WO2023275705A1 - Procédé de préparation de pyrazolopyridine-diamides de formule (i) et de leurs intermédiaires - Google Patents
Procédé de préparation de pyrazolopyridine-diamides de formule (i) et de leurs intermédiaires Download PDFInfo
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- WO2023275705A1 WO2023275705A1 PCT/IB2022/055939 IB2022055939W WO2023275705A1 WO 2023275705 A1 WO2023275705 A1 WO 2023275705A1 IB 2022055939 W IB2022055939 W IB 2022055939W WO 2023275705 A1 WO2023275705 A1 WO 2023275705A1
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- WIPO (PCT)
- Prior art keywords
- formula
- compound
- salt
- group
- methyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title abstract description 23
- 239000000543 intermediate Substances 0.000 title description 12
- ACIGRBIIZATBJV-UHFFFAOYSA-N N1=NC(=C2C1=CC=C(N2)C(=O)N)C(=O)N Chemical class N1=NC(=C2C1=CC=C(N2)C(=O)N)C(=O)N ACIGRBIIZATBJV-UHFFFAOYSA-N 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 172
- 150000001875 compounds Chemical class 0.000 claims abstract description 168
- 238000004519 manufacturing process Methods 0.000 claims abstract description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 87
- 239000002904 solvent Substances 0.000 claims description 81
- 239000002585 base Substances 0.000 claims description 62
- 239000000203 mixture Substances 0.000 claims description 50
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 46
- 229910052739 hydrogen Inorganic materials 0.000 claims description 42
- 239000001257 hydrogen Substances 0.000 claims description 42
- -1 (substituted) cyanomethylphosphonate Chemical class 0.000 claims description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- 239000003153 chemical reaction reagent Substances 0.000 claims description 35
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 32
- 150000002431 hydrogen Chemical group 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 30
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 30
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 150000002367 halogens Chemical class 0.000 claims description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 230000003301 hydrolyzing effect Effects 0.000 claims description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- 229910052705 radium Inorganic materials 0.000 claims description 20
- 229910052701 rubidium Inorganic materials 0.000 claims description 20
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 150000001412 amines Chemical class 0.000 claims description 18
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 16
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 16
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 16
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 16
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 15
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 15
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 15
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 claims description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 13
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 13
- 230000002862 amidating effect Effects 0.000 claims description 13
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 claims description 12
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HVZJRWJGKQPSFL-UHFFFAOYSA-N tert-Amyl methyl ether Chemical compound CCC(C)(C)OC HVZJRWJGKQPSFL-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 229910017711 NHRa Inorganic materials 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 10
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 229910052751 metal Inorganic materials 0.000 claims description 9
- 239000002184 metal Substances 0.000 claims description 9
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 8
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 8
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 8
- ITVPBBDAZKBMRP-UHFFFAOYSA-N chloro-dioxido-oxo-$l^{5}-phosphane;hydron Chemical compound OP(O)(Cl)=O ITVPBBDAZKBMRP-UHFFFAOYSA-N 0.000 claims description 8
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 8
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 8
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 8
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 7
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical group F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 7
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 230000008878 coupling Effects 0.000 claims description 7
- 238000010168 coupling process Methods 0.000 claims description 7
- 238000005859 coupling reaction Methods 0.000 claims description 7
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 7
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 7
- JIKUXBYRTXDNIY-UHFFFAOYSA-N n-methyl-n-phenylformamide Chemical compound O=CN(C)C1=CC=CC=C1 JIKUXBYRTXDNIY-UHFFFAOYSA-N 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 6
- 150000007960 acetonitrile Chemical class 0.000 claims description 6
- 150000004703 alkoxides Chemical class 0.000 claims description 6
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 claims description 6
- 150000004678 hydrides Chemical class 0.000 claims description 6
- 238000011065 in-situ storage Methods 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- 229940043279 diisopropylamine Drugs 0.000 claims description 5
- XQFGVGNRDPFKFJ-UHFFFAOYSA-N 1,2,3,5,6,7-hexahydropyrrolo[1,2-b]pyridazine Chemical compound N1CCC=C2CCCN21 XQFGVGNRDPFKFJ-UHFFFAOYSA-N 0.000 claims description 4
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 claims description 4
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 4
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 4
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 claims description 4
- BJPUIGIKRGIHLU-UHFFFAOYSA-N propan-2-amine;n-propan-2-ylpropan-2-amine Chemical compound CC(C)N.CC(C)NC(C)C BJPUIGIKRGIHLU-UHFFFAOYSA-N 0.000 claims description 4
- RKBCYCFRFCNLTO-UHFFFAOYSA-N triisopropylamine Chemical compound CC(C)N(C(C)C)C(C)C RKBCYCFRFCNLTO-UHFFFAOYSA-N 0.000 claims description 4
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 3
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanol Chemical compound COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 claims description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 3
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 claims description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 3
