction of the compound of general formula (X) with a reagent of general formula R3-OH by means of nucleophilic substitution, to provide the compound of general formula (XI)
in cui R, R1, R2, R3 e R? hanno i significati di cui sopra. where R, R1, R2, R3 and R? have the above meanings.
Preferibilmente, il reagente di formula R3-OH viene sciolto in almeno un solvente organico, pi? preferibilmente in almeno un solvente polare aprotico, ancora pi? preferibilmente in N-metilpirrolidone, N,N-dimetilformammide, N,N-dimetilacetammide o loro miscele. Preferably, the reagent of formula R3-OH is dissolved in at least one organic solvent, plus? preferably in at least one aprotic polar solvent, even more? preferably in N-methylpyrrolidone, N, N-dimethylformamide, N, N-dimethylacetamide or their mixtures.
Alla suddetta miscela di reazione, si aggiunge una base inorganica, preferibilmente un idruro di un metallo alcalino, pi? preferibilmente sodio idruro, mantenendo una temperatura compresa tra 0?C e 10?C. To the aforesaid reaction mixture, an inorganic base is added, preferably a hydride of an alkali metal, plus? preferably sodium hydride, maintaining a temperature between 0 ° C and 10 ° C.
Secondo la presente invenzione, il composto di formula generale (X) viene quindi introdotto nella miscela solvente-base cos? formata, in un rapporto molare rispetto alla quantit? di reagente alchilante compreso tra 0,5 e 1,5, preferibilmente compreso tra 0,8 e 1,1. According to the present invention, the compound of general formula (X) is then introduced into the solvent-base mixture so? formed, in a molar ratio with respect to the quantity? of alkylating reagent between 0.5 and 1.5, preferably between 0.8 and 1.1.
Si riscalda quindi la miscela di reazione ad una temperatura compresa tra temperatura ambiente e temperatura di ebollizione del solvente, preferibilmente ad una temperatura compresa tra 40?C e 100?C, pi? preferibilmente di circa 80?C. The reaction mixture is then heated to a temperature between room temperature and the boiling temperature of the solvent, preferably at a temperature between 40 ° C and 100 ° C, plus? preferably about 80 ° C.
Una volta completata la reazione di sostituzione, si concentra preferibilmente la miscela sotto vuoto e si utilizza direttamente il composto di formula generale (XI) nel passaggio successivo. Once the substitution reaction is completed, the mixture is preferably concentrated under vacuum and the compound of general formula (XI) is used directly in the next step.
I composti di formula generale (I) desiderati vengono preparati mediante ossidazione dei composti di formula generale (XI) The desired compounds of general formula (I) are prepared by oxidation of the compounds of general formula (XI)
in cui R, R1, R2, R3 hanno i significati di cui sopra; wherein R, R1, R2, R3 have the above meanings;
n ? un numero intero compreso tra 1 e 2. n? an integer between 1 and 2.
Il composto di formula generale (XI) viene sciolto in almeno un solvente organico apolare, preferibilmente in almeno un solvente clorurato, pi? preferibilmente in cloroformio, diclorometano, dicloroetano o loro miscele, mantenendo la temperatura della miscela tra 0?C e 10?C. The compound of general formula (XI) is dissolved in at least one non-polar organic solvent, preferably in at least one chlorinated solvent, plus preferably in chloroform, dichloromethane, dichloroethane or their mixtures, keeping the temperature of the mixture between 0 ° C and 10 ° C.
Secondo la presente invenzione, si aggiunge un agente ossidante scelto tra un perossido organico quale acido meta-cloroperbenzoico, acido peracetico, dibenzoil perossido oppure un perossido inorganico quale perossido di idrogeno, perossido di calcio, perossido di sodio, preferibilmente acido metacloroperbenzoico. According to the present invention, an oxidizing agent selected from an organic peroxide such as meta-chloroperbenzoic acid, peracetic acid, dibenzoyl peroxide or an inorganic peroxide such as hydrogen peroxide, calcium peroxide, sodium peroxide, preferably metachloroperbenzoic acid, is added.
Detto agente ossidante viene introdotto nella miscela di reazione in un rapporto molare rispetto alla quantit? di composto di formula generale (XI) compreso tra 0,7 e 3, preferibilmente tra 0,8 e 2,5. Said oxidizing agent is introduced into the reaction mixture in a molar ratio with respect to the quantity. of compound of general formula (XI) comprised between 0.7 and 3, preferably between 0.8 and 2.5.
Una volta completata la reazione, i composti desiderati possono essere isolati e purificati secondo metodologie ben note all?esperto del settore. Ad esempio, la miscela di reazione pu? essere concentrata sotto vuoto, diluita con acqua, ed estratta con un solvente immiscibile con l?acqua. I composti di formula generale (I) possono essere successivamente recuperati per evaporazione del solvente organico e purificato mediante tecniche classiche, quali ad esempio cristallizzazione, precipitazione o cromatografia. Once the reaction is completed, the desired compounds can be isolated and purified according to methods well known to those skilled in the art. For example, the reaction mixture can? be concentrated under vacuum, diluted with water, and extracted with a solvent immiscible with water. The compounds of general formula (I) can be subsequently recovered by evaporation of the organic solvent and purified by classical techniques, such as for example crystallization, precipitation or chromatography.
In una forma di realizzazione preferita, il composto di formula generale (IV) in cui R5 ? idrogeno (corrispondente al composto di formula generale IVa dello Schema 5) ? ottenuto tramite una reazione di ciclizzazione tra un?idrazina monosostituita di formula generale R2NH-NH2 o un suo sale fisiologicamente accettabile ed un beta-chetoestere di formula generale (II) in ambiente acido, per dare il composto di formula generale (IV) In a preferred embodiment, the compound of general formula (IV) in which R5? hydrogen (corresponding to the compound of general formula IVa of Scheme 5)? obtained through a cyclization reaction between a monosubstituted hydrazine of general formula R2NH-NH2 or a physiologically acceptable salt thereof and a beta-ketoester of general formula (II) in an acid environment, to give the compound of general formula (IV)
in cui R1, R2 e R4 hanno i significati di cui sopra; wherein R1, R2 and R4 have the above meanings;
R5 rappresenta un atomo di idrogeno. R5 represents a hydrogen atom.
La reazione di ciclizzazione ? pertanto la seguente: The cyclization reaction? therefore the following:
Come indicato in precedenza, l?uso di un intermedio di formula generale (IV) ottenuto mediante la suddetta reazione di ciclizzazione permette di ottenere il corrispondente composto di formula generale (I) con elevate rese e purezze. As previously indicated, the use of an intermediate of general formula (IV) obtained by means of the aforesaid cyclization reaction allows to obtain the corresponding compound of general formula (I) with high yields and purities.
