EP4225744A1 - Method for producing carbonylaminofurans - Google Patents
Method for producing carbonylaminofuransInfo
- Publication number
- EP4225744A1 EP4225744A1 EP21782572.8A EP21782572A EP4225744A1 EP 4225744 A1 EP4225744 A1 EP 4225744A1 EP 21782572 A EP21782572 A EP 21782572A EP 4225744 A1 EP4225744 A1 EP 4225744A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compounds
- general formula
- alkyl
- methyl
- methylbutyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 8
- WGJPTPNEGGRIRA-UHFFFAOYSA-N 2-isocyanatofuran Chemical class O=C=NC1=CC=CO1 WGJPTPNEGGRIRA-UHFFFAOYSA-N 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 47
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 claims description 4
- NTSLROIKFLNUIJ-UHFFFAOYSA-N 5-Ethyl-2-methylpyridine Chemical compound CCC1=CC=C(C)N=C1 NTSLROIKFLNUIJ-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 claims description 3
- SVYKKECYCPFKGB-UHFFFAOYSA-N N,N-dimethylcyclohexylamine Chemical compound CN(C)C1CCCCC1 SVYKKECYCPFKGB-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 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
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims 2
- -1 dihydrofuran carboxylic acids Chemical class 0.000 description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 5
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 229910019213 POCl3 Inorganic materials 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229910006124 SOCl2 Inorganic materials 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- ZXUQEPZWVQIOJE-UHFFFAOYSA-N methyl 2-chloro-2-oxoacetate Chemical compound COC(=O)C(Cl)=O ZXUQEPZWVQIOJE-UHFFFAOYSA-N 0.000 description 2
- YFVAXGLBXSDYEN-UHFFFAOYSA-N methyl 4-aminofuran-2-carboxylate Chemical compound COC(=O)C1=CC(N)=CO1 YFVAXGLBXSDYEN-UHFFFAOYSA-N 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 125000005919 1,2,2-trimethylpropyl group Chemical group 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- KLRZCGOQZZNVRA-UHFFFAOYSA-N 3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-1,1,1-trifluoropropan-2-one Chemical compound CC1(C)OCC(=CC(=O)C(F)(F)F)O1 KLRZCGOQZZNVRA-UHFFFAOYSA-N 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- WJEKCCOEKJGSGX-UHFFFAOYSA-N 5-methoxycarbonylfuran-3-carboxylic acid Chemical compound COC(=O)C1=CC(C(O)=O)=CO1 WJEKCCOEKJGSGX-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 238000006969 Curtius rearrangement reaction Methods 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- XZSAARMTEXJFKF-UHFFFAOYSA-N NC(=CC(C(F)(F)F)=O)CO Chemical compound NC(=CC(C(F)(F)F)=O)CO XZSAARMTEXJFKF-UHFFFAOYSA-N 0.000 description 1
- YEGXGRWDMWMDSS-UHFFFAOYSA-N NC(CO)=CC(C(F)F)=O Chemical compound NC(CO)=CC(C(F)F)=O YEGXGRWDMWMDSS-UHFFFAOYSA-N 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000012868 active agrochemical ingredient Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000007256 debromination reaction Methods 0.000 description 1
- 238000005695 dehalogenation reaction Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- NSTRXMLJJLAOEL-FNORWQNLSA-N ethyl (3e)-3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-2-oxopropanoate Chemical compound CCOC(=O)C(=O)\C=C1/COC(C)(C)O1 NSTRXMLJJLAOEL-FNORWQNLSA-N 0.000 description 1
- ZOPHPWIYDGESSY-UHFFFAOYSA-N ethyl 4-amino-5-hydroxy-2-oxopent-3-enoate Chemical compound CCOC(=O)C(=O)C=C(N)CO ZOPHPWIYDGESSY-UHFFFAOYSA-N 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- UTVVREMVDJTZAC-UHFFFAOYSA-N furan-2-amine Chemical class NC1=CC=CO1 UTVVREMVDJTZAC-UHFFFAOYSA-N 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- OXATZMLRFPCUDY-UHFFFAOYSA-N methyl 3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-2-oxopropanoate Chemical compound COC(=O)C(=O)C=C1COC(C)(C)O1 OXATZMLRFPCUDY-UHFFFAOYSA-N 0.000 description 1
- WTUVNWUSSGRHAG-UHFFFAOYSA-N methyl 4-(methoxycarbonylamino)furan-2-carboxylate Chemical compound COC(=O)NC1=COC(C(=O)OC)=C1 WTUVNWUSSGRHAG-UHFFFAOYSA-N 0.000 description 1
- NIFWRKXXEPGOFP-UHFFFAOYSA-N methyl 4-[(2,2,2-trifluoroacetyl)amino]furan-2-carboxylate Chemical compound COC(=O)c1cc(NC(=O)C(F)(F)F)co1 NIFWRKXXEPGOFP-UHFFFAOYSA-N 0.000 description 1
- KFWICTDEOIVAFS-UHFFFAOYSA-N methyl 4-amino-5-hydroxy-2-oxopent-3-enoate Chemical compound COC(=O)C(=O)C=C(N)CO KFWICTDEOIVAFS-UHFFFAOYSA-N 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229940072033 potash Drugs 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- OBTWBSRJZRCYQV-UHFFFAOYSA-N sulfuryl difluoride Chemical compound FS(F)(=O)=O OBTWBSRJZRCYQV-UHFFFAOYSA-N 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- UJJDEOLXODWCGK-UHFFFAOYSA-N tert-butyl carbonochloridate Chemical compound CC(C)(C)OC(Cl)=O UJJDEOLXODWCGK-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-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
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical group COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom 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
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom 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
- C07D307/66—Nitrogen atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a new process for preparing carbonylaminofurans of general formula (I).
- 4-Acylamino and alkoxycarbonylaminofurans of the general formula (I) are important precursors of agrochemical active ingredients (cf. WO2018/228985) and pharmaceutical active ingredients (e.g. DNA binding agents: Woods, Craig R et al Bioorganic & Medicinal Chemistry Letters, 12(18), 2647-2650;2002).
- 4-acylaminofurans of the general formula (I) serve as starting material for the production of tetrahydro- and dihydrofuran carboxylic acids - and esters.
- these compounds of formula (I) have been prepared via multi-step synthesis including a bromination, dehalogenation and coupling reaction (see F. Brucoli, et al. Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012).
- the object of the present invention is to find a process for preparing the compounds of the general formula (I) which is inexpensive and can be used on an industrial scale. It is also desirable to obtain these compounds with a high yield and in high purity, so that they do not have to be subjected to any further complex purification.
- R 1 is CF 3 , CF 2 H, C 2 F 5 , CF 2 C1, -COO-(Ci-C 6 )-alkyl, COOH,
- R 2 for H, (Ci-C 6 )-alkyl, Cl, F, CF 3 , CF 2 C1, CC1 3 , -O-(Ci-C 6 )-alkyl, -O-(Ci-C 6 )- alkylaryl,
- R 3 and R 4 independently represent H and (C 1 -C 6 )-alkyl and
- R 1 has the meanings given above, with ammonia in compounds of the general formula (III) wherein
- R 1 has the meanings given above, and these are converted in a second reaction step in the presence of a dehydrating reagent to give compounds of the general formula (IV) in which
- R 1 has the meanings given above, and these subsequently in a third reaction step by means of an acylating agent of the formula (V) wherein
- R 2 is as defined above and
- Alkyl means saturated, straight-chain or branched hydrocarbon radicals with the specified number of carbon atoms, for example (C 1 -C 6 )-alkyl such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1 ,1-dimethyl ethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1- ethylbuty
- Aryl means mono-, bi- or tricyclic aromatic or partially aromatic group containing from 6 to 14 carbon atoms, for example (but not limited to) phenyl, naphthyl, tetrahydronaphthyl, indenyl and indanyl. Attachment to the overall general structure can be through any suitable ring member of the aryl moiety.