- 239000004146 Propane-1,2-diol Substances 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 229940117389 dichlorobenzene Drugs 0.000 claims description 3
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 claims description 3
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- 235000013772 propylene glycol Nutrition 0.000 claims description 3
- 229960004063 propylene glycol Drugs 0.000 claims description 3
- ZYVYEJXMYBUCMN-UHFFFAOYSA-N 1-methoxy-2-methylpropane Chemical compound COCC(C)C ZYVYEJXMYBUCMN-UHFFFAOYSA-N 0.000 claims description 2
- UGDAWAQEKLURQI-UHFFFAOYSA-N 2-(2-hydroxyethoxy)ethanol;hydrate Chemical compound O.OCCOCCO UGDAWAQEKLURQI-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 150000001470 diamides Chemical class 0.000 abstract description 18
- 125000002619 bicyclic group Chemical group 0.000 abstract description 16
- ZJGSHCNIWOBHOH-UHFFFAOYSA-N 1-cyanoethylphosphonic acid Chemical class N#CC(C)P(O)(O)=O ZJGSHCNIWOBHOH-UHFFFAOYSA-N 0.000 abstract description 4
- ZAXKLMCFDFXNJG-UHFFFAOYSA-N CC(=CC1=CC=NN1CC(=O)O)C#N Chemical class CC(=CC1=CC=NN1CC(=O)O)C#N ZAXKLMCFDFXNJG-UHFFFAOYSA-N 0.000 abstract description 4
- VDIKHHGNSVEWPF-UHFFFAOYSA-N OC(=O)CN1N=CC=C1C=O Chemical class OC(=O)CN1N=CC=C1C=O VDIKHHGNSVEWPF-UHFFFAOYSA-N 0.000 abstract description 4
- 238000006243 chemical reaction Methods 0.000 description 74
- 239000011541 reaction mixture Substances 0.000 description 55
- 239000000243 solution Substances 0.000 description 53
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- 239000007787 solid Substances 0.000 description 22
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 17
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 14
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 13
- GQDSTINPTMREFF-UHFFFAOYSA-N C(#N)C(=CC1=CC=NN1CC(=O)OCC)C Chemical compound C(#N)C(=CC1=CC=NN1CC(=O)OCC)C GQDSTINPTMREFF-UHFFFAOYSA-N 0.000 description 13
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 12
- LGJVEUONDVSZOM-UHFFFAOYSA-N ethyl 6-amino-5-methylpyrazolo[1,5-a]pyridine-7-carboxylate Chemical compound CCOC(=O)C1=C(N)C(C)=CC2=CC=NN12 LGJVEUONDVSZOM-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 150000002170 ethers Chemical class 0.000 description 11
- IJIUDYIEBDYJIE-UHFFFAOYSA-N 6-[[5-bromo-2-(3-chloropyridin-2-yl)pyrazole-3-carbonyl]amino]-5-methyl-N-propan-2-ylpyrazolo[1,5-a]pyridine-7-carboxamide Chemical compound BrC1=NN(C(=C1)C(=O)NC=1C(=CC=2N(C=1C(=O)NC(C)C)N=CC=2)C)C1=NC=CC=C1Cl IJIUDYIEBDYJIE-UHFFFAOYSA-N 0.000 description 10
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- 229940093499 ethyl acetate Drugs 0.000 description 10
- 238000002955 isolation Methods 0.000 description 10
- 150000002825 nitriles Chemical class 0.000 description 10
- UMLWEPGSWQNXQX-UHFFFAOYSA-N 2-diethoxyphosphorylpropanenitrile Chemical compound CCOP(=O)(OCC)C(C)C#N UMLWEPGSWQNXQX-UHFFFAOYSA-N 0.000 description 9
- 150000001408 amides Chemical class 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 9
- DCZQFNFSECUXCD-UHFFFAOYSA-N 6-amino-5-methylpyrazolo[1,5-a]pyridine-7-carboxylic acid Chemical compound CC1=CC2=CC=NN2C(C(O)=O)=C1N DCZQFNFSECUXCD-UHFFFAOYSA-N 0.000 description 8
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- AYJRCSIUFZENHW-UHFFFAOYSA-L barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 description 8
- 239000002002 slurry Substances 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 7
- HMYBMFFJJIYTFU-UHFFFAOYSA-N 11-[5-bromo-2-(3-chloropyridin-2-yl)pyrazol-3-yl]-8-methyl-12-oxa-2,3,10-triazatricyclo[7.4.0.02,6]trideca-1(9),3,5,7,10-pentaen-13-one Chemical compound BrC1=NN(C(=C1)C=1OC(C2=C(N=1)C(=CC=1N2N=CC=1)C)=O)C1=NC=CC=C1Cl HMYBMFFJJIYTFU-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 235000019270 ammonium chloride Nutrition 0.000 description 6
- DDTDALGQVIRQJD-UHFFFAOYSA-N ethyl 2-(5-formylpyrazol-1-yl)acetate Chemical compound CCOC(=O)CN1N=CC=C1C=O DDTDALGQVIRQJD-UHFFFAOYSA-N 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 239000013067 intermediate product Substances 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- 150000001409 amidines Chemical class 0.000 description 4
- 229910000019 calcium carbonate Inorganic materials 0.000 description 4
- UUYYJWFAHPQMJY-UHFFFAOYSA-N cyanomethoxy-oxido-oxophosphanium Chemical compound [O-][P+](=O)OCC#N UUYYJWFAHPQMJY-UHFFFAOYSA-N 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 4
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 4
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 4
- 239000001095 magnesium carbonate Substances 0.000 description 4
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 4
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000001174 sulfone group Chemical group 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- FORBXGROTPOMEH-UHFFFAOYSA-N 5-bromo-2-(3-chloropyridin-2-yl)pyrazole-3-carboxylic acid Chemical compound OC(=O)C1=CC(Br)=NN1C1=NC=CC=C1Cl FORBXGROTPOMEH-UHFFFAOYSA-N 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 150000008282 halocarbons Chemical class 0.000 description 3
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 description 3
- AZVCGYPLLBEUNV-UHFFFAOYSA-N lithium;ethanolate Chemical compound [Li+].CC[O-] AZVCGYPLLBEUNV-UHFFFAOYSA-N 0.000 description 3
- HAUKUGBTJXWQMF-UHFFFAOYSA-N lithium;propan-2-olate Chemical compound [Li+].CC(C)[O-] HAUKUGBTJXWQMF-UHFFFAOYSA-N 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 3
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 3
- WQKGAJDYBZOFSR-UHFFFAOYSA-N potassium;propan-2-olate Chemical compound [K+].CC(C)[O-] WQKGAJDYBZOFSR-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- WBQTXTBONIWRGK-UHFFFAOYSA-N sodium;propan-2-olate Chemical compound [Na+].CC(C)[O-] WBQTXTBONIWRGK-UHFFFAOYSA-N 0.000 description 3
- 150000003462 sulfoxides Chemical class 0.000 description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 3
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 2
- KTVKQTNGWVJHFL-UHFFFAOYSA-N 2-ethylchromen-4-one Chemical compound C1=CC=C2OC(CC)=CC(=O)C2=C1 KTVKQTNGWVJHFL-UHFFFAOYSA-N 0.000 description 2
- FVKFHMNJTHKMRX-UHFFFAOYSA-N 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine Chemical compound C1CCN2CCCNC2=N1 FVKFHMNJTHKMRX-UHFFFAOYSA-N 0.000 description 2
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 2
- RVDLHGSZWAELAU-UHFFFAOYSA-N 5-tert-butylthiophene-2-carbonyl chloride Chemical compound CC(C)(C)C1=CC=C(C(Cl)=O)S1 RVDLHGSZWAELAU-UHFFFAOYSA-N 0.000 description 2
