CN114907236B - Aldoxime compound and preparation method and application thereof - Google Patents
Aldoxime compound and preparation method and application thereof Download PDFInfo
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- CN114907236B CN114907236B CN202210505338.7A CN202210505338A CN114907236B CN 114907236 B CN114907236 B CN 114907236B CN 202210505338 A CN202210505338 A CN 202210505338A CN 114907236 B CN114907236 B CN 114907236B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- -1 Aldoxime compound Chemical class 0.000 title claims description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 79
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 12
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 11
- 239000004471 Glycine Substances 0.000 claims description 10
- UYBQBUZXULIDMQ-UHFFFAOYSA-N 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene Chemical compound FC(F)(F)C(=C)C1=CC(Cl)=CC(Cl)=C1 UYBQBUZXULIDMQ-UHFFFAOYSA-N 0.000 claims description 9
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 9
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 claims description 9
- KIPSRYDSZQRPEA-UHFFFAOYSA-N 2,2,2-trifluoroethanamine Chemical compound NCC(F)(F)F KIPSRYDSZQRPEA-UHFFFAOYSA-N 0.000 claims description 8
- RVCJOGNLYVNRDN-UHFFFAOYSA-N 4-bromo-2-methylbenzoic acid Chemical compound CC1=CC(Br)=CC=C1C(O)=O RVCJOGNLYVNRDN-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 239000007789 gas Substances 0.000 claims description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 8
- 230000003301 hydrolyzing effect Effects 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 abstract description 17
- 229910052731 fluorine Inorganic materials 0.000 abstract description 17
- 239000011737 fluorine Substances 0.000 abstract description 17
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000003912 environmental pollution Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- 239000007787 solid Substances 0.000 description 26
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 14
- 238000001819 mass spectrum Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 229960002449 glycine Drugs 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 239000000575 pesticide Substances 0.000 description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical group [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- FZENGILVLUJGJX-NSCUHMNNSA-N (E)-acetaldehyde oxime Chemical compound C\C=N\O FZENGILVLUJGJX-NSCUHMNNSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- VTWKXBJHBHYJBI-SOFGYWHQSA-N (ne)-n-benzylidenehydroxylamine Chemical compound O\N=C\C1=CC=CC=C1 VTWKXBJHBHYJBI-SOFGYWHQSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 241000258242 Siphonaptera Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 241000607479 Yersinia pestis Species 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 230000032798 delamination Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 3
- 229940011051 isopropyl acetate Drugs 0.000 description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 2
- GIUTUZDGHNZVIA-UHFFFAOYSA-N 2-(ethylamino)acetic acid;hydrochloride Chemical group Cl.CCNCC(O)=O GIUTUZDGHNZVIA-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 241000255925 Diptera Species 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000258937 Hemiptera Species 0.000 description 2
- 238000005874 Vilsmeier-Haack formylation reaction Methods 0.000 description 2
- AXJDEHNQPMZKOS-UHFFFAOYSA-N acetylazanium;chloride Chemical compound [Cl-].CC([NH3+])=O AXJDEHNQPMZKOS-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- ZTUJDPKOHPKRMO-UHFFFAOYSA-N hydron;2,2,2-trifluoroethanamine;chloride Chemical compound Cl.NCC(F)(F)F ZTUJDPKOHPKRMO-UHFFFAOYSA-N 0.000 description 2
- 230000000749 insecticidal effect Effects 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- UBKCIXXGQRZHRO-UHFFFAOYSA-N propan-2-yl 2-aminoacetate;hydrochloride Chemical compound Cl.CC(C)OC(=O)CN UBKCIXXGQRZHRO-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- BUZJPENZWLUHJD-UHFFFAOYSA-N 2-(benzylamino)acetic acid;hydrochloride Chemical compound Cl.OC(=O)CNCC1=CC=CC=C1 BUZJPENZWLUHJD-UHFFFAOYSA-N 0.000 description 1
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 description 1
- 241001427556 Anoplura Species 0.000 description 1
- JXYACYYPACQCDM-UHFFFAOYSA-N Benzyl glycinate Chemical compound NCC(=O)OCC1=CC=CC=C1 JXYACYYPACQCDM-UHFFFAOYSA-N 0.000 description 1
- 101100112111 Caenorhabditis elegans cand-1 gene Proteins 0.000 description 1
- 108010062745 Chloride Channels Proteins 0.000 description 1