- Aryl is preferably selected from phenyl, 1-naphthyl and 2-naphthyl. Phenyl is particularly preferred.
- R 1 represents CF 3 , CF 2 H, CF 2 C1 , C 2 F 5 , COOCH 3 , COOC 2 H 5 ,
- R 2 represents H, -(Ci-C 4 )-alkyl, CI, CF 3 , CF 2 C1, CC1 3 , -O-(Ci-C 4 )-alkyl, -O-CH 2 -phenyl, COOCH 3 , COOC2H5 ,
- R 3 and R 4 independently represent H or CH 3 ,
- X represents F, Cl, -OCOR 2 , H 3 CSO 2 O, p-TolSO 2 O.
- radical definitions for the general formulas (I), (II), (HI), (IV) and (V) are the following:
- R 1 represents COOCH 3 , COOC 2 H 5 ,
- R 2 is methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2 -dimethylpropyl, 1-ethylpropyl, CF 3 , -O-methyl, -O-ethyl, -O-propyl, -0-1-methylethyl, -O-butyl, -Ol-methyl- propyl, -O-2-methylpropyl, -O-1,1-dimethylethyl, -O-pentyl, -O-1-methylbutyl, -O-2-methylbutyl, -O-3-methylbutyl, -O-2,2 -dimethylpropyl, -0-1-ethylpropyl, C00CH 3 ,
- R 3 and R 4 independently represent H or CH 3
- X represents CI, -0C0R 2 , H 3 CSO 2 O.
- R 1 is COOCH3, COOC 2 H 5 ,
- R 2 represents H, CH 3 , CF 3 , -0CH 3 , -OC 2 H 5 , (CH 3 ) 3 CO-, CC1 3 , CO0CH 3 , -O-CH 2 -phenyl,
- R 3 and R 4 represent CH 3 .
- X stands for CI, -0C0R 2 .
- R 1 is COOCH3, CO0C 2 H 5 ,
- R2 is CF3 , -0CH3 , -0C2 H5 , (CH3 ) 3 CO- , CC13 , CO0CH3 . -O-CH 2 -phenyl
- R 3 and R 4 represent CH 3 .
- the compounds of the formula (III) are caused to cyclize.
- the ring closure took place in the presence of a dehydrating reagent such as SOCh, POCl3, PCI3, phosgene, diphosgene, triphosgene, C1COCOC1, (CF3CO)2, P4O10, SO2F2, trimethyl and ethyl orthoformate and HCl.
- a dehydrating reagent such as SOCh, POCl3, PCI3, phosgene, diphosgene, triphosgene, C1COCOC1, (CF3CO)2, P4O10, SO2F2, trimethyl and ethyl orthoformate and HCl.
- Preferred reagents are SOCl2, POCl3, oxalyl chloride, phosgene and HCl.
- the molar ratio of the compound of formula (III) to the cyclizing reagents is in the range of about 1:0.1 to 1:5, preferably 1:0.5 to 1:2.
- Reaction step 2 is usually carried out in a temperature range from 0° C. to 40° C. and, if appropriate, in the presence of a solvent or diluent.
- the reaction is preferably carried out at about room temperature (RT) in a solvent.
- the solvents are preferably methanol, ethanol, isopropanol, butanol, acetonitrile, N,N-dimethylacetamide, toluene, chlorobenzene, ethyl acetate, isopropyl acetate.
- the salt-free form can be obtained by treating the salt with a base, e.g., triethylamine in ethyl acetate (see Example 2).
- a base e.g., triethylamine in ethyl acetate
- the compounds of the formula (III) are acylated.
- the acylation takes place with a reagent of formula (V).
- the following compounds of the formula (V) may be mentioned by way of example: acetyl chloride, trichloroacetyl chloride, trifluoroacetic acid chloride or anhydride, methyl oxalyl chloride, methyl chloroformate, tert-butyl chloroformate, benzyl chloroformate, Boc anhydride.
- the molar ratio of the compound of general formula (IV) to the compound of general formula (V) is in the range from about 1:0.9 to 1:2, preferably 1:1 to 1:1.5.
- the acylation can be carried out with or without a base. It is to be regarded as surprising that the salts (especially HCl salts) of the compounds of the general formula (IV) can also be used for the acylation step. If a base is used, the molar ratio of the compounds of the general formula (IV) to the base is 1:0.5 to 1:3. Organic and inorganic compounds can be used as bases.
- Organic bases are: triethylamine, tributylamine, Hünig base, pyridine, alkylpyridine, dimethylcyclohexylamine.
- Preferred bases are triethylamine, Hünig base, 2-methyl-5-ethylpyridine, 3-picoline, dimethylcyclohexylamine.
- Possible inorganic bases are: Potash, Na2COs, NaOAc,
- Reaction step 3 is usually carried out in a temperature range from 10° C. to 40° C. and, if appropriate, in the presence of a solvent or diluent.
- the reaction is preferably carried out at about room temperature (RT) in a solvent.
- Solvents such as toluene, chlorobenzene, acetonitrile, ether, dimethylacetamide, ethyl acetate, isopropyl acetate and dichloromethane are preferred.
- the compounds of the formula (I) are isolated by filtration of the product or extraction with an organic solvent (see examples).
- the products were characterized by means of ⁇ -/ ⁇ C-NMR spectroscopy and/or LC/MS (Liquid Chromatography Mass Spectrometry).
- the NMR spectra were determined with a Bruker Avance 400 equipped with a flow-through probe (60 ⁇ l volume). In individual cases, the NMR spectra were measured with a Bruker Avance II 600. example 1
- Methyl 4-[(2-methoxy-2-oxo-acetyl)amino]furan-2-carboxylate 0.5 g of methyl 4-aminofuran-2-carboxylate hydrochloride was suspended in 15 ml of ethyl acetate and 0.5 g of methyl oxalyl chloride was added at 10°C. The mixture was stirred at RT for 15 h and the precipitate was filtered off. 0.5 g (79%) of the product was obtained.
- methyl 4-aminofuran-2-carboxylate hydrochloride was suspended in 15 ml of ethyl acetate and 0.5 g of methyl chloroformate was added at 10°C. The mixture was stirred at RT for 30 min and 0.5 g of NEts were added portionwise. The mixture was stirred at RT for 10 h and diluted with 30 ml of ethyl acetate. The organic phase was washed with water and evaporated. 0.54 g of the product was obtained.
Abstract
The present invention relates to a novel method for producing carbonylaminofurans of general formula (I).
Description
Verfahren zur Herstellung von Carbonylaminofuranen Process for preparing carbonylaminofurans
Die vorliegende Erfindung betrifft ein neues Verfahren zur Herstellung von Carbonylaminofuranen der allgemeinen Formel (I). The present invention relates to a new process for preparing carbonylaminofurans of general formula (I).
4-Acylamino und Alkoxycarbonylaminofurane der allgemeinen Formel (I) (vor allem R1=COOMethyl, R2=O/Butyl) sind wichtige Vorstufen von agrochemischen Wirkstoffen (vgl. WO2018/228985) und pharmazeutischen Wirkstoffen (z.B. DNA Binding Agents: Woods, Craig R. et al. Bioorganic & Medicinal Chemistry Letters, 12(18), 2647-2650; 2002). 4-Acylamino and alkoxycarbonylaminofurans of the general formula (I) (especially R 1 = COOmethyl, R 2 = O/butyl) are important precursors of agrochemical active ingredients (cf. WO2018/228985) and pharmaceutical active ingredients (e.g. DNA binding agents: Woods, Craig R et al Bioorganic & Medicinal Chemistry Letters, 12(18), 2647-2650;2002).