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- GXOXBTLTKINZPR-UHFFFAOYSA-N CC1=CC2=CC=NN2C(C(O)=O)=C1NC(C1=CC(Br)=NN1C1=NC=CC=C1Cl)=O Chemical compound CC1=CC2=CC=NN2C(C(O)=O)=C1NC(C1=CC(Br)=NN1C1=NC=CC=C1Cl)=O GXOXBTLTKINZPR-UHFFFAOYSA-N 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
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- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 2
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- ORPJQHHQRCLVIC-UHFFFAOYSA-N magnesium;propan-2-olate Chemical compound CC(C)O[Mg]OC(C)C ORPJQHHQRCLVIC-UHFFFAOYSA-N 0.000 description 2
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- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 2
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- PNUWRUPDFQQBRM-UHFFFAOYSA-N pyrazolo[1,5-a]pyridine-7-carboxamide Chemical compound NC(=O)C1=CC=CC2=CC=NN12 PNUWRUPDFQQBRM-UHFFFAOYSA-N 0.000 description 2
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- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 2
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 2
- RYCLIXPGLDDLTM-UHFFFAOYSA-J tetrapotassium;phosphonato phosphate Chemical compound [K+].[K+].[K+].[K+].[O-]P([O-])(=O)OP([O-])([O-])=O RYCLIXPGLDDLTM-UHFFFAOYSA-J 0.000 description 2
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- 241000607479 Yersinia pestis Species 0.000 description 1
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 1
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- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 1
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- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- QDYVPYWKJOJPBF-UHFFFAOYSA-M lithium;hydroxide;dihydrate Chemical compound [Li+].O.O.[OH-] QDYVPYWKJOJPBF-UHFFFAOYSA-M 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002900 organolithium compounds Chemical class 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 102000042094 ryanodine receptor (TC 1.A.3.1) family Human genes 0.000 description 1
- 108091052345 ryanodine receptor (TC 1.A.3.1) family Proteins 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- LENLQGBLVGGAMF-UHFFFAOYSA-N tributyl([1,2,4]triazolo[1,5-a]pyridin-6-yl)stannane Chemical group C1=C([Sn](CCCC)(CCCC)CCCC)C=CC2=NC=NN21 LENLQGBLVGGAMF-UHFFFAOYSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention relates to a process for the preparation of bicyclic anthranilic diamides of formula (I) and salts thereof. More particularly, the present invention relates to a process for preparing bicyclic anthranilic diamides of formula (I), comprising the step of preparing a substituted 2-(5-(2-cyanoprop- l-en-l-yl)-lH-pyrazol-l-yl)acetate of formula (VII) or salts thereof by reacting a substituted 2-(5- formyl-lH-pyrazol-l-yl)acetate of formula (VIII) or salts thereof with a substituted (1- cyanoethyl)phosphonate of formula (IX) or salts thereof.
- the invention further relates to a process for preparing intermediates of formula (Z) or salts thereof, which are useful in the preparation of compound of formula (I) or salts thereof.
- Fused bicyclic anthranilic diamides are reported in the article titled “Bicyclic heterocyclic anthranilic diamides as ryanodine receptor modulators with insecticidal activity” published in Bioorganic and Medicinal Chemistry 24 (2016) 403-427.
- WO2019123195 discloses a compound of the following formula I providing bicyclic anthranilic diamides based on pyrazolo[l,5-a]pyridine-7-carboxamide derivatives, effective as insecticidal agents against harmful pests and useful as crop protecting agents.
- WO2019123195 discloses a process that uses 2-(triphenylphosphanylidene)acetonitrile as a source of cyanoethylene and sodium hexamethyl disilazane (NaHMDS) as a base in the preparation of a certain alkyl 2-(5-(2-cyanoprop-l-en-l-yl)-lH-pyrazol-l-yl)acetate with 52% yield.
- the said alkyl 2-(5-(2- cyanoprop-l-en-l-yl)-lH-pyrazol-l-yl)acetate is a key intermediate in the construction of the pyrazolo[l,5-a]pyridine core.
- the present invention provides a simple, environment-friendly, and cost-effective process for the preparation of bicyclic anthranilic diamide compounds and intermediates thereof, based on readily available starting materials.
- An objective of the present invention is to provide a simple, environment-friendly and cost-effective process for the preparation of bicyclic anthranilic diamides of formula (I) or of salts thereof.
- Another objective of the present invention is to provide a process for preparing bicyclic anthranilic diamides of formula (I) or of salts thereof, comprising the step of preparing a substituted 2-(5-(2- cyanoprop-1-en-1-yl)-1H-pyrazol-1-yl)acetate of formula (VII) or a salt thereof by reacting a substituted 2-(5-formyl-1H-pyrazol-1-yl)acetate of formula (VIII) or a salt thereof with a substituted (1-cyanoethyl)phosphonate of formula (IX) or a salt thereof.
- Yet another objective of the present invention is to provide a process for the preparation of compounds of formula (Z), that are useful intermediates in the preparation of bicyclic anthranilic diamide compounds of formula (I) or of salts thereof.
- the present invention provides a process for preparing bicyclic anthranilic diamides of formula (I) or of salts thereof, wherein, R 1 and R 1a are independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 - alkyl, C 1 -C 4 -haloalkyl, C 2 -C 4 -alkenyl and C 3 -C 6 -cycloalkyl; R a and R b are independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 2 - C 6 -alkenyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -haloalkyl, C 3 -
- reacting or “condensing” or “cyclising” or “hydrolysing” or “coupling” or “amidating” refers to a process of combining reactant(s) in a suitable medium or a solvent, wherein the reactants gets converted into desirable product(s) under reaction condition described.
- a condition A “or” B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B is true (or present).
- the indefinite articles “a” and “an” preceding an element or component of the present invention are intended to be non-restrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore “a” or “an” should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular. The meaning of various terms used in the description shall now be illustrated.
- alkyl means a straight-chain or branched-chain C1 to C6 alkyl group and the representative examples include methyl, ethyl, propyl, isopropyl, butyl or the different isomers.
- alkenyl means a straight-chain or branched C2 to C6 alkenes and the representative examples include ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl or the different isomers.
- cycloalkyl as used herein means alkyl closed to form a ring.