Secondo un ulteriore aspetto, la presente invenzione riguarda un processo per la preparazione dei composti di formula generale (I) secondo lo Schema 6. In accordo con tale schema di reazione, il composto intermedio di partenza ? il composto di formula generale (XII) corrispondente al composto di formula generale (IV) in cui R5 ? un radicale tiadiazolo di formula generale (III) According to a further aspect, the present invention relates to a process for the preparation of compounds of general formula (I) according to Scheme 6. According to this reaction scheme, the starting intermediate compound? the compound of general formula (XII) corresponding to the compound of general formula (IV) wherein R5? a thiadiazole radical of general formula (III)
in cui R rappresenta un atomo di idrogeno, un gruppo alchilico C1-C4, un gruppo cicloalchilico C3-C6 o un gruppo cicloalchilalchilico C4-C7, tutti questi gruppi opzionalmente sostituiti da uno o pi? atomi di alogeno.. wherein R represents a hydrogen atom, a C1-C4 alkyl group, a C3-C6 cycloalkyl group or a C4-C7 cycloalkylalkyl group, all of these groups optionally replaced by one or more? halogen atoms ..
In accordo con lo Schema 6, il gruppo idrossilico del composto di formula generale (XII) viene alchilato con un gruppo R3, mediante reazione con un reagente alchilante di formula generale R3-X, in cui R3 ha il significato di cui sopra e X rappresenta un gruppo uscente, quale un alogeno, un gruppo metansolfonico, un gruppo para-toluensolfonico o un gruppo trifluorometansolfonico. In accordance with Scheme 6, the hydroxyl group of the compound of general formula (XII) is alkylated with a group R3, by reaction with an alkylating reagent of general formula R3-X, in which R3 has the above meaning and X represents a leaving group, such as a halogen, a methanesulfonic group, a para-toluenesulfonic group or a trifluoromethanesulfonic group.
Tale reazione di alchilazione viene condotta in almeno un solvente organico polare, pi? preferibilmente in almeno un solvente polare aprotico, ancora pi? preferibilmente in N,N-dimetilformammide, N-metilpirrolidone o loro miscele. Alla miscela contenente il solvente e l?agente alchilante, si aggiunge una base organica od inorganica, preferibilmente una base inorganica scelta tra un idrossido di metalli alcalini o un carbonato di metalli alcalini, pi? preferibilmente un carbonato di metalli alcalini, quale carbonato di sodio o carbonato di potassio. This alkylation reaction is carried out in at least one polar organic solvent, plus? preferably in at least one aprotic polar solvent, even more? preferably in N, N-dimethylformamide, N-methylpyrrolidone or their mixtures. To the mixture containing the solvent and the alkylating agent, an organic or inorganic base is added, preferably an inorganic base chosen from an alkali metal hydroxide or an alkali metal carbonate, plus an inorganic base. preferably an alkali metal carbonate, such as sodium carbonate or potassium carbonate.
Si riscalda quindi la miscela di reazione ad una temperatura compresa tra temperatura ambiente e temperatura di ebollizione del solvente, preferibilmente ad una temperatura compresa tra 40?C e 100?C, pi? preferibilmente di circa 80?C. The reaction mixture is then heated to a temperature between room temperature and the boiling temperature of the solvent, preferably at a temperature between 40 ° C and 100 ° C, plus? preferably about 80 ° C.
Secondo la presente invenzione, il composto di formula generale (XI) cos? ottenuto viene quindi sottoposto ad una reazione di ossidazione per fornire i composti di formula generale (I) desiderati. According to the present invention, the compound of general formula (XI) cos? obtained is then subjected to an oxidation reaction to provide the desired compounds of general formula (I).
A tale scopo, si aggiunge a detto composto di formula generale (XI) un agente ossidante scelto tra un perossido organico quale acido meta-cloroperbenzoico, acido peracetico, dibenzoil perossido oppure un perossido inorganico quale perossido di idrogeno, perossido di calcio, perossido di sodio, preferibilmente acido meta-cloroperbenzoico. For this purpose, an oxidizing agent selected from an organic peroxide such as meta-chloroperbenzoic acid, peracetic acid, dibenzoyl peroxide or an inorganic peroxide such as hydrogen peroxide, calcium peroxide, sodium peroxide is added to said compound of general formula (XI). , preferably meta-chloroperbenzoic acid.
Detto agente ossidante viene introdotto nella miscela di reazione in un rapporto molare rispetto alla quantit? di composto di formula generale (XI) compreso tra 0,7 e 3, preferibilmente tra 0,8 e 2,5. Said oxidizing agent is introduced into the reaction mixture in a molar ratio with respect to the quantity. of compound of general formula (XI) comprised between 0.7 and 3, preferably between 0.8 and 2.5.
Come apparir? chiaro all?esperto del settore, nella reazione di ossidazione riportata negli Schemi 5 e 6, un rapporto molare tra detto agente ossidante e detto composto di formula generale (XI) compreso tra 0,7 e 1,5 porta alla formazione di un composto di formula generale (I), in cui n ? pari a 1. Analogamente, un rapporto molare tra detto agente ossidante e detto composto di formula generale (XI) compreso tra 1,5 e 3 porta alla formazione di un composto di formula generale (I), in cui n ? pari a 2. How will it appear? clear to the skilled in the art, in the oxidation reaction reported in Schemes 5 and 6, a molar ratio between said oxidizing agent and said compound of general formula (XI) between 0.7 and 1.5 leads to the formation of a compound of general formula (I), in which n? equal to 1. Similarly, a molar ratio between said oxidizing agent and said compound of general formula (XI) of between 1.5 and 3 leads to the formation of a compound of general formula (I), in which n? equal to 2.
Con il processo secondo invenzione gli Schemi 5 e 6, i solfossidi di formula generale (I), ovvero i composti di formula generale (I) in cui n ? pari a 1, vengono preferibilmente ottenuti in forma racemica. With the process according to the invention, Schemes 5 and 6, the sulfoxides of general formula (I), or the compounds of general formula (I) in which n? equal to 1, they are preferably obtained in racemic form.
I due isomeri possono essere separati mediante tecniche ben note all?esperto del settore, quale ad esempio risoluzione chirale, cromatografia chirale, distillazione, precipitazione. The two isomers can be separated by techniques well known to those skilled in the art, such as for example chiral resolution, chiral chromatography, distillation, precipitation.