4-Acylaminofurane der allgemeinen Formel (I) dienen als Ausgangsstoff für die Herstellung von Tetrahydro- und Dihydrofurancarbonsäuren - und estem. Bisher wurden diese Verbindungen der Formel (I) über mehrstufige Synthese inklusive einer Bromierung, Dehalogenierung, und Kupplungsreaktion (siehe F. Brucoli, et al. Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012) hergestellt. 4-acylaminofurans of the general formula (I) serve as starting material for the production of tetrahydro- and dihydrofuran carboxylic acids - and esters. To date, these compounds of formula (I) have been prepared via multi-step synthesis including a bromination, dehalogenation and coupling reaction (see F. Brucoli, et al. Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012).
Schema 1:
a) Br2, A1C13; b) Zn, NH4CI; c) Cul/ (CH3NHCH2)2, Boc-NH2, K2CO3 Scheme 1: a) Br 2 , AlCl 3 ; b) Zn, NH4Cl; c) Cul/ (CH 3 NHCH 2 ) 2 , Boc-NH 2 , K 2 CO 3
Die oben genannte Synthese weist eine große Menge von Nachteilen auf, wie z.B. eine niedrige Atomökonomie (Bromierung und Debromierung), Verwendung von Schwermetallen wie Zink und Verwendung von teuren Reagenzien wie Boc-Amin. Darüber hinaus erfordert das in Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012 beschriebene Verfahren die Verwendung von metallhaltigen (beispielsweise Kupfer(I)-iodid) Katalysatoren. The above synthesis has a large number of disadvantages, such as low atom economy (bromination and debromination), use of heavy metals such as zinc, and use of expensive reagents such as Boc-amine. In addition, as described in Bioorganic & Medicinal Chemistry, 20(6), 2019-2024; 2012 described the use of metal-containing (e.g. cuprous iodide) catalysts.
Diese Nachteile machen das Verfahren zur Herstellung der Verbindungen der allgemeinen Formel (I) unwirtschaftlich und damit sehr teuer.
F. Wolter et al in (Organic Letters, 11(13), 2804-2807; 2009) beschreibt eine andere Methode für die Herstellung von Aminofuranen der allgemeinen Formel (I), und zwar über eine Curtius Umlagerung von Furan-2,4-dicarbonsäure-2-methylester unter Verwendung von (PhO3)2P(O)N3. Diese Methode ist wegen der hochexplosiven Eigenschaften der organischen Azide für großtechnische Anwendungen nicht geeignet. These disadvantages make the process for preparing the compounds of the general formula (I) uneconomical and therefore very expensive. F. Wolter et al in (Organic Letters, 11(13), 2804-2807; 2009) describes another method for the preparation of aminofurans of general formula (I), namely via a Curtius rearrangement of furan-2,4- dicarboxylic acid 2-methyl ester using (PhO 3 ) 2 P(O)N 3 . This method is not suitable for large-scale technical applications because of the highly explosive properties of the organic azides.
Einige Verbindungen der allgemeinen Formel (I), z.B. mit RI=CB, und R2 =NHAryl, wurden in EOC 2018, 3853-3861 beschrieben. Allerdings wurde diese Verbindung im Gemisch von mehreren Komponenten nachgewiesen. Some compounds of the general formula (I), eg with R I= CB and R 2 =NHAryl, have been described in EOC 2018, 3853-3861. However, this compound was detected in a mixture of several components.
Im Lichte des zuvor beschriebenen Standes der Technik liegt der vorliegenden Erfindung die Aufgabe zugrunde, ein Verfahren zur Herstellung der Verbindungen der allgemeinen Formel (I) zu finden, das kostengünstig ist und großtechnisch eingesetzt werden kann. Auch ist es erstrebenswert, diese Verbindungen mit hoher Ausbeute und in hoher Reinheit zu erhalten, so dass sie keiner weiteren komplexen Aufreinigung unterzogen werden müssen. In the light of the prior art described above, the object of the present invention is to find a process for preparing the compounds of the general formula (I) which is inexpensive and can be used on an industrial scale. It is also desirable to obtain these compounds with a high yield and in high purity, so that they do not have to be subjected to any further complex purification.
Die zuvor beschriebene Aufgabe einer einfachen, kostengünstigen und großtechnischen Herstellung wird gelöst durch ein Verfahren zur Herstellung von Verbindungen der allgemeinen Formel (I)
worin The problem described above of a simple, inexpensive and large-scale production is achieved by a process for the preparation of compounds of the general formula (I) wherein
R1 für CF3, CF2H, C2F5, CF2C1, -COO-(Ci-C6)-Alkyl, COOH steht, R 1 is CF 3 , CF 2 H, C 2 F 5 , CF 2 C1, -COO-(Ci-C 6 )-alkyl, COOH,
R2 für H, (Ci-C6)-Alkyl, Cl, F, CF3, CF2C1, CC13, -O-(Ci-C6)-Alkyl, -O-(Ci-C6)-Alkylaryl,R 2 for H, (Ci-C 6 )-alkyl, Cl, F, CF 3 , CF 2 C1, CC1 3 , -O-(Ci-C 6 )-alkyl, -O-(Ci-C 6 )- alkylaryl,
-COO-(Ci-C6)-Alkyl steht, dadurch gekennzeichnet, dass in einem ersten Schritt Verbindungen der allgemeinen Formel (II)
worin -COO-(Ci-C 6 )-alkyl, characterized in that in a first step compounds of the general formula (II) wherein
R3 und R4 unabhängig voneinander für H und (C1-C6)-Alkyl stehen und R 3 and R 4 independently represent H and (C 1 -C 6 )-alkyl and
R1 die oben genannten Bedeutungen hat, mit Ammoniak in Verbindungen der allgemeinen Formel (III)
worin R 1 has the meanings given above, with ammonia in compounds of the general formula (III) wherein
R1 die oben genannten Bedeutungen hat, überführt werden und diese in einem zweiten Reaktionsschritt in Gegenwart eines wasserentziehenden Reagenzes zu Verbindungen der allgemeinen Formel (IV) umgesetzt werden worin
R 1 has the meanings given above, and these are converted in a second reaction step in the presence of a dehydrating reagent to give compounds of the general formula (IV) in which
R1 die oben genannten Bedeutungen hat, und diese anschließend in einem dritten Reaktionsschritt mittels eines Acylierungsreagenzes der Formel (V)
worin R 1 has the meanings given above, and these subsequently in a third reaction step by means of an acylating agent of the formula (V) wherein
R2 wie oben definiert ist und R 2 is as defined above and
X für F, CI, Br, H3CSO2O, p-TolSO2O, -OCOR2 steht, zu Verbindungen der allgemeinen Formel (I) umgesetzt werden.
Definitionen X stands for F, CI, Br, H 3 CSO 2 O, p-TolSO 2 O, -OCOR 2 , to give compounds of the general formula (I). definitions
Alkyl bedeutet gesättigte, geradkettige oder verzweigte Kohlenwasserstoffreste mit der jeweils angegebenen Anzahl von Kohlenstoffatomen, z.B. (C1-C6)-Alkyl wie Methyl, Ethyl, Propyl, 1- Methylethyl, Butyl, 1 -Methyl-propyl, 2-Methylpropyl, 1,1 -Dimethyl ethyl, Pentyl, 1 -Methylbutyl, 2- Methylbutyl, 3 -Methylbutyl, 2,2-Di-methylpropyl, 1 -Ethylpropyl, Hexyl, 1 , 1 -Dimethylpropyl, 1,2- Dimethylpropyl, 1 -Methylpentyl, 2-Methylpentyl, 3 -Methylpentyl, 4-Methylpentyl, 1 , 1 -Dimethylbutyl, 1 ,2-Dimethylbutyl, 1,3 -Dimethylbutyl, 2,2-Dimethylbutyl, 2,3 -Dimethylbutyl, 3,3- Dimethylbutyl, 1 -Ethylbutyl, 2-Ethylbutyl, 1,1,2-Trimethylpropyl, 1,2,2-Trimethylpropyl, 1-Ethyl- 1 -methylpropyl und l-Ethyl-2-methylpropyl. Alkyl means saturated, straight-chain or branched hydrocarbon radicals with the specified number of carbon atoms, for example (C 1 -C 6 )-alkyl such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1 ,1-dimethyl ethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1- ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.
