WO2022218853A1 - Verfahren zur chlorierung von benzaldehydoximen - Google Patents
Verfahren zur chlorierung von benzaldehydoximen Download PDFInfo
- Publication number
- WO2022218853A1 WO2022218853A1 PCT/EP2022/059428 EP2022059428W WO2022218853A1 WO 2022218853 A1 WO2022218853 A1 WO 2022218853A1 EP 2022059428 W EP2022059428 W EP 2022059428W WO 2022218853 A1 WO2022218853 A1 WO 2022218853A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- fluorine
- fluoro
- methyl
- difluoromethyl
- trifluoromethyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 20
- VTWKXBJHBHYJBI-UHFFFAOYSA-N n-benzylidenehydroxylamine Chemical class ON=CC1=CC=CC=C1 VTWKXBJHBHYJBI-UHFFFAOYSA-N 0.000 title description 3
- FZIVKDWRLLMSEJ-UHFFFAOYSA-N n-[(2-chlorophenyl)methylidene]hydroxylamine Chemical class ON=CC1=CC=CC=C1Cl FZIVKDWRLLMSEJ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 21
- 229910052731 fluorine Inorganic materials 0.000 claims description 21
- 239000011737 fluorine Substances 0.000 claims description 21
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 claims description 16
- -1 difluoromethoxy, trifluoromethoxy, fluoro, methoxy Chemical group 0.000 claims description 15
- VTWKXBJHBHYJBI-VURMDHGXSA-N (nz)-n-benzylidenehydroxylamine Chemical compound O\N=C/C1=CC=CC=C1 VTWKXBJHBHYJBI-VURMDHGXSA-N 0.000 claims description 14
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 12
- NZMAJUHVSZBJHL-UHFFFAOYSA-N n,n-dibutylformamide Chemical compound CCCCN(C=O)CCCC NZMAJUHVSZBJHL-UHFFFAOYSA-N 0.000 claims description 11
- 229950009390 symclosene Drugs 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 150000001408 amides Chemical class 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 8
- 229940011051 isopropyl acetate Drugs 0.000 description 8
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 8
- NINQBDWXDZJNJQ-UHFFFAOYSA-N n-[(3,5-difluorophenyl)methylidene]hydroxylamine Chemical compound ON=CC1=CC(F)=CC(F)=C1 NINQBDWXDZJNJQ-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000005660 chlorination reaction Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- ZFSLODLOARCGLH-UHFFFAOYSA-N isocyanuric acid Chemical compound OC1=NC(O)=NC(O)=N1 ZFSLODLOARCGLH-UHFFFAOYSA-N 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- JWWDYDQORXKMAP-YRNVUSSQSA-N (1e)-3,5-difluoro-n-hydroxybenzenecarboximidoyl chloride Chemical compound O\N=C(\Cl)C1=CC(F)=CC(F)=C1 JWWDYDQORXKMAP-YRNVUSSQSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229910000831 Steel Inorganic materials 0.000 description 2
- 210000003298 dental enamel Anatomy 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 239000010959 steel Substances 0.000 description 2
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- 102100031817 Delta-type opioid receptor Human genes 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 101100295829 Homo sapiens OPRD1 gene Proteins 0.000 description 1
- 101100244562 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) oprD gene Proteins 0.000 description 1
- 239000012868 active agrochemical ingredient Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/12—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reactions not involving the formation of oxyimino groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/02—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by halogen atoms
Definitions
- the present invention relates to a new process for preparing chlorobenzaldehyde oximes of the general formula (I).
- Chlorobenzaldehyde oximes of the general formula (I) are important precursors of agrochemical active ingredients (cf. WO 2018/228985) and pharmaceutical active ingredients (e.g. DNA binding agents: Woods, Craig R. et al. Bioorganic & Medicinal Chemistryêts, 12(18), 2647-2650; 2002).
- chlorobenzaldehyde oximes Numerous chlorination methods are described in the prior art, for example WO 2004/29066 teaches the preparation of chlorobenzaldehyde oximes by reacting oximes with N-chlorosuccinimide (NCS) and subsequent aqueous work-up (extraction with EtOAcTFO).
- NCS N-chlorosuccinimide
- EtOAcTFO aqueous work-up
- only small amounts (2.45 g) of the chlorobenzaldehyde oximes obtained were isolated as a solid in the process described.
- the isolation of chlorobenzaldehyde oximes on an industrial scale as a solid is undesirable, since chlorobenzaldehyde oximes are often high-energy compounds which have a high tendency to decompose.
- WO 2004/29066 uses dimethylformamide (DMF) as a solvent.
- DMF dimethylformamide
- the object of the invention was therefore to provide a process for the chlorination of benzaldehyde oximes which, on the one hand, can dispense with DMF as a solvent and, on the other hand, does not result in the yield losses caused by stronger bases, such as triethylamine, and is at the same time inexpensive and can be used on an industrial scale.