In alternativa, tali isomeri possono essere ottenuti mediante reazioni enantioselettive, ad esempio mediante ossidazione enantioselettiva da solfuro a solfossido (come riportato in Chem. Comm. 2008, pp. 1704-1706, o in Angew. Chem. 2007, vol. 46, pp. 4729-4731), oppure per riduzione del solfone a solfossido. Alternatively, these isomers can be obtained by enantioselective reactions, for example by enantioselective oxidation from sulphide to sulfoxide (as reported in Chem. Comm. 2008, pp. 1704-1706, or in Angew. Chem. 2007, vol. 46, pp. . 4729-4731), or by reduction of the sulfone to sulfoxide.
In una forma di realizzazione preferita, il composto di formula generale (IV) in cui R5 ? un gruppo tiadiazolico di formula generale (III) (corrispondente al composto di formula generale (XII) dello Schema 6), ? ottenuto tramite una reazione di ciclizzazione tra un?idrazina monosostituita di formula generale R2NH-NH2 o un suo sale fisiologicamente accettabile ed un beta-chetoestere di formula generale (II) in ambiente acido, per dare il composto di formula generale (IV) In a preferred embodiment, the compound of general formula (IV) in which R5? a thiadiazole group of general formula (III) (corresponding to the compound of general formula (XII) of Scheme 6),? obtained through a cyclization reaction between a monosubstituted hydrazine of general formula R2NH-NH2 or a physiologically acceptable salt thereof and a beta-ketoester of general formula (II) in an acid environment, to give the compound of general formula (IV)
in cui R1, R2 e R4 hanno i significati di cui sopra; wherein R1, R2 and R4 have the above meanings;
R5 rappresenta un tiadiazolo di formula generale (III) R5 represents a thiadiazole of general formula (III)
in cui R rappresenta un atomo di idrogeno, un gruppo alchilico C1-C4, un gruppo cicloalchilico C3-C6 o un gruppo cicloalchilalchilico C4-C7, tutti questi gruppi opzionalmente sostituiti da uno o pi? atomi di alogeno wherein R represents a hydrogen atom, a C1-C4 alkyl group, a C3-C6 cycloalkyl group or a C4-C7 cycloalkylalkyl group, all of these groups optionally replaced by one or more? halogen atoms
La reazione di ciclizzazione ? pertanto la seguente: The cyclization reaction? therefore the following:
Come indicato in precedenza, l?uso di un intermedio di formula generale (IV) ottenuto mediante la suddetta reazione di ciclizzazione permette di ottenere il corrispondente composto di formula generale (I) con elevate rese e purezze. Il beta-chetoestere di formula generale (IIb), non essendo disponibile in commercio, pu? essere preparato secondo le metodologie riportate di seguito. Secondo una forma di realizzazione della presente invenzione, il betachetoestere di formula generale (IIb) pu? essere preparato in due passaggi. Il primo passaggio prevede la condensazione tra un derivato tiadiazolico di formula generale (IX) ed un acrilato di formula generale (XIII), formando un derivato tiadiazolico recante un gruppo estereo di formula generale (XIV). Tale composto viene successivamente acilato con un reagente di formula generale R1C(O)X, in cui R1 ha il significato di cui sopra, X ? un atomo di cloro o di bromo, per fornire il beta-chetoestere di formula generale (IIb) desiderato. As previously indicated, the use of an intermediate of general formula (IV) obtained by means of the aforesaid cyclization reaction allows to obtain the corresponding compound of general formula (I) with high yields and purities. The beta-ketoester of general formula (IIb), not being commercially available, can? be prepared according to the methodologies listed below. According to an embodiment of the present invention, the beta-ketoester of general formula (IIb) can? be prepared in two steps. The first step involves the condensation between a thiadiazole derivative of general formula (IX) and an acrylate of general formula (XIII), forming a thiadiazole derivative bearing an ester group of general formula (XIV). This compound is subsequently acylated with a reagent of general formula R1C (O) X, in which R1 has the above meaning, X? a chlorine or bromine atom, to provide the desired beta-ketoester of general formula (IIb).
Secondo un?altra forma di realizzazione della presente invenzione, il betachetoestere di formula generale (IIb) viene preferibilmente preparato secondo la metodologia riportata in Advanced Synthesis and Catalysis 2009, vol. 351, pp. 3269-3278, ovvero mediante condensazione del beta-chetoestere di formula generale (IIa) con un derivato tiadiazolico di formula generale (IX) in presenza di formaldeide. According to another embodiment of the present invention, the beta-ketoester of general formula (IIb) is preferably prepared according to the methodology reported in Advanced Synthesis and Catalysis 2009, vol. 351, pp. 3269-3278, or by condensation of the beta-ketoester of general formula (IIa) with a thiadiazole derivative of general formula (IX) in the presence of formaldehyde.
in cui R, R1 e R4 hanno i significati di cui sopra. wherein R, R1 and R4 have the above meanings.
Ad una soluzione di beta-chetoestere di formula generale (IIa) in un solvente polare, preferibilmente in acqua, si aggiunge una soluzione diluita di formaldeide in acqua. A dilute solution of formaldehyde in water is added to a solution of beta-ketoester of general formula (IIa) in a polar solvent, preferably in water.
Secondo la presente invenzione, viene utilizzata una soluzione diluita di formaldeide avente una concentrazione preferibilmente compresa tra il 20% e il 50% in acqua. According to the present invention, a dilute solution of formaldehyde is used having a concentration preferably between 20% and 50% in water.
Il rapporto molare della suddetta formaldeide rispetto alla quantit? del suddetto beta-chetoestere di formula generale (IIa) ? preferibilmente compreso tra 0,5 e 1,5, pi? preferibilmente ? di circa 1. The molar ratio of the aforementioned formaldehyde with respect to the quantity? of the above beta-ketoester of general formula (IIa)? preferably comprised between 0.5 and 1.5, plus preferably? about 1.
Alla miscela di reazione cos? formata, viene aggiunto il composto di formula generale (IX) in un rapporto molare compreso tra 0,2 e 0,8, preferibilmente compreso tra 0,4 e 0,6, pi? preferibilmente di circa 0,5, rispetto alla quantit? di beta chetoestere di formula generale (IIa). To the reaction mixture so? formed, the compound of general formula (IX) is added in a molar ratio comprised between 0.2 and 0.8, preferably comprised between 0.4 and 0.6, plus. preferably of about 0.5, with respect to the quantity? of beta ketoester of general formula (IIa).
Successivamente, la reazione viene preferibilmente portata ad una temperatura compresa tra temperatura ambiente e 100?C, pi? preferibilmente compresa tra 40?C e 80?C. Subsequently, the reaction is preferably brought to a temperature comprised between room temperature and 100 ° C, plus? preferably between 40 ° C and 80 ° C.
Vengono ora forniti alcuni esempi che sono da intendersi come descrittivi e non limitativi della presente invenzione. Some examples are now provided which are intended as descriptive and not limitative of the present invention.