Aryl bedeutet mono-, bi- oder tricyclische aromatische oder teilweise aromatische Gruppe mit 6 bis 14 Kohlenstoffatomen, zum Beispiel (jedoch nicht darauf beschränkt) Phenyl, Naphthyl, Tetrahydronaphthyl, Indenyl und Indanyl. Die Bindung an die übergeordnete allgemeine Struktur kann über ein beliebiges geeignetes Ringglied des Arylrests erfolgen. Aryl ist vorzugsweise aus Phenyl, 1 -Naphthyl und 2-Naphthyl ausgewählt. Phenyl ist besonders bevorzugt. Aryl means mono-, bi- or tricyclic aromatic or partially aromatic group containing from 6 to 14 carbon atoms, for example (but not limited to) phenyl, naphthyl, tetrahydronaphthyl, indenyl and indanyl. Attachment to the overall general structure can be through any suitable ring member of the aryl moiety. Aryl is preferably selected from phenyl, 1-naphthyl and 2-naphthyl. Phenyl is particularly preferred.
Die erfindungsgemäßen Verbindungen sind durch die Formel (I) allgemein definiert. Bevorzugte Substituenten bzw. Bereiche der in der oben und nachstehend erwähnten Formeln aufgeführten Reste werden im Folgenden erläutert: The compounds according to the invention are generally defined by the formula (I). Preferred substituents or ranges of the radicals listed in the formulas mentioned above and below are explained below:
Bevorzugte Restedefinitionen für die allgemeinen Formeln (I), (II), (HI), (IV) und (V) sind die folgenden: Preferred radical definitions for the general formulas (I), (II), (HI), (IV) and (V) are the following:
R1 steht für CF3, CF2H, CF2C1, C2F5, COOCH3, COOC2H5, R 1 represents CF 3 , CF 2 H, CF 2 C1 , C 2 F 5 , COOCH 3 , COOC 2 H 5 ,
R2 steht für H, -(Ci-C4)-Alkyl, CI, CF3, CF2C1, CC13, -O-(Ci-C4)-Alkyl, -O-CH2-Phenyl, COOCH3, COOC2H5, R 2 represents H, -(Ci-C 4 )-alkyl, CI, CF 3 , CF 2 C1, CC1 3 , -O-(Ci-C 4 )-alkyl, -O-CH 2 -phenyl, COOCH 3 , COOC2H5 ,
R3 und R4 stehen unabhängig voneinander für H oder CH3, R 3 and R 4 independently represent H or CH 3 ,
X steht für F, CI, -OCOR2, H3CSO2O, p-TolSO2O. X represents F, Cl, -OCOR 2 , H 3 CSO 2 O, p-TolSO 2 O.
Besonders bevorzugte Restedefinitionen für die allgemeinen Formeln (I), (II), (HI), (IV) und (V) sind die folgenden: Particularly preferred radical definitions for the general formulas (I), (II), (HI), (IV) and (V) are the following:
R1 steht für COOCH3, COOC2H5, R 1 represents COOCH 3 , COOC 2 H 5 ,
R2 steht für Methyl, Ethyl, Propyl, 1 -Methylethyl, Butyl, 1 -Methyl-propyl, 2-Methylpropyl, 1,1- Dimethyl ethyl, Pentyl, 1 -Methylbutyl, 2-Methylbutyl, 3 -Methylbutyl, 2,2-Di-methylpropyl, 1- Ethylpropyl, CF3, -O-Methyl, -O-Ethyl, -O-Propyl, -0-1 -Methylethyl, -O-Butyl, -O-l-Methyl-
propyl, -O-2-Methylpropyl, -0-1,1 -Dimethylethyl, -O-Pentyl, -0-1 -Methylbutyl, -O-2-Methylbutyl, -0-3 -Methylbutyl, -O-2,2-Di-methylpropyl, -0-1 -Ethylpropyl, C00CH3, R 2 is methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2 -dimethylpropyl, 1-ethylpropyl, CF 3 , -O-methyl, -O-ethyl, -O-propyl, -0-1-methylethyl, -O-butyl, -Ol-methyl- propyl, -O-2-methylpropyl, -O-1,1-dimethylethyl, -O-pentyl, -O-1-methylbutyl, -O-2-methylbutyl, -O-3-methylbutyl, -O-2,2 -dimethylpropyl, -0-1-ethylpropyl, C00CH 3 ,
R3 und R4 stehen unabhängig voneinander fur H oder CH3 R 3 and R 4 independently represent H or CH 3
X steht für CI, -0C0R2, H3CSO2O. X represents CI, -0C0R 2 , H 3 CSO 2 O.
Ganz besonders bevorzugte Restedefinitionen für die allgemeinen Formeln (I), (II), (III), (IV) und (V) sind die folgenden: Very particularly preferred definitions of radicals for the general formulas (I), (II), (III), (IV) and (V) are as follows:
R1 steht fur COOCH3, COOC2H5, R 1 is COOCH3, COOC 2 H 5 ,
R2 steht für H, CH3, CF3, -0CH3, -OC2H5, (CH3)3CO-, CC13, C00CH3, -O-CH2-Phenyl, R 2 represents H, CH 3 , CF 3 , -0CH 3 , -OC 2 H 5 , (CH 3 ) 3 CO-, CC1 3 , CO0CH 3 , -O-CH 2 -phenyl,
R3 und R4 stehen für CH3, R 3 and R 4 represent CH 3 ,
X steht für CI, -0C0R2. X stands for CI, -0C0R 2 .
Am stärksten bevorzugte Restedefinitionen für die allgemeinen Formeln (I), (II), (III), (IV) und (V) sind die folgenden: Most preferred radical definitions for general formulas (I), (II), (III), (IV) and (V) are as follows:
R1 steht fur COOCH3, C00C2H5, R 1 is COOCH3, CO0C 2 H 5 ,
R2 steht für CF3, -0CH3, -0C2H5, (CH3)3C0-, CC13, C00CH3. -O-CH2-Phenyl R2 is CF3 , -0CH3 , -0C2 H5 , (CH3 ) 3 CO- , CC13 , CO0CH3 . -O-CH 2 -phenyl
R3 und R4 stehen für CH3, R 3 and R 4 represent CH 3 ,
X steht für CI. X stands for CI.
Die Reaktionsfolge zur Herstellung von Verbindungen der Formel (I) ist im Schema 2 dargestellt. The reaction sequence for preparing compounds of formula (I) is shown in Scheme 2.
Schema 2
Scheme 2
Die Verbindungen der Formel (II) reagieren mit Ammoniak unter Bildung der Verbindungen der allgemeinen Formel (III), die dann im zweiten Reaktionsschritt unter Wasserabspaltung in Verbindungen der allgemeinen Formel (IV) umgewandelt werden und dann mit einem Acylierungsreagenz der allgemeinen Formel (V) zu Verbindungen der allgemeinen Formel (I)
umgesetzt werden. The compounds of the formula (II) react with ammonia to form the compounds of the general formula (III), which are then converted in the second reaction step into compounds of the general formula (IV) with elimination of water and then with an acylating reagent of the general formula (V). Compounds of general formula (I) be implemented.
Schritt 1 Step 1
Die Verbindungen der Formel (II) reagieren mit Ammoniak unter Bildung der Verbindungen der allgemeinen Formel (III). The compounds of formula (II) react with ammonia to form the compounds of general formula (III).
Die Synthese der Verbindungen der der allgemeinen Formel (II) und (III), in denen R1, R3, R4 und R5 die oben genannten Bedeutungen haben, sind bekannt. Die Herstellung dieser Verbindungen kann nach dem aus WO 2011/073100, WO 2011/073101 und European Journal of Organic Chemistry (2018), 2018(27-28), 3853-3861 bekannten Verfahren erfolgen. The synthesis of the compounds of the general formulas (II) and (III) in which R 1 , R 3 , R 4 and R 5 have the meanings given above are known. These compounds can be prepared by the method known from WO 2011/073100, WO 2011/073101 and European Journal of Organic Chemistry (2018), 2018(27-28), 3853-3861.