- 102000011045 Chloride Channels Human genes 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000255777 Lepidoptera Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 244000000054 animal parasite Species 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- VLQHNAMRWPQWNK-UHFFFAOYSA-N benzyl 2-aminoacetate;hydron;chloride Chemical compound Cl.NCC(=O)OCC1=CC=CC=C1 VLQHNAMRWPQWNK-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- MLBZKOGAMRTSKP-UHFFFAOYSA-N fluralaner Chemical compound C1=C(C(=O)NCC(=O)NCC(F)(F)F)C(C)=CC(C=2CC(ON=2)(C=2C=C(Cl)C=C(Cl)C=2)C(F)(F)F)=C1 MLBZKOGAMRTSKP-UHFFFAOYSA-N 0.000 description 1
- 229960004498 fluralaner Drugs 0.000 description 1
- 150000002332 glycine derivatives Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 150000002547 isoxazolines Chemical class 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 239000000276 potassium ferrocyanide Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- YLGOWOYJZYKTDO-UHFFFAOYSA-N propan-2-yl 2-aminoacetate Chemical compound CC(C)OC(=O)CN YLGOWOYJZYKTDO-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- XOGGUFAVLNCTRS-UHFFFAOYSA-N tetrapotassium;iron(2+);hexacyanide Chemical compound [K+].[K+].[K+].[K+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] XOGGUFAVLNCTRS-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/32—Oximes
- C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C251/48—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a compound shown in a formula IV, a preparation method thereof and application of the compound in preparation of a fluorine Lei Lana medicament. The beneficial effects brought by the invention are as follows: the synthesis raw materials are cheap and easy to obtain, the intermediate preparation condition is mild, the operation is safe, the environmental pollution is small, and the method is more suitable for industrialized mass production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a compound of a formula II, a compound of a formula III, a compound of a formula IV, a preparation method of the compound and application of the compound in preparation of fluorine Lei Lana medicines.
Background
Isoxazolines are a novel class of highly potent pesticides that die by interfering with the gamma-aminobutyric acid (GABA) -gated chloride ion channels of parasites, resulting in their nervous system becoming overstimulated. Fluorine Lei Lana (Fluralaner) is an isoxazoline-type broad-spectrum pesticide developed by Japanese chemical industry Co., ltd (Nissan Chemical Industries Japan). The chemical name of the compound is 4- [5- (3, 5-dichlorophenyl) -4, 5-dihydro-5-trifluoromethyl-3-isoxazolyl ] -2-methyl-nitrogen- [ 2-oxo-2- [ (2, 2-trifluoroethyl) amino ] benzamide, the product is Bravect, and the structural formula is as follows:
fluorine Lei Lana is used as a broad-spectrum pesticide, and has good insecticidal effect on most agricultural pests except animal parasites, such as pests of the order of Siphonaptera (Anoplura), siphonaptera (Siphonaptera), hemiptera (Hemiptera), diptera (Diptera) and Lepidoptera (Lepidotera), and the toxicity of the pesticide is higher than or equal to that of common pesticides. It has no obvious mutual resistance with the existing pesticide, and has better insecticidal activity even to partial resistant pests.
The oxime compound is an organic compound generated by the action of aldehyde and ketone compounds containing carbonyl and hydroxylamine, has a structural general formula of C=NOH, and is an important intermediate for synthesizing isoxazoline pesticides. At present, the international patent WO2008122375A2 is mainly referred to for preparing a fluorine Lei Lana aldoxime intermediate at home and abroad, the 2-methyl-4-bromobenzoic acid is used as a raw material, esters are used for protecting carboxyl, and the fluorine Lei Lana aldoxime intermediate is prepared through Vilsmeier-Haack reaction, esterification reaction, nucleophilic addition elimination and other multi-step reactions. In the technical scheme, n-butyllithium is required to be used in the first-step Vilsmeier-Haack reaction at the temperature of minus 78 ℃, the preparation condition is more severe, and a large amount of n-butyllithium is used with a large safety risk. In addition, esters are adopted to protect carboxyl groups, and in the subsequent synthetic route of fluorine Lei Lana, expensive 2-amino-N- (2, 2-trifluoroethyl) acetamide hydrochloride is required to be used as a material for amide condensation, so that the market price of the material is about 8000-10000 yuan/kg, the material cost is high, and the commercial production is not facilitated.