PARTE SPERIMENTALE EXPERIMENTAL PART
Esempio 1 Example 1
Preparazione di 2-[(1-metil-3-trifluorometil-5-(2,2,2-trifluoroetossi)-pirazol-4-il)sulfinil]-5-metil-1,3,4-tiadiazolo [Composto (I), R = CH3, R1 = CF3, R2 = CH3, R3 = CH2CF3, n = 1] Preparation of 2 - [(1-methyl-3-trifluoromethyl-5- (2,2,2-trifluoroethoxy) -pyrazol-4-yl) sulfinyl] -5-methyl-1,3,4-thiadiazole [Compound (I ), R = CH3, R1 = CF3, R2 = CH3, R3 = CH2CF3, n = 1]
a) Preparazione di 1-metil-3-(trifluorometil)-1H-pirazol-5-olo [composto di formula generale (IVa)] a) Preparation of 1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-ol [compound of general formula (IVa)]
A una soluzione sotto azoto di 2,9 ml (54,34 mmol) di metilidrazina in 40 ml di etanolo sono stati gocciolati 10g (54,34 mmol) di trifluoroacetoacetato di etile (IIa), mantenendo una temperatura di circa 4-5?C con bagno di ghiaccio; dopo circa 1h30? a temperatura ambiente sono stati aggiunti 2 ml di acido cloridrico concentrato. 10g (54.34 mmol) of ethyl trifluoroacetoacetate (IIa) was dropped into a nitrogen solution of 2.9 ml (54.34 mmol) of methylhydrazine in 40 ml of ethanol, maintaining a temperature of approximately 4-5? C with ice bath; after about 1h30? at room temperature 2 ml of concentrated hydrochloric acid were added.
La miscela ? stata scaldata a riflusso per 13h. The mixture ? was heated under reflux for 13h.
Dopo controllo in GC-MS e LC-MS la miscela ? stata concentrata a pressione ridotta, quindi diluita con acqua; la fase acquosa ? stata estratta tre volte con acetato di etile. Le fasi organiche riunite sono state lavate con acqua e soluzione satura di cloruro di sodio. After checking the mixture in GC-MS and LC-MS? been concentrated under reduced pressure, then diluted with water; the aqueous phase? was extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride solution.
Dopo anidrificazione su solfato di sodio, filtrazione ed evaporazione del solvente a pressione ridotta sono stati ottenuti 8,9g del prodotto desiderato come solido giallo. Il grezzo cos? ottenuto ? stato triturato con esano, filtrato e seccato all?aria, ottenendo 7,8g (46,98 mmol) di prodotto desiderato come solido bianco. Resa 86,5% LC-MS [M+H] = 167. After drying over sodium sulphate, filtration and evaporation of the solvent under reduced pressure, 8.9 g of the desired product as a yellow solid were obtained. The crude cos? obtained ? was triturated with hexane, filtered and air dried, obtaining 7.8g (46.98 mmol) of the desired product as a white solid. Yield 86.5% LC-MS [M + H] = 167.
b) Preparazione di 5-cloro-1-metil-3-(trifluorometil)-1H-pirazolo-4-carbaldeide [composto di formula generale (V)] b) Preparation of 5-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazole-4-carbaldehyde [compound of general formula (V)]
A 7ml (88,54 mmol) di N,N-dimetilformammide sono stati gocciolati 24,3 ml (265,62 mmol) di ossicloruro di fosforo, mantenendo una temperatura di circa 4-5?C con bagno di ghiaccio; sono stati quindi aggiunti 7,35g (44,27 mmol) di 1-metil-3-(trifluorometil)-1H-pirazol-5-olo (IVa) a temperatura ambiente. 24.3 ml (265.62 mmol) of phosphorus oxychloride were dropped to 7ml (88.54 mmol) of N, N-dimethylformamide, maintaining a temperature of about 4-5 ° C with an ice bath; 7.35g (44.27 mmol) of 1-methyl-3- (trifluoromethyl) -1H-pyrazol-5-ol (IVa) were then added at room temperature.
La miscela ? stata scaldata a riflusso per 1h. The mixture ? was heated under reflux for 1 hour.
Dopo controllo in GC-MS e LC-MS la miscela ? stata cautamente versata in acqua e ghiaccio; la fase acquosa ? stata estratta tre volte con cloroformio. Le fasi organiche riunite sono state lavate con soluzione satura di NaHCO3, acqua e soluzione satura di NaCl. After checking the mixture in GC-MS and LC-MS? was carefully poured into ice and water; the aqueous phase? was extracted three times with chloroform. The combined organic phases were washed with saturated solution of NaHCO3, water and saturated solution of NaCl.
Dopo anidrificazione su solfato di sodio, filtrazione ed evaporazione del solvente a pressione ridotta sono stati ottenuti 7,4g del prodotto desiderato (34,9 mmol), come solido marrone. Resa 79,4% After drying over sodium sulphate, filtration and evaporation of the solvent under reduced pressure, 7.4 g of the desired product (34.9 mmol), as a brown solid, were obtained. Yield 79.4%
LC-MS [M+H] = 213. LC-MS [M + H] = 213.
c) Preparazione di 5-fluoro-1-metil-3-(trifluorometil)-1H-pirazolo-4-carbaldeide [composto di formula generale (VI), R? = F] c) Preparation of 5-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazole-4-carbaldehyde [compound of general formula (VI), R? = F]
A una soluzione sotto azoto di 7g (33,02 mmol) di 5-cloro-1-metil-3-(trifluorometil)-1H-pirazolo-4-carbaldeide (V) in 80ml di dimetilsolfossido sono stati aggiunti 4,8g (82,55 mmol) di KF a temperatura ambiente. 4.8g (82 , 55 mmol) of KF at room temperature.
La miscela ? stata scaldata a 120-130?C per 5h. The mixture ? been heated at 120-130 ° C for 5h.
Dopo controllo in GC-MS e LC-MS la miscela ? stata versata in acqua; la fase acquosa ? stata estratta tre volte con acetato di etile. Le fasi organiche riunite sono state lavate con acqua e soluzione satura di NaCl. After checking the mixture in GC-MS and LC-MS? been poured into water; the aqueous phase? was extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated NaCl solution.