Beispielhaft seien folgende Verbindungen der Formel (II) genannt:
The following compounds of the formula (II) may be mentioned by way of example:
3 -(2,2-Dimethyl- 1 ,3 -dioxolan-4-yliden)- 1,1,1 -trifluor-propan-2-on 3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-1,1,1-trifluoro-propan-2-one
3 -( 1 ,3 -Dioxolan-4-yliden)- 1,1,1 -trifluor-propan-2-on 3-(1,3-dioxolan-4-ylidene)-1,1,1-trifluoro-propan-2-one
Methyl-3-(2,2-dimethyl-l,3-dioxolan-4-yliden)-2-oxo-propanoat Methyl 3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-2-oxo-propanoate
Ethyl-3-(2,2-dimethyl-l,3-dioxolan-4-yliden)-2-oxo-propanoat Ethyl 3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)-2-oxo-propanoate
Beispielhaft seien folgende Verbindungen der Formel (III) genannt:
The following compounds of the formula (III) may be mentioned by way of example:
4-Amino- 1,1,1 -trifluoro— 5 -hydroxy-pent-3 -en-2-on 4-amino-1,1,1-trifluoro-5-hydroxy-pent-3-en-2-one
4-Amino- 1 , 1 -difluoro— 5 -hydroxy-pent-3 -en-2-on 4-amino-1,1-difluoro-5-hydroxy-pent-3-en-2-one
4-Amino- 1,1,1 -trichloro— 5 -hydroxy-pent-3 -en-2-on
Methyl -4-amino-5 -hydroxy-2-oxo-pent-3 -enoat 4-amino-1,1,1-trichloro-5-hydroxy-pent-3-en-2-one Methyl 4-amino-5-hydroxy-2-oxo-pent-3-enoate
Ethyl -4-amino-5 -hydroxy-2-oxo-pent-3 -enoat Ethyl 4-amino-5-hydroxy-2-oxo-pent-3-enoate
Schritt 2 step 2
Im zweiten Reaktionsschritt werden die Verbindungen der Formel (III) zum Zyklisieren gebracht. Der Ringschluss erfolgte in Gegenwart eines wasserentziehenden Reagenzes wie SOCh, POCI3, PCI3, Phosgen, Diphosgen, Triphosgen, C1COCOC1, (CF3CO)2, P4O10, SO2F2, Orthoameisensäuretrimethyl- und ethylester und HCl. Bevorzugte Reagenzien sind SOCI2, POCI3, Oxalylchlorid, Phosgen und HCl.In the second reaction step, the compounds of the formula (III) are caused to cyclize. The ring closure took place in the presence of a dehydrating reagent such as SOCh, POCl3, PCI3, phosgene, diphosgene, triphosgene, C1COCOC1, (CF3CO)2, P4O10, SO2F2, trimethyl and ethyl orthoformate and HCl. Preferred reagents are SOCl2, POCl3, oxalyl chloride, phosgene and HCl.
Das molare Verhältnis der Verbindung der Formel (III) zu den Zyklisierungsreagenzien liegt im Bereich von etwa 1:0,1 bis 1:5, bevorzugt 1:0,5 bis 1:2. The molar ratio of the compound of formula (III) to the cyclizing reagents is in the range of about 1:0.1 to 1:5, preferably 1:0.5 to 1:2.
Die Reaktionsschritt 2 wird gewöhnlich in einem Temperaturbereich von 0 °C bis 40 °C und gegebenenfalls in Gegenwart eines Lösungs- oder Verdünnungsmittel durchgefuhrt. Vorzugsweise wird die Umsetzung bei etwa Raumtemperatur (RT) in einem Lösemittel vorgenommen. Reaction step 2 is usually carried out in a temperature range from 0° C. to 40° C. and, if appropriate, in the presence of a solvent or diluent. The reaction is preferably carried out at about room temperature (RT) in a solvent.
Bevorzugt sind die Lösemitteln Methanol, Ethanol, Isopropanol, Butanol, Acetonitrile, N,N- Dimethylacetamid, Toluene, Chlorobenzene, Ethylacetate, Isopropylacetate. The solvents are preferably methanol, ethanol, isopropanol, butanol, acetonitrile, N,N-dimethylacetamide, toluene, chlorobenzene, ethyl acetate, isopropyl acetate.
Bei der Umsetzung mit SOCI2, POCI3, PCL, Phosgen, Diphosgen, Triphosgen, C1COCOC1 fallen die Verbindungen der allgemeinen Formel (IV) in Form ihrer HCl-Salze an. In the reaction with SOCl2, POCl3, PCL, phosgene, diphosgene, triphosgene, C1COCOC1, the compounds of the general formula (IV) are obtained in the form of their HCl salts.
Die salzfreie Form kann gewonnen werden, indem das Salz mit einer Base, z.B. Triethylamin in Ethylacetate, behandelt wird (s. Beispiel 2). The salt-free form can be obtained by treating the salt with a base, e.g., triethylamine in ethyl acetate (see Example 2).
Beispielhaft seien folgende Verbindungen der Formel (IV) genannt:
The following compounds of the formula (IV) may be mentioned by way of example:
Methyl 4-aminofuran-2-carboxylathydrochlorid/Methyl 4-aminofuran-2-carboxylat Methyl 4-aminofuran-2-carboxylate hydrochloride/methyl 4-aminofuran-2-carboxylate
Ethyl 4-aminofuran-2-carboxylathydrochlorid/ Ethyl 4-aminofuran-2-carboxylat Ethyl 4-aminofuran-2-carboxylate hydrochloride/ Ethyl 4-aminofuran-2-carboxylate
4-Amino-2-trifluormethylfuranhydrochlorid 4-amino-2-trifluoromethylfuran hydrochloride
Schritt 3 step 3
Im dritten Reaktionsschritt werden die Verbindungen der Formel (III) acyliert. Die Acylierung erfolgt mit
einem Reagenz der Formel (V). Beispielhaft seien folgende Verbindungen der Formel (V) genannt, Acetylchlorid, Trichloracetylchlorid, Trifluoressigsäuerechlorid oder Anhydrid, Methyloxalylchlorid, Methylchlorformiat, tert-Butylchlorformiat, Benzylchlorformiat, Boc-Anhydrid. In the third reaction step, the compounds of the formula (III) are acylated. The acylation takes place with a reagent of formula (V). The following compounds of the formula (V) may be mentioned by way of example: acetyl chloride, trichloroacetyl chloride, trifluoroacetic acid chloride or anhydride, methyl oxalyl chloride, methyl chloroformate, tert-butyl chloroformate, benzyl chloroformate, Boc anhydride.
Das molare Verhältnis der Verbindung der allgemeinen Formel (IV) zu der Verbindung der allgemeinen Formel (V) liegt im Bereich von etwa 1:0,9 bis 1:2, bevorzugt 1: 1 bis 1: 1,5. The molar ratio of the compound of general formula (IV) to the compound of general formula (V) is in the range from about 1:0.9 to 1:2, preferably 1:1 to 1:1.5.
Die Acylierung kann mit oder ohne Base durchgeführt werden. Als überraschend ist anzusehen, dass für den Acylierungsschritt auch die Salze (vor allem HCl Salze) der Verbindungen der allgemeinen Formel (IV) verwendet werden können. Wird eine Base eingesetzt, beträgt das molare Verhältnis der Verbindungen der allgemeinen Formel (IV) zur Base 1:0,5 bis 1:3. Als Basen kommen organische und anorganische Verbindungen in Frage. The acylation can be carried out with or without a base. It is to be regarded as surprising that the salts (especially HCl salts) of the compounds of the general formula (IV) can also be used for the acylation step. If a base is used, the molar ratio of the compounds of the general formula (IV) to the base is 1:0.5 to 1:3. Organic and inorganic compounds can be used as bases.