- Representative examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- This definition also applies to cycloalkyl as a part of a composite substituent, for example cycloalkylalkyl etc., unless specifically defined elsewhere.
- This definition also applies to cycloalkyl as a part of a composite substituent, for example halocycloalkyl group, wherein; a cycloalkyl group is partially or fully substituted with halogen atoms which may be the same or different.
- halogen includes fluorine, chlorine, bromine or iodine and the term “haloalkyl”, as used herein means an alkyl group is partially or fully substituted with halogen atoms which may be the same or different.
- haloalkyl include chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro- 2-fluoroethyl, 2,2,2-trichloroethyl
- the compounds synthesized by the novel and inventive process of the present invention may, if appropriate, be present as mixtures of different possible isomeric forms, especially of stereoisomers, for example E and Z, threo and erythro, and also optical isomers, but if appropriate also of tautomers. Both the E and the Z isomers, and also the threo and erythro isomers, and the optical isomers, any desired mixtures of these isomers and the possible tautomeric forms are disclosed and claimed.
- the present invention provides a process for preparing bicyclic anthranilic diamides of formula (I) or a salt thereof, wherein, R 1 and R 1a are independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 - alkyl, C 1 -C 4 -haloalkyl, C 2 -C 4 -alkenyl and C 3 -C 6 -cycloalkyl; R a and R b are independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 2 - C 6 -alkenyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -halocycloalkyl, and C 3 -C 6 -cycloalkyl- C 1 -C 6 -alkyl; R 2 is selected from the group consisting of halogen, CHF 2 , CF 3
- the present invention provides a process for the synthesis of a compound of formula (I) comprising the steps of: Reacting a compound of formula (VI) with a compound of formula (IV) in the presence of a suitable reagent to obtain a compound of formula (IIIA). Reacting the compound of formula (IIIA) with a suitable amine to obtain a compound of formula (I) as shown in the scheme below: .
- the present invention provides an alternative process for preparing the compound of formula (V) comprising the steps of: cyclizing the compound of formula (VII) or a salt thereof, in the presence of a suitable base, and a suitable solvent to obtain a compound of formula (VI) or a salt thereof; which is reacted in situ with a suitable hydrolysing agent to obtain a compound of formula (V) or a salt thereof as shown in the scheme below: , wherein, R 1 , R 1a , R 6 , are each as defined above.
- the present invention provides an alternative process for preparing the compound of formula (V) comprising the steps of: condensing the compound of formula (IX) or a salt thereof with a compound of formula (VIII) or a salt thereof, in the presence of a suitable base, and a suitable solvent to obtain a compound of formula (VII) or a salt thereof; which is reacted in situ with a suitable base to obtain a compound of formula (VI) or a salt thereof; which is reacted in situ with a suitable hydrolysing agent to obtain the compound of formula (V) or a salt thereof; as shown in the scheme below: , wherein, R 1 , R 1a , R 6 , are each as defined above.
- the present invention provides a compound of formula (IIIA) wherein, R 1 and R 1a are independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 - alkyl, C 1 -C 4 -haloalkyl, C 2 -C 4 -alkenyl and C 3 -C 6 -cycloalkyl;
- R 2 is selected from the group consisting of halogen, CHF 2 , CF 3 , OCF 2 H, OCH 2 CF 3 , and ; wherein A represents CR c R c , NR c , O or S(O) 0-2 ;
- R c is selected from the group consisting of hydrogen and C 1- C 4 -alkyl;
- R 3 is selected from the group consisting of hydrogen, halogen, C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl;
- R 6 is selected from the group consisting of hydrogen and C 1 -C 4 -al
- the present invention provides a process for preparing bicyclic anthranilic diamides of formula (I), comprising the step of preparing a substituted 2-(5-(2-cyanoprop-1-en-1-yl)-1H-pyrazol- 1-yl)acetate of formula (VII) or a salt thereof, by reacting a substituted 2-(5-formyl-1H-pyrazol-1- yl)acetate of formula (VIII) or a salt thereof, with a substituted (1-cyanoethyl)phosphonate of formula (IX) or a salt thereof, in the presence of a suitable base and a suitable solvent.
- the substituted acetonitrile of formula (X) is (R 1 CH 2 -CN) wherein R 1 is selected from the group consisting of hydrogen, C 1 -C 3 -alkyl and C 1 -C 3 -haloalkyl.
- the present invention provides a phosphorochloridate of formula (XI) or a salt thereof, wherein the preferred groups R 4 and R 5 are each independently selected as C 1 -C 3 -alkyl or R 4 and R 5 together with the O atom to which they are attached may form a 5-8-membered ring.
- the present invention provides a compound of formula (IX) or a salt thereof, wherein the preferred group R 1 is selected from the group consisting of hydrogen, C 1 -C 3 -alkyl, C 1 -C 3 - haloalkyl and C 3 -C 4 -cycloalkyl and R 4 and R 5 are each independently selected as C 1 -C 3 -alkyl or R 4 and R 5 together with the O atom to which they are attached may form a 5-8-membered ring.
- the compound of formula (VIII) can be prepared according to the procedure as reported in WO2019123195.
- the present invention provides a compound of formula (VIII) or a salt thereof, wherein R 6 is C 1 -C 4 -alkyl.
- R 6 is C 1 -C 4 -alkyl.
- R 1 is selected from the group consisting of hydrogen, C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl and C 3 -C 4 -cycloalkyl; and R 6 is C 1 -C 3 -alkyl.
- Yet another embodiment of the present invention provides a compound of formula (II) or a salt thereof, wherein R a and R b are independently selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 3 - C 6 -cycloalkyl, C 1 -C 4 -haloalkyl, C 3 -C 6 -halocycloalkyl and C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl.
- Yet another embodiment of the present invention provides a compound of formula (I) or a salt thereof, wherein R 1 , R a and R b , R 2 and R 3 are as defined above.