Dopo anidrificazione su solfato di sodio, filtrazione ed evaporazione del solvente a pressione ridotta sono stati ottenuti 5,3g del prodotto desiderato (27,04 mmol), come olio marrone. Resa 82% After drying over sodium sulphate, filtration and evaporation of the solvent under reduced pressure, 5.3 g of the desired product (27.04 mmol), as brown oil, were obtained. Yield 82%
LC-MS [M+H] = 197. LC-MS [M + H] = 197.
d) Preparazione di [5-fluoro-1-metil-3-(trifluorometil)-1H-pirazol-4-il]metanolo [composto di formula generale (VII)] d) Preparation of [5-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-4-yl] methanol [compound of general formula (VII)]
A una soluzione sotto azoto di 5g (25,51 mmol) di 5-fluoro-1-metil-3-(trifluorometil)-1H-pirazolo-4-carbaldeide (VI) in 80ml di THF sono stati aggiunti 1,06g (28,06 mmol) di sodio boroidruro a porzioni, mantenendo una temperatura di circa 4-5?C con bagno di ghiaccio. 1.06g (28 , 06 mmol) of sodium borohydride in portions, maintaining a temperature of about 4-5 ° C with an ice bath.
La miscela ? stata lasciata a circa 10?C per 5h. The mixture ? been left at around 10? C for 5h.
Dopo controllo in GC-MS la miscela ? stata concentrata a pressione ridotta e versata in acqua; la fase acquosa ? stata estratta tre volte con acetato di etile. Le fasi organiche riunite sono state lavate con soluzione satura di NaHCO3, acqua e soluzione satura di NaCl. After I check the mixture in GC-MS? was concentrated under reduced pressure and poured into water; the aqueous phase? was extracted three times with ethyl acetate. The combined organic phases were washed with saturated solution of NaHCO3, water and saturated solution of NaCl.
Dopo anidrificazione su solfato di sodio, filtrazione ed evaporazione del solvente a pressione ridotta sono stati ottenuti 4,9g del prodotto desiderato (24,75 mmol), come olio marrone. Resa 97% After drying over sodium sulphate, filtration and evaporation of the solvent under reduced pressure, 4.9 g of the desired product (24.75 mmol), as brown oil, were obtained. Yield 97%
GC-MS [m/z] = 198. GC-MS [m / z] = 198.
e) Preparazione di 5-fluoro-4-(clorometil)-1-metil-3-(trifluorometil)-1H-pirazolo [composto di formula generale (VIII)] e) Preparation of 5-fluoro-4- (chloromethyl) -1-methyl-3- (trifluoromethyl) -1H-pyrazole [compound of general formula (VIII)]
A una soluzione sotto azoto di 4,9g (24,75 mmol) di [5-fluoro-1-metil-3-(trifluorometil)-1H-pirazol-4-il]metanolo (VII) in 85 ml di diclorometano sono stati aggiunti per gocciolamento 2,17 ml (29,70 mmol) di tionilcloruro, a temperatura ambiente. At a solution under nitrogen of 4.9g (24.75 mmol) of [5-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-4-yl] methanol (VII) in 85 ml of dichloromethane were added dropwise 2.17 ml (29.70 mmol) of thionyl chloride, at room temperature.
La miscela ? stata lasciata sotto agitazione magnetica e a temperatura ambiente per 2h. The mixture ? was left under magnetic stirring and at room temperature for 2h.
Dopo controllo in GC-MS la miscela ? stata concentrata a pressione ridotta, azeotropando con toluene per rimuovere il tionilcloruro in eccesso. After I check the mixture in GC-MS? was concentrated under reduced pressure, azeotroping with toluene to remove excess thionyl chloride.
Sono stati ottenuti 5,3g del prodotto desiderato (24,75 mmol), come olio marrone. Resa quantitativa. 5.3g of the desired product (24.75mmol) was obtained, as brown oil. Quantitative yield.
GC-MS [m/z] = 216. GC-MS [m / z] = 216.
f) Preparazione di 2-({[5-fluoro-1-metil-3-(trifluorometil)-1H-pirazol-4-il]metil}tio)-5-metil-1,3,4-tiadiazolo [composto di formula generale (X)] A una sospensione sotto azoto di 3,05 g (23,09 mmol) di 5-metil-1,3,4-tiadiazolo-2-tiolo (IX) in 30 ml di cloroformio sono stati gocciolati 3,20 ml (23,09 mmol) di trietilammina a temperatura ambiente; sono stati quindi aggiunti 5,0 g (23,09 mmol) di 5-fluoro-4-(clorometil)-1-metil-3(trifluorometil)-1H-pirazolo (VIII) sciolti in 10 ml di cloroformio. Infine sono stati gocciolati 4,8 ml (34,64 mmol) di trietilammina. f) Preparation of 2 - ({[5-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-4-yl] methyl} thio) -5-methyl-1,3,4-thiadiazole [compound of general formula (X)] A suspension under nitrogen of 3.05 g (23.09 mmol) of 5-methyl-1,3,4-thiadiazole-2-thiol (IX) in 30 ml of chloroform was dropped 3 20 ml (23.09 mmol) of triethylamine at room temperature; 5.0 g (23.09 mmol) of 5-fluoro-4- (chloromethyl) -1-methyl-3 (trifluoromethyl) -1H-pyrazole (VIII) dissolved in 10 ml of chloroform were then added. Finally, 4.8 ml (34.64 mmol) of triethylamine was dropped.
La miscela ? stata lasciata sotto agitazione magnetica a temperatura ambiente per una notte. The mixture ? was left under magnetic stirring at room temperature overnight.
Dopo controllo in GC-MS e LC-MS la miscela ? stata diluita con acqua e sono state quindi separate le fasi; la fase acquosa ? stata riestratta due volte con diclorometano. Le fasi organiche riunite sono state lavate con acqua e soluzione satura di cloruro di sodio. After checking the mixture in GC-MS and LC-MS? was diluted with water and the phases were then separated; the aqueous phase? was re-extracted twice with dichloromethane. The combined organic phases were washed with water and saturated sodium chloride solution.
Dopo anidrificazione su solfato di sodio, filtrazione ed evaporazione del solvente a pressione ridotta sono stati ottenuti 6,48g del prodotto desiderato (20,78 mmol), come olio marrone. Resa 90% After drying over sodium sulphate, filtration and evaporation of the solvent under reduced pressure, 6.48 g of the desired product (20.78 mmol), as brown oil, were obtained. Yield 90%
LC-MS [M+H] = 313. LC-MS [M + H] = 313.
g) Preparazione di 2-metil-5-({[1-metil-5-(2,2,2-trifluoroetossi)-3-(trifluorometil)-1H-pirazol-4-il]metil}tio)-1,3,4-tiadiazolo [composto di formula generale (XI)] g) Preparation of 2-methyl-5 - ({[1-methyl-5- (2,2,2-trifluoroethoxy) -3- (trifluoromethyl) -1H-pyrazol-4-yl] methyl} thio) -1, 3,4-thiadiazole [compound of general formula (XI)]
In un pallone contenente 4,15 ml (57,69 mmol) di trifluoroetanolo sono stati aggiunti 1,15g (48,08 mmol) di sodio idruro a porzioni, mantenendo una temperatura di circa 4-5?C con bagno di ghiaccio e lasciando reagire a tale temperatura per circa 30 minuti. In a flask containing 4.15 ml (57.69 mmol) of trifluoroethanol, 1.15 g (48.08 mmol) of sodium hydride was added in portions, maintaining a temperature of about 4-5 ° C with an ice bath and leaving react at this temperature for about 30 minutes.