Organische Basen sind: Triethylamin, Tributylamin, Hünig Base, Pyridine, Alkylpyridine, Dimethylcyclohexylamin. Bevorzugte Basen sind Triethylamin, Hünig-Base, 2-Methyl-5-ethylpyridine, 3-Picolin, Dimethylcyclohexylamin. Organic bases are: triethylamine, tributylamine, Hünig base, pyridine, alkylpyridine, dimethylcyclohexylamine. Preferred bases are triethylamine, Hünig base, 2-methyl-5-ethylpyridine, 3-picoline, dimethylcyclohexylamine.
Mögliche anorganische Basen sind: Pottasche, Na2COs, NaOAc, Possible inorganic bases are: Potash, Na2COs, NaOAc,
Die Reaktionsschritt 3 wird gewöhnlich in einem Temperaturbereich von 10 °C bis 40 °C und gegebenenfalls in Gegenwart eines Lösungs- oder Verdünnungsmittel durchgeführt. Vorzugsweise wird die Umsetzung bei etwa Raumtemperatur (RT) in einem Lösemittel vorgenommen. Reaction step 3 is usually carried out in a temperature range from 10° C. to 40° C. and, if appropriate, in the presence of a solvent or diluent. The reaction is preferably carried out at about room temperature (RT) in a solvent.
Bevorzugt sind Lösungsmittel wie Toluol, Chlorbenzol, Acetonitrile, Ether, Dimethylacetamid, Ethylacetate, Isopropylacetat, Dichlormethan. Die Isolierung der Verbindungen der Formel (I) erfolgt durch Filtration des Produktes oder Extraktion mit einem organischen Lösungsmittel (siehe Beispiele). Solvents such as toluene, chlorobenzene, acetonitrile, ether, dimethylacetamide, ethyl acetate, isopropyl acetate and dichloromethane are preferred. The compounds of the formula (I) are isolated by filtration of the product or extraction with an organic solvent (see examples).
Erläuterung der Verfahren und Zwischenprodukte Explanation of the processes and intermediates
Beispiele examples
Die vorliegende Erfindung wird anhand der nachfolgenden Beispiele näher erläutert, ohne die Erfindung dabei auf diese einzuschränken. The present invention is explained in more detail using the following examples, without restricting the invention to these.
Messverfahren measurement method
Die Produkte wurden mittels ^-/^C-NMR Spektroskopie und/oder LC/MS (Liquid Chromatography Mass Spectrometry) charakterisiert. The products were characterized by means of ^-/^C-NMR spectroscopy and/or LC/MS (Liquid Chromatography Mass Spectrometry).
Die NMR-Spektren wurden mit einem Bruker Avance 400, ausgestattet mit einem Durchflussprobenkopf (60 pl Volumen), bestimmt. In Einzelfällen wurden die NMR Spektren mit einem Bruker Avance II 600 gemessen.
Beispiel 1 The NMR spectra were determined with a Bruker Avance 400 equipped with a flow-through probe (60 μl volume). In individual cases, the NMR spectra were measured with a Bruker Avance II 600. example 1
Methyl 4-aminofuran-2-carboxylathydrochlorid (HCl Salz der Verbindungen der Formel (IV)). Methyl 4-aminofuran-2-carboxylate hydrochloride (HCl salt of the compounds of formula (IV)).
15,9 g (0.1 mol) Methyl 4-amino-5-hydroxy-2-oxo-pent-3-enoat wurden in 50 ml Methanol suspendiert und das Gemisch auf 0°C gekühlt. 17,7 g (0,15 mol) von SOCb wurden bei 0°C binnen 2 Stunden (Std.) dazu dosiert. Das Gemisch wurde 5 Std. bei 10°C nachgerührt und der Niederschlag wurde abfiltriert, mit 5 ml Methanol gewaschen und getrocknet. Man erhielt 16,8 g, 95 % von hell beigen Kristallen. 15.9 g (0.1 mol) of methyl 4-amino-5-hydroxy-2-oxo-pent-3-enoate were suspended in 50 ml of methanol and the mixture was cooled to 0°C. 17.7 g (0.15 mol) of SOCb were metered in at 0° C. within 2 hours (hours). The mixture was stirred at 10° C. for 5 hours and the precipitate was filtered off, washed with 5 ml of methanol and dried. 16.8 g, 95% of light beige crystals were obtained.
'H-NMR (400MHz, CDCI3): δ 10.07 (3H, s, br.); 8.10 (1H, d); 7.32 (1H, d); 3,83 (3H, s) ppm. 'H-NMR (400MHz, CDCl3): δ 10.07 (3H, s, br.); 8.10(1H,d); 7.32 (1H,d); 3.83(3H,s)ppm.
13C-NMR 158,0 (s); 143,6 (s); 140,2 (d); 121,8 (s); 114,5 (d); 52,3 (q) ppm. 13 C NMR 158.0 (s); 143.6(s); 140.2 (d); 121.8(s); 114.5(d); 52.3 (q)ppm.
Beispiel 2 example 2
Überführung von Methyl 4-aminofuran-2-carboxylathydrochlorid (Salz der Formel (IV)) in Methyl 4-aminofuran-2-carboxylat (salzfreies Produkt der Formel (IV) Conversion of methyl 4-aminofuran-2-carboxylate hydrochloride (salt of formula (IV)) to methyl 4-aminofuran-2-carboxylate (salt free product of formula (IV)
9,2 g von Methyl 4-aminofuran-2-carboxylathydrochlorid wurden in 50 ml Ethylacetate suspendiert und 15,7 g von Et3N wurden zugegeben. Das Gemisch wurde 3 Std bei RT gerührt, der Niederschlag wurde abfiltriert und Ethylacetat komplett im Vakuum eingeengt. Man erhielt 6,96 g, 95 % von beigen Kristallen. 9.2 g of methyl 4-aminofuran-2-carboxylate hydrochloride was suspended in 50 mL of ethyl acetate and 15.7 g of Et3N was added. The mixture was stirred at RT for 3 h, the precipitate was filtered off and ethyl acetate was completely concentrated in vacuo. There was obtained 6.96 g, 95% of beige crystals.
'H-NMR (400MHz, CDCI3): δ: 7,24 (1H, d); 6,8 (1H, d) ; 4,3 (2H,s ) 3,75 (3H, s) ppm. 'H NMR (400MHz, CDCl3): δ: 7.24 (1H, d); 6.8(1H,d) ; 4.3(2H,s) 3.75(3H,s)ppm.
Beispiel 3 Example 3
Methyl-4- [(2,2,2-trifluoracetyl)amino] furan-2-carboxylat Methyl 4-[(2,2,2-trifluoroacetyl)amino]furan-2-carboxylate
0,5 g von Methyl 4-aminofuran-2-carboxylathydrochlorid wurden in 15 ml Ethylacetate suspendiert und 1 g von (CF3CO)O wurden bei 10°c zugegeben. Das Gemisch wurde 5 Std bei RT gerührt und der Niederschlag wurde abfiltriert. Man erhielt 0,55 g des Produktes als Feststoff. 0.5 g of methyl 4-aminofuran-2-carboxylate hydrochloride was suspended in 15 ml of ethyl acetate and 1 g of (CF 3 CO)O was added at 10°C. The mixture was stirred at RT for 5 h and the precipitate was filtered off. 0.55 g of the product was obtained as a solid.