Therefore, the invention aims to provide an aldoxime compound based on the research at home and abroad, the material for preparing the fluorine Lei Lana by taking the aldoxime compound as the intermediate is cheaper and easier to obtain, and the intermediate preparation condition is milder and environment-friendly, thereby being more suitable for industrialized mass production.
Disclosure of Invention
The invention discloses a compound of a formula II, which has the following structure:
R 1 selected from C1-C12 alkyl;
preferably, R 1 Selected from C1-C8 alkyl;
further preferably, R 1 Selected from C2-C7 alkyl;
still more preferably, R 1 Selected from ethyl, propyl, isopropyl or benzyl.
The invention also discloses a preparation method of the compound of the formula II: 2-methyl-4-bromobenzoic acid reacts with glycine ester derivatives to generate a compound of formula I, and then reacts with a cyanating reagent to prepare the compound:
preferably, the substituent R1 in the glycine ester derivative is as defined above; the cyanidation reagent is selected from cuprous cyanide, zinc cyanide, potassium ferrocyanide, sodium cyanide and potassium cyanide;
further preferably, the glycine ester derivative is selected from ethyl glycinate hydrochloride, isopropyl glycinate hydrochloride, benzyl glycinate hydrochloride; the cyanidation reagent is cuprous cyanide.
The invention also discloses a compound of the formula III, which has the following structure:
wherein R1 is as defined above.
The invention also discloses a preparation method of the compound of the formula III: dissolving the compound of formula II in organic solvent, adding anhydrous stannous chloride, introducing dry hydrogen chloride gas to react to obtain
Preferably, the organic solvent is ethyl acetate.
The invention also discloses a compound shown in a formula IV, wherein:
wherein R1 is as defined above.
The invention also discloses a preparation method for preparing the compound shown in the formula IV, which comprises the following steps: the compound of formula III is reacted with hydroxylamine or a salt thereof
The invention also discloses a preparation process for synthesizing fluorine Lei Lana by taking the compound structure of the formula IV as an intermediate, which comprises the following steps:
step 1: reacting a compound of formula IV with 1, 3-dichloro-5- (1-trifluoromethyl-vinyl) benzene to obtain an intermediate V compound;
step 2: hydrolyzing the intermediate in the formula V to obtain an intermediate in the formula VI;
step 3: reaction of the intermediate of formula VI with trifluoroethylamine or a salt thereof affords fluoro Lei Lana.
The invention also discloses a preparation process for synthesizing fluorine Lei Lana by taking the compound structure of the formula III as an intermediate, which comprises the following steps:
step 1: reacting the intermediate of formula III with hydroxylamine or a salt thereof to form an intermediate of formula IV;
step 2: reacting the intermediate of formula IV with 1, 3-dichloro-5- (1-trifluoromethyl-vinyl) benzene to form an intermediate of formula V;
step 3: hydrolyzing the intermediate in the formula V to obtain an intermediate in the formula VI;
step 4: reaction of the intermediate of formula VI with trifluoroethylamine or a salt thereof affords fluoro Lei Lana.
The invention also discloses a preparation process for synthesizing fluorine Lei Lana by taking the compound structure of the formula II as an intermediate, which comprises the following steps:
step 1: dissolving a compound of a formula II in an organic solvent, adding anhydrous stannous chloride, and introducing dry hydrogen chloride gas to react to prepare an intermediate of the formula III;
step 2: reacting the intermediate of formula III with hydroxylamine or a salt thereof to form an intermediate of formula IV;
step 3: reacting the intermediate of formula IV with 1, 3-dichloro-5- (1-trifluoromethyl-vinyl) benzene to form an intermediate of formula V;
step 4: hydrolyzing the intermediate in the formula V to obtain an intermediate in the formula VI;
step 5: reaction of the intermediate of formula VI with trifluoroethylamine or a salt thereof affords fluoro Lei Lana.