- the present invention provides a process for preparing bicyclic anthranilic diamides of the formula (Ia) or a salt thereof, wherein, R 1 is selected from the group consisting of methyl, trifluromethyl, or halogen; R a is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-, iso- or tert-butyl; and R b is selected from the group consisting of hydrogen or methyl; comprising the steps of: a) reacting an acetonitrile (CH 3 CH 2 -CN) of formula (Xa) with a phosphorochloridate of formula (XIa) or a salt thereof, in the presence of a suitable base, a suitable reagent and a suitable solvent, to obtain a diethyl (R 1 substituted) cyanomethylphosphonate of formula (IXa) or a salt thereof; wherein R 1 is as defined herein above;
- R 1 , R a and R b are as defined herein above; f) coupling the compound of formula (Va) or a salt thereof, with a compound of formula (IVa) or a salt thereof, in the presence of a suitable coupling reagent, a suitable base and a suitable solvent, to obtain a compound of formula (IIIa) or a salt there of wherein R 1 is as defined herein above and; g) amidating the compound of formula (IIIa) or a salt thereof, with a suitable amine [(CH 3 ) 2 CH- NH 2 ] of formula (IIa), to obtain a compound of formula (Ia) or a salt thereof.
- R 1 , R a and R b are as defined herein above; optionally, h) coupling the compound of formula (XIIa) or a salt thereof, wherein R 1 , R a and R b are as defined herein above; with a compound of formula (IVa) or a salt thereof, in the presence of a suitable reagent, a suitable base and a suitable solvent, to obtain a compound of formula (Ia) or a salt there of; wherein R 1 , R a and R b are as defined herein above;.
- the reaction step (a) of the above described process for the preparation of anthranilic diamides of formula (I) or a salt thereof can be performed at a temperature ranging from -100 °C to 100 °C for a period of few minutes to several hours, optionally under an inert atmosphere to afford a compound of formula (IX).
- the reaction temperature ranges from - 80 °C to 40 °C for a period of few minutes to 24 hours under an inert atmosphere.
- the process is performed in the presence of a base selected from organic, inorganic or organometallics bases.
- the inorganic base is selected from alkali metal hydroxide for example lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide; alkaline earth metal hydroxides for example, calcium hydroxide, barium hydroxide, magnesium hydroxide; alkali carbonate for example lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate; alkaline earth carbonate for example magnesium carbonate, calcium carbonate, barium carbonate; alkali hydride for example lithium hydride, sodium hydride, potassium hydride; alkaline hydride for example magnesium hydride, calcium hydride, barium hydride; metal phosphates for example sodium diphosphate, sodium phosphate, potassium diphosphate, potassium phosphate and the like.
- alkali metal hydroxide for example lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide
- alkaline earth metal hydroxides for example, calcium hydroxide, barium hydroxide, magnesium hydroxide
- alkali carbonate for
- the organic base is selected from amines which includes but is not limited to ethylamine, triethylamine, isopropylamine diisopropylamine, triisopropylamine, pyridine, piperidine, N,N- (dimethylamino)pyridine (DMAP), tetramethylammonium hydroxide, tetrabutylammonium hydroxide, choline hydroxide; amidine base for example, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, (TBD), 2,3,4,6,7,8,9,10-octahydropyrimidol[1,2-a]azepine (DBU), 1,8-diazabicyclo(5.4.0)undec-7-ene, 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO) or triethylenediamine).
- the organometallic base is selected from metal alkoxide which include but is not limited to lithium alkoxide, for example, lithium methoxide, lithium ethoxide, lithium isopropoxide; sodium alkoxide for example, sodium methoxide, sodium ethoxide, sodium isopropoxide; potassium alkoxide, for example potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide; magnesium alkoxide, for example, magnesium ethoxide, magnesium tert-butoxide, magnesium isopropoxide; aluminium alkoxide, for example, aluminium ethoxide, aluminum isopropoxide; titanium alkoxide, for example, titanium(IV) ethoxide titanium(IV) isopropoxide and the like or a mixture thereof.
- metal alkoxide which include but is not limited to lithium alkoxide, for example, lithium methoxide, lithium ethoxide, lithium isopropoxide; sodium alk
- Suitable solvents for carrying out the process according to the present invention are all inert organic solvents. These preferably include aliphatic, alicyclic or aromatic hydrocarbons such as, for example, petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons such as, chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane or trichloroethane; ethers, such as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2- dimethoxyethane, 1,2-diethoxyethane or anisole; ketones, such as acetone, butanone, methyl
- reaction step (a) is performed in the presence of a suitable reagent selected from organolithium compounds, preferably the reagent is alkyllithium such as n-butyllithium and as suitable organic base such as diisopropylamine.
- a suitable reagent selected from organolithium compounds, preferably the reagent is alkyllithium such as n-butyllithium and as suitable organic base such as diisopropylamine.
- the reaction step (a) is performed in a solvent selected from aliphatic, alicyclic or aromatic hydrocarbons, for example petroleum ether, n-hexane, n-heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; ethers such as diethyl ether, diisopropyl ether, methyl tert -butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,2-dimethoxyethane, 1,2- diethoxyethane, cyclopentylmethylether or anisole; amides such as N,N- dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone, N,N′- dimethylpropyleneurea or hexamethyl
- the reaction step (a) of the above described process can be performed at a temperature ranging from -100 °C to 50 °C for a period of few minutes to several hours, In one embodiment, the reaction step (a) is performed under atmospheric pressure, but can also be carried out under increased or reduced pressure. In one embodiment, after completion of the reaction, the reaction step (a) can be continued to the next step (b) with or without isolation of the intermediate product of formula (IX).
- the suitable base for performing the reaction step (b) is selected from the suitable bases as provided above. Preferably, the suitable base is selected from alkali carbonate, alkali hydride, amidine, organic amine, or a mixture thereof.
- the base is selected from alkali carbonate, amidine or organic amines; such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, 2,3,4,6,7,8,9,10-octahydropyrimidol[1,2-a]azepine (DBU), 1,8- diazabicyclo(5.4.0)undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4- diazabicyclo[2.2.2]octane (DABCO), ethylamine, triethylamine, isopropylamine diisopropylamine, triisopropylamine, pyridine, piperidine, N,N-(dimethylamino)pyridine (DMAP) or a mixture thereof.
- DBU 2,3,4,6,7,8,9,10-octahydropyrimidol[1,2-a]azepine
- DBN 1,8- diazabicyclo(
- the suitable solvent for performing the reaction step (b) is selected from the suitable solvents as provided for the reaction step above.
- the suitable solvent is selected from ethers, nitriles, amides, sulfoxides or a mixture thereof.