- the object was achieved according to the invention by a process for preparing chlorobenzaldehyde oximes of the general formula (I) where X 2 is H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine, CN,
- X 3 is H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine, chlorine, CN,
- X 4 is H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine, CN,
- X 5 is H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine, chlorine, CN,
- X 6 is H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine, CN, characterized in that the compounds of the general formula (II) wherein
- X 2 to X 6 have the meanings given above, with the aid of trichloroisocyanuric acid (TCCA) and an amide base to give compounds of the general formula (I).
- TCCA trichloroisocyanuric acid
- Preferred radical definitions for the compounds of the general formulas (I) and (II) are the following: X 2 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluoro, methoxy, CN,
- X 3 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluoro, chloro, methoxy, CN
- X 4 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluoro, methoxy, CN,
- X 5 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluoro, chloro, methoxy, CN,
- X 6 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluoro, methoxy, CN.
- radical definitions for the compounds of the general formulas (I) and (II) are the following:
- X2 is H
- X 3 is H, methyl, trifluoromethyl, difluoromethyl, fluoro, chloro, methoxy, CN, X 4 is fluoro, H,
- X 5 is H, methyl, trifluoromethyl, difluoromethyl, fluoro, chloro, methoxy, CN,
- X 3 is H, fluorine
- X 4 is H, fluorine
- X 5 is H, fluorine
- X2 is H
- X 3 is fluorine
- X 4 is H
- X 5 is fluorine
- the compounds of formula (I) can exist as geometric mixtures of isomers:
- TCCA trichloroisocyanuric acid
- the method according to the invention has the advantage that DMF is avoided as a solvent. This minimizes the risk that the reaction will be highly exothermic and uncontrolled. Consequently, the reaction is suitable for large-scale operation.
- Suitable amide bases are, for example, dibutylformamide (DBF), diethylformamide (DEF), or dimethylacetamide (DMAc), with dibutylformamide being preferred.
- DPF dibutylformamide
- DEF diethylformamide
- DMAc dimethylacetamide
- the chlorination is usually carried out in a temperature range of -10°C to 40°C, preferably -5°C to 10°C, particularly preferably 0 to 5°C.
- the chlorination is carried out in the presence of a solvent or diluent, the solvents preferably being tetrahydrofuran, Me-THF, acetonitrile, N,N-dimethylacetamide, toluene, ethyl acetate, isopropyl acetate, methyl tert-butyl ether.
- a solvent or diluent the solvents preferably being tetrahydrofuran, Me-THF, acetonitrile, N,N-dimethylacetamide, toluene, ethyl acetate, isopropyl acetate, methyl tert-butyl ether.
- TCCA trichloroisocyanuric acid
- concentration of the solution depends on the solubility of TCCA in the respective solvent. For example, up to approx. 25 w/w% dissolves in ethyl acetate and up to approx. 20 w/w% in isopropyl ester.
- the products were characterized by means of ⁇ - and/or 19 F-NMR spectroscopy and/or HPLC 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 2 Additional Example 2 (Addition of the TCCA as a 20% by weight solution in isopropyl acetate)
- Example 3 (19 kg solution (19.7 w/w% in toluene/THF) batch on an industrial scale)
- reaction solution was filtered through a layer of kieselguhr and washed with 5 L of isopropyl acetate.
- the resulting product solution (33.7 kg) showed complete conversion of the N-(3,5-difluorobenzylidene)hydroxylamine via HPLC, with a yield of 89% (19F Q-NMR).
- reaction solution was filtered through a layer of kieselguhr and washed with 2 L of isopropyl acetate.