Preferably, the invention discloses a preparation process of the fluororalreceived, which comprises the following steps:
step 1: reacting commercially available 2-methyl-4-bromobenzoic acid with glycine ester derivatives to generate a compound shown in a formula I; the substituent R1 in the glycine ester derivative is defined as above;
step 2: reacting a compound of formula I with a cyanating agent, as defined above, to produce a compound of formula II;
step 3: dissolving a compound of a formula II in an organic solvent, adding anhydrous stannous chloride, and introducing dry hydrogen chloride gas to react to prepare an intermediate of the formula III;
step 4: reacting the intermediate of formula III with hydroxylamine or a salt thereof to form an intermediate of formula IV;
step 5: reacting the intermediate of formula IV with 1, 3-dichloro-5- (1-trifluoromethyl-vinyl) benzene to form an intermediate of formula V;
step 6: hydrolyzing the intermediate in the formula V to obtain an intermediate in the formula VI;
step 7: reaction of the intermediate of formula VI with trifluoroethylamine or a salt thereof affords fluoro Lei Lana.
The invention has the following beneficial effects:
in the prior art, esters are generally adopted to protect carboxyl, so that 2-amino-N- (2, 2-trifluoroethyl) acetamide hydrochloride (8000-10000 yuan/kg) is used as a material for amide condensation in a subsequent synthesis route of fluorine Lei Lana, and the material cost is high, so that the method is not beneficial to commercial production. The invention abandons the inertia thinking in the prior art, adopts glycine esters to protect carboxyl groups so as to develop a brand-new synthesis line for preparing fluorine Lei Lana, so that materials in the subsequent condensation step adopt low-cost trifluoroethylamine hydrochloride (1000-2000 yuan/kg), the material cost is reduced to 1/5 of the original cost, the yield equivalent to or higher than that in the prior art is achieved, the production cost is greatly reduced, and the method is more suitable for industrialized mass production.
The preparation condition of the fluorine Lei Lana intermediate is milder, environment-friendly and safer to operate, and the use of active hydrogen reducing agents such as n-butyllithium and the like with higher risk is avoided. Meanwhile, the obtained intermediate aldoxime type IV compound is simple to purify, and is directly cooled and crystallized after the reaction is completed, so that the refining is not needed, and the preparation time of the fluorine Lei Lana aldoxime type intermediate is shortened.
Detailed Description
The present invention is described in further detail below with reference to examples, but is not limited to the following examples, and any equivalents in the art, which are in accordance with the present disclosure, are intended to fall within the scope of the present invention.
The structure of the compound is characterized by Mass Spectrum (MS) or nuclear magnetic resonance 1 HNMR).
Nuclear magnetic resonance 1 HNMR) displacement (δ) is given in parts per million (ppm); nuclear magnetic resonance 1 HNMR) is measured by Bruker AVANCE-400 nuclear magnetic resonance apparatus, the measuring solvent is deuterated dimethyl sulfoxide (DMSO), the internal standard is Tetramethylsilane (TMS), and the chemical shift is 10 -6 (ppm) is given as a unit.
The Mass Spectrum (MS) was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: therm, model: finnigan LCQ advantage MAX).
In the case where no specific explanation is given to the present invention, the solution mentioned in the reaction of the present invention is an aqueous solution.
The term "room temperature" in the present invention means that the temperature is between 10℃and 25 ℃.
EXAMPLE 1 preparation of the Compound (2-methyl-4-bromo-benzoyl) glycine ethyl ester of formula I
2-methyl-4-bromobenzoic acid (100.0 g,1.0 eq), 300ml DMF and CDI (113.1 g,1.5 eq) were added to a three-necked flask and activated for 1h at room temperature. Ethyl glycinate hydrochloride (90.9 g,1.4 eq) was added and reacted at room temperature for 18h. Ethyl acetate and water are added and stirred for layering, the ethyl acetate layer is washed by saline solution, dried by anhydrous sodium sulfate and concentrated under reduced pressure to obtain 139.2g of reddish brown solid, the yield is 99.7%, and the chromatographic purity is 97.5%, namely the compound of the formula I. The obtained solid is detected by nuclear magnetic resonance and mass spectrum.