La miscela cos? preparata ? stata aggiunta a una soluzione sotto azoto di 6g (19,23 mmol) di 2-({[5-fluoro-1-metil-3-(trifluorometil)-1H-pirazol-4-il]metil}tio)-5-metil-1,3,4-tiadiazolo (X) in 20 ml di N-metil-2-pirrolidone a temperatura ambiente. The mixture so? prepared? was added to a 6g (19.23 mmol) nitrogen solution of 2 - ({[5-fluoro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-4-yl] methyl} thio) -5- methyl-1,3,4-thiadiazole (X) in 20 ml of N-methyl-2-pyrrolidone at room temperature.
La miscela ? stata scaldata a 80?C per 6h. The mixture ? been heated at 80? C for 6h.
Dopo controllo in GC-MS e LC-MS la miscela ? stata versata in acqua; la fase acquosa ? stata estratta tre volte con acetato di etile. Le fasi organiche riunite sono state lavate con acqua e soluzione satura di cloruro di sodio. After checking the mixture in GC-MS and LC-MS? been poured into water; the aqueous phase? was extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride solution.
Dopo anidrificazione su solfato di sodio, filtrazione ed evaporazione del solvente a pressione ridotta sono stati ottenuti 7,16g del prodotto desiderato (18,27 mmol), come olio marrone. Resa 95% After drying over sodium sulphate, filtration and evaporation of the solvent under reduced pressure, 7.16 g of the desired product (18.27 mmol), as brown oil, were obtained. Yield 95%
LC-MS [M+H] = 393. LC-MS [M + H] = 393.
h) Preparazione di 2-[(1-metil-3-trifluorometil-5-(2,2,2-trifluoroetossi)-pirazol-4-il)sulfinil]-5-metil-1,3,4-tiadiazolo [Composto di formula generale (I)] h) Preparation of 2 - [(1-methyl-3-trifluoromethyl-5- (2,2,2-trifluoroethoxy) -pyrazol-4-yl) sulfinyl] -5-methyl-1,3,4-thiadiazole [Compound of general formula (I)]
A 7,0g (17,8 mmol) di 2-metil-5-({[1-metil-5-(2,2,2-trifluoroetossi)-3-(trifluorometil)-1H-pirazol-4-il]metil}tio)-1,3,4-tiadiazolo (XI), sciolti in 35 ml di cloroformio, sono stati aggiunti, mantenendo una temperatura di circa 4-5?C con bagno di ghiaccio, 4,4g (19,58 mmol) di acido 4-cloro-perbenzoico al 77%, la miscela ? stata poi lasciata sotto agitazione magnetica a temperatura ambiente per una notte. A 7.0g (17.8 mmol) of 2-methyl-5 - ({[1-methyl-5- (2,2,2-trifluoroethoxy) -3- (trifluoromethyl) -1H-pyrazol-4-yl] methyl} thio) -1,3,4-thiadiazole (XI), dissolved in 35 ml of chloroform, 4.4g (19.58 mmol ) of 77% 4-chloro-perbenzoic acid, the mixture? it was then left under magnetic stirring at room temperature overnight.
Dopo controllo in LC-MS la miscela ? stata diluita con acqua e sono state quindi separate le fasi; la fase acquosa ? stata riestratta due volte con diclorometano. Le fasi organiche riunite sono state lavate con NaHSO3 soluzione acquosa al 5%, soluzione satura di NaHCO3,acqua e soluzione satura di NaCl. After checking the mixture in LC-MS? was diluted with water and the phases were then separated; the aqueous phase? was re-extracted twice with dichloromethane. The combined organic phases were washed with NaHSO3 aqueous solution at 5%, saturated solution of NaHCO3, water and saturated solution of NaCl.
Dopo anidrificazione su solfato di sodio, filtrazione ed evaporazione del solvente a pressione ridotta sono stati ottenuti 7,1 g del prodotto desiderato (17,4 mmol), come olio giallo. Il grezzo cos? ottenuto ? stato purificato per flash cromatografia (eluente esano/acetato di etile 6:4), ottenendo 6,0g (14,77 mmol) di prodotto desiderato come solido giallo. Resa 83,0% After drying over sodium sulphate, filtration and evaporation of the solvent under reduced pressure, 7.1 g of the desired product (17.4 mmol), as yellow oil, were obtained. The crude cos? obtained ? was purified by flash chromatography (eluent hexane / ethyl acetate 6: 4), obtaining 6.0g (14.77 mmol) of the desired product as a yellow solid. Yield 83.0%
LC-MS [M+H] = 409 LC-MS [M + H] = 409
Esempio 2 Example 2
Preparazione di 2-metil-5-({[1-metil-5-(2,2,2-trifluoroetossi)-3-(trifluorometil)-1H-pirazol-4-il]metil}tio)-1,3,4-tiadiazolo [Composto di formula generale (XI), R = CH3, R1 = CF3, R2 = CH3, R3 = CH2CF3] Preparation of 2-methyl-5 - ({[1-methyl-5- (2,2,2-trifluoroethoxy) -3- (trifluoromethyl) -1H-pyrazol-4-yl] methyl} thio) -1,3, 4-thiadiazole [Compound of general formula (XI), R = CH3, R1 = CF3, R2 = CH3, R3 = CH2CF3]
a) Preparazione di 4,4,4-trifluoro-2-{[(5-metil-1,3,4-tiadiazol-2-il)tio]metil}-3-ossobutanoato di etile [composto di formula generale (IIb)] A una miscela sotto azoto di 12,3g (151,5 mmol) di formaldeide soluzione al 37% in acqua e 27,8g (151,5 mmol) di trifluoroacetoacetato di etile (IIa) in 70 ml di acqua sono stati aggiunti 10g (75,7 mmol) di 5-metil-1,3,4-tiadiazolo-2-tiolo (IX) a temperatura ambiente. a) Preparation of 4,4,4-trifluoro-2 - {[(5-methyl-1,3,4-thiadiazol-2-yl) thio] methyl} -3-oxobutanoate of ethyl [compound of general formula (IIb )] To a mixture under nitrogen of 12.3g (151.5mmol) of formaldehyde solution at 37% in water and 27.8g (151.5mmol) of ethyl trifluoroacetoacetate (IIa) in 70ml of water were added 10g (75.7 mmol) of 5-methyl-1,3,4-thiadiazole-2-thiol (IX) at room temperature.