- the resulting product solution (33.3 kg) showed complete conversion of the N-(3,5-difluorobenzylidene)hydroxylamine via HPLC, with a yield of 86% ( 19 F Q-NMR).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202280028061.1A CN117222618A (zh) | 2021-04-13 | 2022-04-08 | 苯甲醛肟的氯化方法 |
IL307487A IL307487A (en) | 2021-04-13 | 2022-04-08 | A method for the chlorination of benzaldehyde oximes |
EP22722154.6A EP4323334A1 (de) | 2021-04-13 | 2022-04-08 | Verfahren zur chlorierung von benzaldehydoximen |
KR1020237038218A KR20230169208A (ko) | 2021-04-13 | 2022-04-08 | 벤즈알데히드 옥심의 염소화 방법 |
JP2023563047A JP2024513598A (ja) | 2021-04-13 | 2022-04-08 | ベンズアルデヒドオキシムの塩素化方法 |
US18/554,920 US20240132443A1 (en) | 2021-04-13 | 2022-04-08 | Method for chlorinating benzaldehyde oximes |
BR112023019712A BR112023019712A2 (pt) | 2021-04-13 | 2022-04-08 | Processo para a cloração de oximas de benzaldeído |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP21168079 | 2021-04-13 | ||
EP21168079.8 | 2021-04-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022218853A1 true WO2022218853A1 (de) | 2022-10-20 |
Family
ID=75801394
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2022/059428 WO2022218853A1 (de) | 2021-04-13 | 2022-04-08 | Verfahren zur chlorierung von benzaldehydoximen |
Country Status (9)
Country | Link |
---|---|
US (1) | US20240132443A1 (de) |
EP (1) | EP4323334A1 (de) |
JP (1) | JP2024513598A (de) |
KR (1) | KR20230169208A (de) |
CN (1) | CN117222618A (de) |
BR (1) | BR112023019712A2 (de) |
IL (1) | IL307487A (de) |
TW (1) | TW202304853A (de) |
WO (1) | WO2022218853A1 (de) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004029066A2 (en) | 2002-09-26 | 2004-04-08 | Rib-X Pharmaceuticals, Inc. | Bifunctional heterocyclic compounds and methods of making and using same |
WO2018228985A1 (de) | 2017-06-13 | 2018-12-20 | Bayer Aktiengesellschaft | Herbizid wirksame 3-phenylisoxazolin-5-carboxamide von tetrahydro- und dihydrofurancarbonsäuren und -estern |
-
2022
- 2022-04-08 IL IL307487A patent/IL307487A/en unknown
- 2022-04-08 KR KR1020237038218A patent/KR20230169208A/ko unknown
- 2022-04-08 US US18/554,920 patent/US20240132443A1/en active Pending
- 2022-04-08 JP JP2023563047A patent/JP2024513598A/ja active Pending
- 2022-04-08 EP EP22722154.6A patent/EP4323334A1/de active Pending
- 2022-04-08 WO PCT/EP2022/059428 patent/WO2022218853A1/de active Application Filing
- 2022-04-08 CN CN202280028061.1A patent/CN117222618A/zh active Pending
- 2022-04-08 BR BR112023019712A patent/BR112023019712A2/pt unknown
- 2022-04-11 TW TW111113620A patent/TW202304853A/zh unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004029066A2 (en) | 2002-09-26 | 2004-04-08 | Rib-X Pharmaceuticals, Inc. | Bifunctional heterocyclic compounds and methods of making and using same |
WO2018228985A1 (de) | 2017-06-13 | 2018-12-20 | Bayer Aktiengesellschaft | Herbizid wirksame 3-phenylisoxazolin-5-carboxamide von tetrahydro- und dihydrofurancarbonsäuren und -estern |
Non-Patent Citations (9)
Title |
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"Fragmentation of Nitrile Oxides with Triethylamine", TETRAHEDRON LETT., vol. 24, 1983, pages 4377 - 4380 |
BULL. CHEM. SOC. JPN., vol. 67, 1994, pages 156 |
DAYANNE DA ROCHA DE MENEZES ET AL: "Hydroxamic acid derivatives: a promising scaffold for rational compound optimization in Chagas disease", JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, vol. 31, no. 6, 31 August 2015 (2015-08-31), GB, pages 964 - 973, XP055457816, ISSN: 1475-6366, DOI: 10.3109/14756366.2015.1077330 * |
FRÁGUAS RODRIGO M. ET AL: "Toxicities of 4,5-Dihydroisoxazoles Against Root-Knot Nematodes and in Silico Studies of Their Modes of Action", vol. 68, no. 2, 15 January 2020 (2020-01-15), US, pages 523 - 529, XP055845877, ISSN: 0021-8561, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/acs.jafc.9b07839> DOI: 10.1021/acs.jafc.9b07839 * |
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, vol. 31, no. 6, 2016, pages 964 - 973 |
MOLINA C T ET AL: "SYNTHESIS OF NEW 4,5-DIHYDROISOXAZOLES WITH POTENTIAL ANTI-INFLAMMATORY ACTIVITY", HETEROCYCLIC COMMUNICATIONS, DE GRUYTER, DE, vol. 9, no. 5, 1 January 2003 (2003-01-01), pages 535 - 538, XP009044208, ISSN: 0793-0283 * |
OPRD, vol. 24, 2020, pages 1586 |
PROF. DR. R. HUISGEN: "Kinetik und Mechanismus 1.3-Dipolarer Cycloadditionen", ANGEW. CHEM., vol. 75, no. 742-754, 1963, pages 751 |
WOODS, CRAIG R. ET AL.: "DNA Binding Agents", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 12, no. 18, 2002, pages 2647 - 2650 |
Also Published As
Publication number | Publication date |
---|---|
TW202304853A (zh) | 2023-02-01 |
US20240132443A1 (en) | 2024-04-25 |
CN117222618A (zh) | 2023-12-12 |
IL307487A (en) | 2023-12-01 |
JP2024513598A (ja) | 2024-03-26 |
EP4323334A1 (de) | 2024-02-21 |
BR112023019712A2 (pt) | 2023-10-31 |
KR20230169208A (ko) | 2023-12-15 |
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