- the solvent is selected from ethers, such as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; ketones, such as acetone, butanone, methyl isobutyl ketone or cyclohexanone; nitriles, such as acetonitrile, propionitrile, n- or i- butyronitrile or benzonitrile; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N- methylformanilide, N-methylpyrrolidone, N,N′-Dimethylpropyleneurea or hexamethylphosphoramide; esters such as methyl acetate or ethyl acetate; sulphoxides,
- the reaction step (b) of the above described process can be performed at a temperature ranging from -25 °C to 150 °C for a period of few minutes to several hours, Preferably, the reaction temperature ranges from 0 °C to 100 °C for a period of few minutes to 36 hours.
- the reaction step (b) is performed under atmospheric pressure, but can also be carried out under increased or reduced pressure.
- the reaction step (b) can be continue to the next step (c) with or without isolation of the intermediate product of formula (VII).
- the reaction step (b) can be continue to the next step (d) with or without isolation of the intermediate of formula (VII) and (VI).
- the base for performing the reaction step (c) is selected from the suitable bases as provided above.
- the suitable base is selected alkali carbonate for example lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate; alkaline earth carbonate for example magnesium carbonate, calcium carbonate, barium carbonate; alkali hydride for example lithium hydride, sodium hydride, potassium hydride; alkaline hydride for example magnesium hydride, calcium hydride, barium hydride; metal phosphates for example sodium diphosphate, sodium phosphate, potassium diphosphate, potassium phosphate and the like; metal alkoxide which include but is not limited to lithium alkoxide, for example, lithium methoxide, lithium ethoxide, lithium isopropoxide; sodium alkoxide for example, sodium methoxide, sodium ethoxide, sodium isopropoxide; potassium alkoxide, for example potassium methoxide,
- the suitable base is selected from metal carbonate, metal alkoxide, such potassium tert-butoxide or a mixture thereof.
- the solvent for carrying out the reaction step (c) is selected from the suitable solvents as provided above.
- the suitable solvent is selected from ethers, nitriles, amides, sulfoxides or a mixture thereof.
- the solvent is selected from ethers, such as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2- dimethoxyethane, 1,2-diethoxyethane or anisole; ketones, such as acetone, butanone, methyl isobutyl ketone or cyclohexanone; nitriles, such as acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N- methylpyrrolidone, N,N′-dimethylpropyleneurea or hexamethylphosphoramide; esters such as methyl acetate or ethyl acetate; sulphoxides,
- the reaction step (c) of the above described process can be performed at a temperature ranging from -50 °C to 150 °C for a period of few minutes to several hours, optionally under inert atmosphere to afford a compound of formula (VI).
- the reaction temperature ranges from -25 °C to 100 °C for a period of few minutes to 24 hours.
- the reaction step (c) is performed under atmospheric pressure, but can also be carried out under increased or reduced pressure.
- the reaction step (c) can be continued to the next step (d) with or without isolation of the intermediate product of formula (VI).
- the compound of formula (VI) is optionally isolated.
- the reaction step (d) is performed in the presence of a suitable hydrolysing reagent selected from metal hydroxide, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide; metal carbonate, for example lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, barium carbonate; metal alkoxides, for example lithium methoxide, lithium ethoxide, lithium isopropoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert- butoxide, magnesium ethoxide, magnesium tert-butoxide, magnesium isopropoxide, aluminium ethoxide, aluminum isopropoxide; titanium(IV) ethoxide titanium(IV) isopropoxide or a mixture thereof.
- metal hydroxide for example,
- the suitable hydrolysing agent is selected from metal hydroxides, metal carbonate or a mixture thereof. More preferably, the suitable hydrolysing agent is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or a mixture thereof.
- the suitable solvent for carrying out the reaction step (d) is selected from suitable solvents as provided above. Preferably, the suitable solvent is selected from alcohol, ethers, nitriles or a mixture thereof.
- the suitable solvent is selected from diisopropyl ether, methyl t- butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane; alcohols such as methanol, ethanol, n- or i-propanol, n-, i-, sec- or tert-butanol, ethanediol, propane- 1,2-diol, ethoxyethanol, methoxyethanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, water or mixtures thereof.
- the reaction step (d) of the above described process can be performed at a temperature ranging from -20 °C to 100 °C for a period of few minutes to several hours, optionally under inert atmosphere to afford compound of formula (V).
- the reaction temperature ranges from -20 °C to 75 °C for a period of few minutes to 24 hours.
- the reaction step (d) is performed under atmospheric pressure, but can also be carried out under increased or reduced pressure.
- the reaction step (d) can be continued to the next step (e) with or without isolation of the intermediate product of formula (V).
- the reaction steps are performed in presence of a suitable base selected from organic amine bases for example, ethylamine, triethylamine, isopropylamine diisopropylamine, triisopropylamine, pyridine, 3-methylpyridine, piperidine, N,N-(dimethylamino)pyridine (DMAP); amidine for example, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, (TBD), 2,3,4,6,7,8,9,10- octahydropyrimidol[1,2-a]azepine (DBU) 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4- diazabicyclo[2.2.2]octane (DABCO, triethylenediamine) or a mixture thereof or the inorganic base is selected from alkali carbonate for example lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate;
- a suitable base selected from organic amine bases
- the suitable base is selected from amine base and alkali carbonate; more preferably, the suitable base is selected from triethylamine, diisopropylamine, 3-methylpyridine, pyridine, piperidine, lithium carbonate, sodium carbonate, potassium carbonate or a mixture thereof.
- the reaction could also be performed without additional base.
- the solvent for carrying out the reaction steps is selected from the suitable solvents as provided above.
- the suitable solvent is usually selected from ethers, nitriles, ketones, halogenated hydrocarbons, amides or a mixture thereof.
- the suitable solvent is selected from ethers, such as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; ketones, such as acetone, butanone, methyl isobutyl ketone or cyclohexanone; nitriles, such as acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile; halogenated hydrocarbons such as, chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane or trichloroethane; or a mixture thereof.
- ethers such as diethyl ether, diisopropyl ether, methyl t-butyl
- reaction steps (e, f or h) are performed under atmospheric pressure, but can also be carried out under increased or reduced pressure.
- the reaction steps (e, f or h) can be performed at a temperature ranging from 0 °C to 150 °C for a period of few minutes to several hours.
- the reaction temperature ranges from 0 °C to 75 °C for a period of few minutes to 24 hours.