'H-NMR (400MHz, CDCI3): 5 11.76 (1H, s, br.); 8.26 (1H, d); 7.24 (1H, d); 3,76 (3H, s) ppm. nC-NMR 158,2 (s); 154,1 (s, q); 142,5 (s); 137,4 (d); 124,7 (s); 115,8 (s); 112,1 (d); 52,3 (q) ppm. 'H NMR (400MHz, CDCl3): 5 11.76 (1H, s, br.); 8.26 (1H,d); 7.24 (1H,d); 3.76(3H,s)ppm. n C NMR 158.2(s); 154.1 (s, q); 142.5(s); 137.4(d); 124.7(s); 115.8(s); 112.1(d); 52.3 (q)ppm.
Beispiel 4 example 4
Methyl-4-[(2-methoxy-2-oxo-acetyl)amino]furan-2-carboxylat
0,5 g von Methyl 4-aminofuran-2-carboxylathydrochlorid wurden in 15 ml Ethylacetate suspendiert und 0,5 g von Methyl oxalyl chlorid wurden bei 10°c zugegeben. Das Gemisch wurde 15 Std bei RT gerührt und der Niederschlag wurde abfiltriert. Man erhielt 0,5 g (79 %) des Produktes. Methyl 4-[(2-methoxy-2-oxo-acetyl)amino]furan-2-carboxylate 0.5 g of methyl 4-aminofuran-2-carboxylate hydrochloride was suspended in 15 ml of ethyl acetate and 0.5 g of methyl oxalyl chloride was added at 10°C. The mixture was stirred at RT for 15 h and the precipitate was filtered off. 0.5 g (79%) of the product was obtained.
Mass Spectra m/z 227. Mass Spectra m/z 227.
'H-NMR (400MHz, CDC13): 8 11.56 (1H, s, br.); 8.32 (1H, d); 7.36 (1H, d); 3,82 (3H, s), 3,32 (3H,s) ppm. 'H NMR (400MHz, CDC1 3 ): 8 11.56 (1H, s, br.); 8.32 (1H,d); 7.36 (1H,d); 3.82(3H,s), 3.32(3H,s)ppm.
Beispiel 5 Example 5
Methyl-4-(methoxycarbonylamino)furan-2-carboxylat Methyl 4-(methoxycarbonylamino)furan-2-carboxylate
0,5 g von Methyl 4-aminofuran-2-carboxylathydrochlorid wurden in 15 ml Ethylacetate suspendiert und 0,5 g von Chlorameisensäuremethylester wurden bei 10°C zugegeben. Das Gemisch wurde 30 min bei RT gerührt und 0,5 g NEts wurden portionsweise zugegeben. Das Gemisch wurde 10 Std bei RT gerührt und mit 30 ml Ethylacetat verdünnt. Die organisch Phase wurde mit Wasser gewaschen und einrotiert. Man erhielt 0,54 g des Produktes. 0.5 g of methyl 4-aminofuran-2-carboxylate hydrochloride was suspended in 15 ml of ethyl acetate and 0.5 g of methyl chloroformate was added at 10°C. The mixture was stirred at RT for 30 min and 0.5 g of NEts were added portionwise. The mixture was stirred at RT for 10 h and diluted with 30 ml of ethyl acetate. The organic phase was washed with water and evaporated. 0.54 g of the product was obtained.
'H-NMR (400MHz, CDCI3): 8 9,82 (1H, s, br.); 7,99 (1H, d); 7, 15 (1H, d); 3,86 (3H, s), 3,73 ppm 'H NMR (400MHz, CDCl3 ): δ 9.82 (1H, s, br.); 7.99 (1H,d); 7, 15 (1H,d); 3.86(3H,s), 3.73ppm
Beispiel 6 Example 6
Methyl-4-(benzyloxycarbonylamino)furan-2-carboxylat Methyl 4-(benzyloxycarbonylamino)furan-2-carboxylate
Man arbeitet wie im Beispiel 5 beschrieben, nimmt jedoch 1,5 Eq Chlorameisensäurebenzylester. The procedure is as described in Example 5, but takes 1.5 eq of benzyl chloroformate.
Ausbeute 96; m/z 275. yield 96; m/z 275.
'H-NMR (400MHz, CDCI3): 8 9,85 (1H, s, br.); 7,95 (1H, d); 7,4-7,15 (5H, m); 7,2 (1H, d), 5,2 (2H. s) 3,75 (3H, s) ppm. 'H NMR (400MHz, CDCl3): δ 9.85 (1H, s, br.); 7.95 (1H,d); 7.4-7.15 (5H,m); 7.2 (1H, d), 5.2 (2H, s) 3.75 (3H, s) ppm.
Beispiel 7 Example 7
Methyl-4-[(2,2,2-trichloracetyl)amino]furan-2-carboxylat Methyl 4-[(2,2,2-trichloroacetyl)amino]furan-2-carboxylate
Man arbeitet wie im Beispiel 4 beschrieben, nimmt jedoch 1,2 Eq CCI3COCI. One works as described in Example 4, but takes 1.2 Eq CCI3COCI.
Ausbeute 88 %, m/z 286.
'H-NMR (400MHz, CDC13): δ 11,2 (1H, s, br.); 8,45 (1H, d); 7, 45 (1H, d); 3,80 (3H, s), 3,73 ppm
Yield 88%, m/z 286. 'H NMR (400MHz, CDC1 3 ): δ 11.2 (1H, s, br.); 8.45 (1H,d); 7, 45 (1H,d); 3.80 (3H,s), 3.73ppm
Claims
1. Verfahren zur Herstellung von Verbindungen der allgemeinen Formel (I)
worin 1. Process for preparing compounds of general formula (I) wherein
R1 für CF3, CF2H, C2F5, CF2C1, -COO-(Ci-C6)-Alkyl, COOH steht, R 1 is CF 3 , CF 2 H, C 2 F 5 , CF 2 C1, -COO-(Ci-C 6 )-alkyl, COOH,
R2 für H, (Ci-C6)-Alkyl, Cl, F, CF3, CF2C1, CC13, -O-(Ci-C6)-Alkyl, -O-(Ci-C6)-Alkylaryl,R 2 for H, (Ci-C 6 )-alkyl, Cl, F, CF 3 , CF 2 C1, CC1 3 , -O-(Ci-C 6 )-alkyl, -O-(Ci-C 6 )- alkylaryl,
-COO-(Ci-C6)-Alkyl steht, dadurch gekennzeichnet, dass in einem ersten Schritt Verbindungen der allgemeinen Formel (II)
worin -COO-(Ci-C 6 )-alkyl, characterized in that in a first step compounds of the general formula (II) wherein
R3 und R4 unabhängig voneinander für H und (Ci-Ce)-Alkyl stehen R 3 and R 4 independently represent H and (Ci-Ce)-alkyl
R1 die oben genannten Bedeutungen hat, mit Ammoniak in Verbindungen der allgemeinen Formel (III)
worin R 1 has the meanings given above, with ammonia in compounds of the general formula (III) wherein
R1 die oben genannten Bedeutungen hat, überführt werden und diese in einem zweiten Reaktionsschritt in Gegenwart eines wasserentziehenden Reagenzes zu Verbindungen der allgemeinen Formel (IV) umgesetzt werden
worin R 1 has the meanings given above, and these are converted in a second reaction step in the presence of a dehydrating reagent to give compounds of the general formula (IV). wherein
R1 die oben genannten Bedeutungen hat, und diese anschließend in einem dritten Reaktionsschritt mittels eines Acylierungsreagenzes der Formel (V) R 1 has the meanings given above, and these subsequently in a third reaction step by means of an acylating agent of the formula (V)
R2COX R2 COX
(V), worin (V), wherein
R2 wie oben definiert ist und R 2 is as defined above and
X für F, Cl, Br, H3CSO2O, p-TolSO2O, -OCOR2 steht, zu Verbindungen der allgemeinen Formel (I) umgesetzt werden. X stands for F, Cl, Br, H 3 CSO 2 O, p-TolSO 2 O, -OCOR 2 , to give compounds of the general formula (I).