La miscela ? stata scaldata a 60?C per 24h. The mixture ? been heated at 60? C for 24h.
Dopo controllo in LC-MS la miscela ? stata estratta tre volte con acetato di etile. Le fasi organiche riunite sono state lavate con acqua e soluzione satura di cloruro di sodio. After checking the mixture in LC-MS? was extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride solution.
Dopo anidrificazione su solfato di sodio, filtrazione ed evaporazione del solvente a pressione ridotta sono stati ottenuti 27,7g del prodotto desiderato come olio incolore. Il grezzo cos? ottenuto ? stato purificato per flash cromatografia (eluente eptano/acetato di etile 8:2), ottenendo 15,1g (46,04 mmol) di prodotto desiderato come solido giallo. Resa 60,8% After drying over sodium sulphate, filtration and evaporation of the solvent under reduced pressure, 27.7 g of the desired product were obtained as a colorless oil. The crude cos? obtained ? was purified by flash chromatography (eluent heptane / ethyl acetate 8: 2), obtaining 15.1g (46.04 mmol) of the desired product as a yellow solid. Yield 60.8%
LC-MS [M+H] = 329 LC-MS [M + H] = 329
b) Preparazione di 1-metil-4-{[(5-metil-1,3,4-tiadiazol-2-il)tio]metil}-3-(trifluorometil)-1H-pirazol-5-olo [composto di formula generale (XII)] A una soluzione sotto azoto di 1,3 ml (24,4 mmol) di metilidrazina in 30 ml di etanolo sono stati gocciolati 8g (24,4 mmol) di 4,4,4-trifluoro-2-{[(5-metil-1,3,4-tiadiazol-2-il)tio]metil}-3-ossobutanoato di etile (IIb), sciolti in 10 ml di etanolo, mantenendo una temperatura di circa 4-5?C con bagno di ghiaccio; dopo circa 1h30? a temperatura ambiente sono stati aggiunti 2ml di acido cloridrico concentrato. b) Preparation of 1-methyl-4 - {[(5-methyl-1,3,4-thiadiazol-2-yl) thio] methyl} -3- (trifluoromethyl) -1H-pyrazol-5-ol [compound of general formula (XII)] To a nitrogen solution of 1.3 ml (24.4 mmol) of methylhydrazine in 30 ml of ethanol 8g (24.4 mmol) of 4,4,4-trifluoro-2- was dropped {[(5-methyl-1,3,4-thiadiazol-2-yl) thio] methyl} -3-oxobutanoate of ethyl (IIb), dissolved in 10 ml of ethanol, maintaining a temperature of about 4-5 ° C with ice bath; after about 1h30? 2ml of concentrated hydrochloric acid was added at room temperature.
La miscela ? stata scaldata a riflusso per 5h. The mixture ? was heated under reflux for 5h.
Dopo controllo in LC-MS la miscela ? stata concentrata a pressione ridotta, quindi diluita con acqua; la fase acquosa ? stata estratta tre volte con acetato di etile. Le fasi organiche riunite sono state lavate con acqua e soluzione satura di cloruro di sodio. After checking the mixture in LC-MS? been concentrated under reduced pressure, then diluted with water; the aqueous phase? was extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride solution.
Dopo anidrificazione su solfato di sodio, filtrazione ed evaporazione del solvente a pressione ridotta sono stati ottenuti 6,7 g del prodotto desiderato come solido giallo. Resa 88,5% After drying over sodium sulphate, filtration and evaporation of the solvent under reduced pressure, 6.7 g of the desired product as a yellow solid were obtained. Yield 88.5%
LC-MS [M+H] = 311. LC-MS [M + H] = 311.
c) Preparazione di 2-metil-5-({[1-metil-5-(2,2,2-trifluoroetossi)-3-(trifluorometil)-1H-pirazol-4-il]metil}tio)-1,3,4-tiadiazolo [composto di formula generale (XI)] c) Preparation of 2-methyl-5 - ({[1-methyl-5- (2,2,2-trifluoroethoxy) -3- (trifluoromethyl) -1H-pyrazol-4-yl] methyl} thio) -1, 3,4-thiadiazole [compound of general formula (XI)]
A una miscela di 4,0g (12,9 mmol) di 1-metil-4-{[(5-metil-1,3,4-tiadiazol-2-il)tio]metil}-3-(trifluorometil)-1H-pirazol-5-olo (XII) e 2,7 g (19,4 mmol) di carbonato di potassio in 50 ml di N,N-dimetilformammide, lasciata sotto agitazione magnetica e a temperatura ambiente per 30 minuti, sono stati aggiunti 4,9g (19,4 mmol) di 2,2,2-trifluoroetil-4-metilbenzenesolfonato. To a mixture of 4.0g (12.9 mmol) of 1-methyl-4 - {[(5-methyl-1,3,4-thiadiazol-2-yl) thio] methyl} -3- (trifluoromethyl) - 1H-pyrazol-5-ol (XII) and 2.7 g (19.4 mmol) of potassium carbonate in 50 ml of N, N-dimethylformamide, left under magnetic stirring and at room temperature for 30 minutes, were added 4 , 9g (19.4 mmol) of 2,2,2-trifluoroethyl-4-methylbenzenesulfonate.
La miscela ? stata scaldata a 80?C per 4h. The mixture ? been heated at 80? C for 4h.
Dopo controllo in LC-MS la miscela ? stata versata in acqua; la fase acquosa ? stata estratta tre volte con acetato di etile. Le fasi organiche riunite sono state lavate con acqua e soluzione satura di cloruro di sodio. After checking the mixture in LC-MS? been poured into water; the aqueous phase? was extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride solution.
Dopo anidrificazione su solfato di sodio, filtrazione ed evaporazione del solvente a pressione ridotta sono stati ottenuti 3,5 g del prodotto desiderato (8,92 mmol), come solido marrone. Il grezzo cos? ottenuto ? stato purificato per flash cromatografia (eluente eptano/acetato di etile 7:3), ottenendo 1,5g (3,87 mmol) di prodotto desiderato come solido giallo. Resa 30% After drying over sodium sulphate, filtration and evaporation of the solvent under reduced pressure, 3.5 g of the desired product (8.92 mmol), as a brown solid, were obtained. The crude cos? obtained ? was purified by flash chromatography (eluent heptane / ethyl acetate 7: 3), obtaining 1.5g (3.87 mmol) of the desired product as a yellow solid. Yield 30%
Esempio 3 Example 3
Preparazione di 2-metil-5-({[1-metil-5-(2,2,2-trifluoroetossi)-3-(trifluorometil)-1H-pirazol-4-il]metil}tio)-1,3,4-tiadiazolo [composto di formula generale (XI)] Preparation of 2-methyl-5 - ({[1-methyl-5- (2,2,2-trifluoroethoxy) -3- (trifluoromethyl) -1H-pyrazol-4-yl] methyl} thio) -1,3, 4-thiadiazole [compound of general formula (XI)]
A una sospensione sotto azoto di 0,7g (16,7 mmol) di sodio idruro in 15 ml di N,N-dimetilformammide sono stati aggiunti per gocciolamento 1,2 ml (16,7 mmol) di trifluoroetanolo, mantenendo una temperatura di circa 4-5?C con bagno di ghiaccio e lasciando reagire a tale temperatura per circa 1h. To a suspension under nitrogen of 0.7 g (16.7 mmol) of sodium hydride in 15 ml of N, N-dimethylformamide, 1.2 ml (16.7 mmol) of trifluoroethanol was added dropwise, maintaining a temperature of approx. 4-5 ° C with an ice bath and letting it react at this temperature for about 1 hour.