- the suitable reagent for steps include but are not limited to oxalyl chloride, sulphonyl chloride, for example thionyl chloride, methanesulphonyl chloride, benzenesulfonyl chloride; carbodiimides, for example N,N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC); aminium compounds, for example (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridin
- the suitable reagent is selected from sulphonyl chloride, carbodiimides or mixture thereof. More preferably, the suitable reagent is selected from sulphonyl chloride such as oxalyl chloride or methanesulphonyl chloride.
- the reaction step (f) can be continued to the next step (g) with or without isolation of the intermediate product of formula (III).
- the solvent used for carrying out the reaction step (g) is selected from suitable solvents as provided above.
- the suitable solvent is selected from ethers, nitriles, amides, sulfoxides or a mixture thereof.
- the suitable solvent is selected from ether, nitriles, amides or a mixture thereof.
- the reaction can also be carried out in the absence of a solvent.
- the reaction step (g) of the above described process can be performed at a temperature ranging from 0 °C to 150 °C for a period of few minutes to several hours, optionally under inert atmosphere to afford the compound of formula (I).
- the reaction temperature ranges from 0 °C to 100 °C for a period of few minutes to 24 hours.
- the reaction step (g) is performed under atmospheric pressure, but can also be carried out under increased or reduced pressure.
- the processes as disclosed in the present invention are preferably carried out batch-wise.
- reaction passages e.g., under flow conditions
- the processes as disclosed in the present invention can be carried out in the absence of a suitable solvent or in the presence of one or more suitable solvent.
- the optional suitable solvent should be resistant against oxidation (i.e. a solvent will be preferred whose rate of oxidation is substantially lower than that of the compounds of formula I to XI) and suitable for suspending, or preferably dissolving the reactants.
- the isolation of the reaction product can be carried out by a technique which includes but is not limited to decantation, centrifugation, evaporation, liquid-liquid extraction, distillation, recrystallization, chromatography and the like or a combination thereof.
- the process steps according to the invention are generally carried out under atmospheric pressure. Alternatively, however, it is also possible to work under or increased pressure.
- the reaction time is not critical and depends on the batch size, temperature, reagent and solvent employed. Typically, the reaction time may vary from a few minutes to several hours. Any person skilled in the art knows the best work-up of the reaction mixtures after the end of the respective reactions. In one embodiment, the work-up is usually carried out by isolation of the product, and optionally washing with suitable solvent, and further optionally drying of the product if useful or required.
- the isolation of the reaction product can be carried out by a technique which includes but is not limited to decantation, filtration, centrifugation, evaporation, liquid-liquid extraction, distillation, recrystallization, chromatography and the like or a combination thereof.
- the process steps according to the invention are generally carried out under atmospheric pressure. Alternatively, however, it is also possible to work under reduced pressure or under pressure.
- reaction mixture was stirred for 30 min at -78°C, then allowed to warm up to 0 °C and further stirred for 30 min. Then, a solution of propionitrile (Xa, 2.02 mL, 29.0 mmol) in tetrahydrofuran (20 mL) was charged at -78 °C, and the resulting mixture was stirred for 15 min. A solution of diethyl phosphorochloridate (XIa, 4.20 mL, 29.0 mmol) in tetrahydrofuran (10 mL) was added slowly to this reaction mixture which was stirred for 45 min at -78°C. The reaction mixture was allowed to warm up to 25 °C and further stirred for 15 min.
- Xa diethyl phosphorochloridate
- reaction mixture was diluted in saturated aq. ammonium chloride solution (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain ethyl 2-(5-(2-cyanoprop-1-en-1-yl)-1H-pyrazol-1-yl)acetate (VIIa, 1.0 g, 4.56 mmol, 83% yield) as an off white solid.
- reaction mixture was stirred for 1.5 h at -20 °C to -10°C. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (250 mL) and quenched with saturated aqueous ammonium chloride solution (250 mL). The organic layer was separated and the aqueous layer was extracted again with ethyl acetate (2 x 250 mL). The combined organic layers were washed with water (250 mL), brine solution (250 mL) and concentrated to afford ethyl 6-amino-5- methylpyrazolo[1,5-a]pyridine-7-carboxylate (VIa, 92 g, 420 mmol, 92% yield) as a light green oil.
- reaction mixture was slowly warmed to 25 °C and stirred for 2.5 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with water (1.5 L), pH was adjusted to 4-5 by using 40% aq. solution of citric acid. The obtained precipitate was stirred for further 1 h and filtered. The wet cake which was obtained was washed with water (200 mL) and dried under reduced pressure to afford 6-amino-5-methylpyrazolo[1,5-a]pyridine- 7-carboxylic acid (Va, 100 g, 523 mmol, 89% yield) as an off white solid.
- Va 6-amino-5-methylpyrazolo[1,5-a]pyridine- 7-carboxylic acid
- reaction mixture was stirred for 12 h at 25 °C. After completion of the reaction, the reaction mixture was diluted with water (50 mL), the aqueous layer was separated and pH was adjusted to 4-5 using 20% aq. citric acid solution. The obtained precipitate was stirred further for 30 min and filtered. The resulting wet cake was washed with water (5 mL) and dried under reduced pressure to afford 6-amino-5-methylpyrazolo[1,5-a]pyridine-7-carboxylic acid (Va, 7.6 g, 39.8 mmol, 92% yield) as an off white solid.
- reaction mixture was slowly warmed to 25 °C and stirred further for 16 h. After completion of the reaction, the reaction mixture was filtered. Potassium tert-butoxide (17.55 g, 156.0 mmol) was added to the filtrate portion wise at 0-3 °C. The reaction mixture was then stirred for 60 min at 4-10 °C. After completion of the reaction, the reaction mixture was diluted with water (100 mL) followed by the addition of aq.2M NaOH solution (52.1 mL, 104.0 mmol) at 5 °C and continued to stir further for 16 h at 25 °C. The reaction mixture was diluted with water (50 mL), aqueous layer was separated and pH was adjusted to 4-5 using 20% aq.
- the reaction mixture was stirred for 1 h at a temperature between 4 °C to 10 °C. After completion of the reaction, water (250 mL) and aq. 2M NaOH solution (90 mL, 181.0 mmol) were added at 5 °C. The reaction mixture was stirred further for 16 h at 25°C and then diluted with water (150 mL). Aqueous layer was separated and pH was adjusted to 4-5 using 20% aq. citric acid solution. The precipitate obtained was stirred for further 1 h and then filtered.