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass die Restedefmitionen für die Verbindungen der allgemeinen Formeln (I), (II), (III), (IV) und (V) die folgenden sind: 2. Process according to Claim 1, characterized in that the radical definitions for the compounds of the general formulas (I), (II), (III), (IV) and (V) are the following:
R1 steht für CF3, CF2H, CF2C1, C2F5, COOCH3, COOC2H5, R 1 represents CF 3 , CF 2 H, CF 2 C1 , C 2 F 5 , COOCH 3 , COOC 2 H 5 ,
R2 steht für H, -(Ci-C4)-Alkyl, CI, CF3, CF2C1, CC13, -O-(Ci-C4)-Alkyl, -O-CH2-Phenyl,R 2 represents H, -(Ci-C 4 )-alkyl, CI, CF 3 , CF 2 C1, CC1 3 , -O-(Ci-C 4 )-alkyl, -O-CH 2 -phenyl,
COOCH3, COOC2H5, COOCH3 , COOC2 H5 ,
R3 und R4 stehen unabhängig voneinander für H oder CH3, R 3 and R 4 independently represent H or CH 3 ,
X steht für F, CI, -OCOR2, H3CSO2O, p-TolSO2O.
14 X represents F, Cl, -OCOR 2 , H 3 CSO 2 O, p-TolSO 2 O. 14
3. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass die Restedefinitionen für die Verbindungen der allgemeinen Formeln (I), (II), (III), (IV) und (V) die folgenden sind: 3. The method according to claim 1, characterized in that the radical definitions for the compounds of the general formulas (I), (II), (III), (IV) and (V) are the following:
R1 steht für COOCH3, COOC2H5, R 1 represents COOCH 3 , COOC 2 H 5 ,
R2 steht für Methyl, Ethyl, Propyl, 1 -Methylethyl, Butyl, 1 -Methyl-propyl, 2-Methylpropyl, 1,1 -Dimethyl ethyl, Pentyl, 1 -Methylbutyl, 2-Methylbutyl, 3 -Methylbutyl, 2,2-Di- methylpropyl, 1 -Ethylpropyl, CF3, -O-Methyl, -O-Ethyl, -O-Propyl, -0-1 -Methylethyl, -O- Butyl, -0-1 -Methyl-propyl, -O-2-Methylpropyl, -0-1,1 -Dimethylethyl, -O-Pentyl, -0-1- Methylbutyl, -O-2-Methylbutyl, -0-3 -Methylbutyl, -O-2,2-Di-methylpropyl, -0-1- Ethylpropyl, COOCH3, R 2 is methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2 -dimethylpropyl, 1-ethylpropyl, CF 3 , -O-methyl, -O-ethyl, -O-propyl, -0-1-methylethyl, -O-butyl, -0-1-methyl-propyl, -O -2-methylpropyl, -0-1,1-dimethylethyl, -O-pentyl, -0-1-methylbutyl, -O-2-methylbutyl, -0-3-methylbutyl, -O-2,2-dimethylpropyl , -0-1-ethylpropyl, COOCH3,
R3 und R4 stehen unabhängig voneinander für H oder CH3 R 3 and R 4 are independently H or CH3
X steht für CI, -0C0R2, H3CSO2O. X represents CI, -0C0R 2 , H 3 CSO 2 O.
4. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass die Restedefinitionen für die Verbindungen der allgemeinen Formeln (I), (II), (III), (IV) und (V) die folgenden sind: 4. The method according to claim 1, characterized in that the radical definitions for the compounds of the general formulas (I), (II), (III), (IV) and (V) are the following:
R1 steht fur COOCH3, COOC2H5, R 1 is COOCH3, COOC 2 H 5 ,
R2 steht für H, CH3, CF3, -0CH3, -OC2H5, (CH3)3CO-, CC13, C00CH3, -O-CH2-Phenyl, R 2 represents H, CH 3 , CF 3 , -0CH 3 , -OC 2 H 5 , (CH 3 ) 3 CO-, CC1 3 , CO0CH 3 , -O-CH 2 -phenyl,
R3 und R4 stehen für CH3, R 3 and R 4 represent CH 3 ,
X steht für CI, -0C0R2. X stands for CI, -0C0R 2 .
5. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass die Restedefinitionen für die Verbindungen der allgemeinen Formeln (I), (II), (III), (IV) und (V) die folgenden sind: 5. The method according to claim 1, characterized in that the radical definitions for the compounds of the general formulas (I), (II), (III), (IV) and (V) are the following:
R1 steht für COOCH3, C00C2H5, R1 is COOCH3 , CO0C2H5 ,
R2 steht für CF3, -0CH3, -0C2H5, (CH3)3C0-, CC13, C00CH3. -O-CH2-Phenyl R2 is CF3 , -0CH3 , -0C2 H5 , (CH3 ) 3 CO- , CC13 , CO0CH3 . -O-CH 2 -phenyl
R3 und R4 stehen für CH3, R 3 and R 4 represent CH 3 ,
X steht für CI. X stands for CI.
6. Verfahren nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, dass 1:0,1 bis 1:5 Äquivalente Zyklisierungsreagenz bezogen auf die Verbindungen der allgemeinen Formel (III) eingesetzt werden.
15 6. The method as claimed in any of claims 1 to 5, characterized in that 1:0.1 to 1:5 equivalents of cyclization reagent are used, based on the compounds of the general formula (III). 15
7. Verfahren nach einem der Ansprüche 1 bis 6, dadurch gekennzeichnet, dass das Zyklisierungsreagenz SOCf, POCh, Oxalylchlorid, Phosgen oder HCl ist. 7. The method according to any one of claims 1 to 6, characterized in that the cyclization reagent is SOCf, POCh, oxalyl chloride, phosgene or HCl.
8. Verfahren nach einem der Ansprüche 1 bis 7, dadurch gekennzeichnet, dass 1:0,9 bis 1:2 Äquivalente der Verbindung der allgemeinen Formel (IV) bezogen auf Verbindungen der allgemeinen8. The method according to any one of claims 1 to 7, characterized in that 1: 0.9 to 1: 2 equivalents of the compound of general formula (IV) based on compounds of general
Formel (V) eingesetzt werden. Formula (V) are used.
9. Verfahren nach einem der Ansprüche 1 bis 8, dadurch gekennzeichnet, dass Triethylamin, Hünig Base, 2-Methyl-5-ethylpyridine, 3-Picolin oder Dimethylcyclohexylamin als Base in Schritt 3 eingesetzt werden.
9. The method according to any one of claims 1 to 8, characterized in that triethylamine, Hünig base, 2-methyl-5-ethylpyridine, 3-picoline or dimethylcyclohexylamine are used as the base in step 3.
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KR (1) | KR20230083283A (en) |
CN (1) | CN116209656A (en) |
IL (1) | IL301696A (en) |
MX (1) | MX2023004094A (en) |
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BR112012014416B1 (en) | 2009-12-15 | 2017-08-08 | Bayer Cropscience Ag | DIOXOLAN AND DIOXAN DERIVATIVE COMPOUNDS, METHOD FOR PRODUCING AND USING THE DIOXOLANES AND DIOXANES |
ES2894277T3 (en) | 2017-06-13 | 2022-02-14 | Bayer Ag | 3-Phenylisoxazolin-5-carboxamides of tetrahydro and dihydrofurancarboxylic acids and esters with herbicidal effect |
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- 2021-10-04 US US18/247,795 patent/US20240010626A1/en active Pending
- 2021-10-04 EP EP21782572.8A patent/EP4225744A1/en active Pending
- 2021-10-04 JP JP2023521155A patent/JP2023545715A/en active Pending
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MX2023004094A (en) | 2023-04-27 |
CN116209656A (en) | 2023-06-02 |
TW202231186A (en) | 2022-08-16 |
US20240010626A1 (en) | 2024-01-11 |
KR20230083283A (en) | 2023-06-09 |
WO2022073943A1 (en) | 2022-04-14 |
IL301696A (en) | 2023-05-01 |
JP2023545715A (en) | 2023-10-31 |
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