Alla miscela cos? preparata sono stati aggiunti 5g (15,2 mmol) di 2-({[5-cloro-1-metil-3-(trifluorometil)-1H-pirazol-4-il]metil}tio)-5-metil-1,3,4-tiadiazolo (X), sciolti in 5 ml di N,N-dimetilformammide, mantenendo una temperatura di circa 4-5?C con bagno di ghiaccio. To the mixture cos? 5g (15.2 mmol) of 2 - ({[5-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-4-yl] methyl} thio) -5-methyl-1, 3,4-thiadiazole (X), dissolved in 5 ml of N, N-dimethylformamide, maintaining a temperature of about 4-5 ° C with an ice bath.
La miscela ? stata scaldata a 80?C per 6h. The mixture ? been heated at 80? C for 6h.
Dopo controllo in LC-MS la miscela ? stata versata in acqua; la fase acquosa ? stata estratta tre volte con acetato di etile. Le fasi organiche riunite sono state lavate con acqua e soluzione satura di cloruro di sodio. After checking the mixture in LC-MS? been poured into water; the aqueous phase? was extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride solution.
Dopo anidrificazione su solfato di sodio, filtrazione ed evaporazione del solvente a pressione ridotta sono stati ottenuti 7,16g del prodotto desiderato (18,27 mmol), come olio marrone. Resa 95% After drying over sodium sulphate, filtration and evaporation of the solvent under reduced pressure, 7.16 g of the desired product (18.27 mmol), as brown oil, were obtained. Yield 95%
Esempio 4 Example 4
Preparazione di 4,4,4-trifluoro-2-{[(5-metil-1,3,4-tiadiazol-2-il)tio]metil}-3-ossobutanoato di butile [composto di formula generale (IIb), Preparation of butyl 4,4,4-trifluoro-2 - {[(5-methyl-1,3,4-thiadiazol-2-yl) thio] methyl} -3-oxobutanoate [compound of general formula (IIb),
a) Preparazione di 3-[(5-metil-1,3,4-tiadiazol-2-il)tio]propanoato di butile [composto di formula generale (XIV)] a) Preparation of butyl 3 - [(5-methyl-1,3,4-thiadiazol-2-yl) thio] propanoate [compound of general formula (XIV)]
A una soluzione sotto azoto di 10,0g (75,6 mmol) di 5-metil-1,3,4-tiadiazolo-2-tiolo (IX) in 300 ml di MeOH sono stati aggiunti 10,6g (83,2 mmol) di acrilato di butile (XIII) e 11,0 ml (79,4 mmol) di trietilammina, a temperatura ambiente. To a nitrogen solution of 10.0g (75.6 mmol) of 5-methyl-1,3,4-thiadiazole-2-thiol (IX) in 300 ml of MeOH was added 10.6g (83.2 mmol ) of butyl acrylate (XIII) and 11.0 ml (79.4 mmol) of triethylamine, at room temperature.
La miscela ? stata scaldata a riflusso per 8h. The mixture ? was heated under reflux for 8h.
Dopo controllo in GC-MS il solvente ? stato rimosso a pressione ridotta ottenendo 18,3 g del prodotto desiderato (70,4 mmol), come olio giallo. Resa 93% After checking the solvent in GC-MS? was removed under reduced pressure to obtain 18.3 g of the desired product (70.4 mmol), as yellow oil. Yield 93%
GC-MS [m/z] = 260. GC-MS [m / z] = 260.
b) Preparazione di 4,4,4-trifluoro-2-{[(5-metil-1,3,4-tiadiazol-2-il)tio]metil}-3-ossobutanoato di butile [composto di formula generale (IIb)] A una sospensione, sotto azoto, di 8,5g (75,8 mmol) di tBuOK in 250ml di tetraidrofurano sono stati aggiunti 18,6g (70,4 mmol) di 3-[(5-metil-1,3,4-tiadiazol-2-il)tio]propanoato di butile (XIV). b) Preparation of 4,4,4-trifluoro-2 - {[(5-methyl-1,3,4-thiadiazol-2-yl) thio] methyl} -3-oxobutanoate of butyl [compound having general formula (IIb )] 18.6g (70.4 mmol) of 3 - [(5-methyl-1,3, 4-thiadiazol-2-yl) thio] butyl propanoate (XIV).
Dopo circa 15 minuti a temperatura ambiente ? stato gorgogliato il trifluoroacetilcloruro e la miscela di reazione ? stata mantenuta a 50?C per 8 ore. After about 15 minutes at room temperature? was the trifluoroacetyl chloride and the reaction mixture bubbled? was kept at 50 ° C for 8 hours.
Dopo controllo in LC-MS la miscela ? stata estratta tre volte con acetato di etile. Le fasi organiche riunite sono state lavate con acqua e soluzione satura di cloruro di sodio. After checking the mixture in LC-MS? was extracted three times with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride solution.
Dopo anidrificazione su solfato di sodio, filtrazione ed evaporazione del solvente a pressione ridotta sono stati ottenuti 23,7g del prodotto desiderato come olio marrone Il grezzo cos? ottenuto ? stato purificato per flash cromatografia (eluente eptano/acetato di etile 8:2), ottenendo 15,0g (42,13 mmol) di prodotto desiderato come solido Resa 55,5% After drying on sodium sulphate, filtration and evaporation of the solvent under reduced pressure, 23.7g of the desired product were obtained as brown oil. obtained ? purified state by flash chromatography (eluent heptane / ethyl acetate 8: 2), obtaining 15.0g (42.13 mmol) of desired product as solid Yield 55.5%
Claims (15)
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| PCT/IB2016/051399 WO2016142918A1 (en) | 2015-03-12 | 2016-03-11 | Pyrazole derivatives and relative use for the preparation of 1,3,4-thiadiazoles |
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