- reaction mixture was diluted with water (2000 mL) and stirred for 30 min.
- the resulting slurry mass was filtered and the solid cake was washed with water and dried under reduced pressure to afford 7-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl)-5-methyl-9H- pyrazolo[1',5':1,6]pyrido[3,2-d][1,3]oxazin-9-one (IIIa, 320 g, 699 mmol, 89% yield) as a light green solid.
- reaction mixture was diluted with water (10 mL) and stirred for 30 min.
- the resulting slurry mass was filtered to obtained a solid cake, which was washed with water and dried under reduced pressure to obtain 7-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl)-5-methyl-9H- pyrazolo[1',5':1,6]pyrido[3,2-d][1,3]oxazin-9-one (IIIa, 0.9 g, 1.966 mmol, 75% yield) as a light green solid.
- reaction mixture was allowed to warm up to 25 °C and stirred for 2 h. After completion of the reaction, the reaction mixture was diluted with water (4 L) and stirred for 1 h. The resulting slurry mass was filtered to obtain a solid cake, which was washed with water (0.5 L) and dried under reduced pressure to afford 6-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamido)-N-isopropyl-5- methylpyrazolo[1,5-a]pyridine-7-carboxamide (Ia, 600 g, 1161 mmol, 90% yield) as an off white solid.
- reaction mixture was allowed to warm up to 25 °C and stirred for 2 h. After completion of the reaction, the reaction mixture was diluted with water (1000 mL) and extracted with ethyl acetate (2 x 500 mL). The organic layer was concentrated to obtain a residue, which was subjected to a solution of acetonitrile (400 mL) in water (1600 mL), which was stirred for 1 h at 25 °C.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
La présente invention concerne un procédé de préparation de diamides anthraniliques bicycliques de formule (I) ou de sels de ceux-ci, R1, R2, Ra, Rb et R3 étant tels que décrits dans la description. Plus particulièrement, la présente invention concerne un procédé de préparation de diamides anthraniliques bicycliques de formule (I), comprenant l'étape de préparation d'un 2-(5-(2-cyanoprop-1-en-1-yl)-1H-pyrazol-1-yl)acétate substitué de formule (VII) ou de sels de celui-ci par réaction d'un 2-(5-formyl-1H-pyrazol-1-yl)acétate substitué de formule (VIII) ou de sels de celui-ci avec un (1-cyanoéthyl)phosphonate substitué de formule (IX) ou de sels de celui-ci. L'invention concerne en outre un procédé de préparation de composés intermédiaires de formule (Z) ou de sels de ceux-ci, qui sont utiles dans la préparation d'un composé de formule (I) ou de sels de celui-ci.
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IN202111028885 | 2021-06-28 | ||
IN202111028885 | 2021-06-28 |
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PCT/IB2022/055939 WO2023275705A1 (fr) | 2021-06-28 | 2022-06-27 | Procédé de préparation de pyrazolopyridine-diamides de formule (i) et de leurs intermédiaires |
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AR (1) | AR126248A1 (fr) |
TW (1) | TW202317562A (fr) |
UY (1) | UY39833A (fr) |
WO (1) | WO2023275705A1 (fr) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2019123195A1 (fr) | 2017-12-20 | 2019-06-27 | Pi Industries Ltd. | Pyrazolopyridine-diamides, leur utilisation en tant qu'insecticide et leurs procédés de préparation |
WO2020170178A1 (fr) * | 2019-02-22 | 2020-08-27 | Pi Industries Ltd. | Procédé de synthèse de composés diamide anthranilique et intermédiaires associés |
WO2021010492A1 (fr) * | 2019-07-17 | 2021-01-21 | Ono Pharmaceutical Co., Ltd. | Composé présentant une activité inhibitrice de kdm5 et utilisation pharmaceutique associée |
WO2022023931A1 (fr) * | 2020-07-27 | 2022-02-03 | Pi Industries Ltd | Mélange d'actifs à action pesticide comprenant un composé d'anthranilamide de pyrazolopyridine, des oxydes ou des sels de celui-ci |
-
2022
- 2022-06-27 AR ARP220101674A patent/AR126248A1/es unknown
- 2022-06-27 WO PCT/IB2022/055939 patent/WO2023275705A1/fr active Application Filing
- 2022-06-28 UY UY0001039833A patent/UY39833A/es unknown
- 2022-06-28 TW TW111124150A patent/TW202317562A/zh unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019123195A1 (fr) | 2017-12-20 | 2019-06-27 | Pi Industries Ltd. | Pyrazolopyridine-diamides, leur utilisation en tant qu'insecticide et leurs procédés de préparation |
WO2020170178A1 (fr) * | 2019-02-22 | 2020-08-27 | Pi Industries Ltd. | Procédé de synthèse de composés diamide anthranilique et intermédiaires associés |
WO2021010492A1 (fr) * | 2019-07-17 | 2021-01-21 | Ono Pharmaceutical Co., Ltd. | Composé présentant une activité inhibitrice de kdm5 et utilisation pharmaceutique associée |
WO2022023931A1 (fr) * | 2020-07-27 | 2022-02-03 | Pi Industries Ltd | Mélange d'actifs à action pesticide comprenant un composé d'anthranilamide de pyrazolopyridine, des oxydes ou des sels de celui-ci |
Non-Patent Citations (2)
Title |
---|
"Bicyclic heterocyclic anthranilic diamides as ryanodine receptor modulators with insecticidal activity", BIOORGANIC AND MEDICINAL CHEMISTRY, vol. 24, 2016, pages 403 - 427 |
IORGA BOGDAN ET AL: "Carbanionic displacement reactions at phosphorus. Part III. Cyanomethylphosphonate vs. cyanomethylenediphosphonate. Synthesis and solid-state structures", ROYAL CHEMICAL SOCIETY. JOURNAL. PERKIN TRANSACTIONS 1, no. 19, 1 January 2000 (2000-01-01), GB, pages 3311 - 3316, XP055962834, ISSN: 1470-4358, DOI: 10.1039/b003371p * |
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UY39833A (es) | 2023-01-31 |
AR126248A1 (es) | 2023-10-04 |
TW202317562A (zh) | 2023-05-01 |
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