1 H-NMR(400MHz，DMSO-d6)：δ8.75-8.73ppm(1H)，7.51-7.45ppm(2H)，7.30-7.28ppm(1H)，4.15-4.05ppm(2H)，3.96-3.95ppm(2H)，2.35ppm(3H)，1.23-1.17ppm(3H)。
EIMS m/z 300.2([M+H] + )。
EXAMPLE 2 preparation of Compound (2-methyl-4-cyano-benzoyl) glycine ethyl ester of formula II
The compound of formula I (139.0 g,1.0 eq) obtained in example 1 was dissolved in 500ml DMSO, cuprous cyanide (83.0 g,2.0 eq) was added, and the temperature was raised to 120℃for 16h. Dichloromethane and ammonia water are added, stirred, filtered and insoluble matters are removed. The filtrate was separated from the organic layer, which was washed 1 time with 10% aqueous ammonia, 1 time with brine, dried over sodium sulfate, and concentrated to 106.6g of a gray solid. The mixture was recrystallized from 220ml isopropyl acetate, and 92.4g of an off-white solid was filtered and dried to give a yield of 81.0% and a chromatographic purity of 98.3%, i.e., the compound of formula II. The obtained solid is detected by nuclear magnetic resonance and mass spectrum.
1 H-NMR(400MHz，DMSO-d6)δ8.93-8.91ppm(1H)，7.78-7.73ppm(2H)，7.50-7.48ppm(1H)，4.16-4.11ppm(2H)，4.00-3.98ppm(2H)，2.39ppm(3H)，1.24-1.20ppm(3H)。
EIMS m/z 247.4([M+H] + )。
EXAMPLE 3 preparation of the Compound (4- (benzaldoxime) -2-methylbenzoyl) glycine ethyl ester of formula IV
A three-necked flask was charged with the compound of the formula II obtained in example 2 (92.0 g,1.0 eq), anhydrous stannous chloride (177.1 g,2.5 eq) and 1000ml of ethyl acetate, and the mixture was stirred at room temperature for 5 hours. 800ml of water was added thereto and stirred, followed by delamination. The ethyl acetate layer was washed with acid water, brine and concentrated under reduced pressure to give 95.6g of a brown oil, the yield was calculated as 100%, the compound of formula III, which was taken to the next step without purification. The obtained sample is detected by nuclear magnetic resonance and mass spectrum.
1 H-NMR(400MHz，DMSO-d6)δ9.93(1H)，8.93-8.89ppm(1H)，7.75-7.70ppm(2H)，7.50-7.46ppm(1H)，4.18-4.13ppm(2H)，4.01-3.98ppm(2H)，2.40ppm(3H)，1.24-1.21ppm(3H)。
EIMS m/z 250.2([M+H] + )。
The compound (95.4 g,1.0 eq) of formula III obtained in the previous step is dissolved in 180ml of ethanol, hydroxylamine hydrochloride (31.2 g,1.2 eq) is added, the temperature is raised to 60 ℃ for reaction for 3 hours, then the temperature is reduced to-10 to 0 ℃ for crystallization for 2 hours, filtration and drying are carried out, 82.8g of white solid, namely the compound of formula IV, is obtained, the yield of two steps is 83.9%, and the chromatographic purity is 97.3%. The obtained solid is detected by nuclear magnetic resonance and mass spectrum.
1 H-NMR(400MHz，DMSO-d6)：δ11.35(1H)，8.73-8.70ppm(1H)，8.13ppm(1H)，7.45-7.36ppm(3H)，4.16-4.11ppm(2H)，3.97-3.95ppm(2H)，2.37ppm(3H)，1.23-1.20ppm(3H)。
EIMS m/z 265.2([M+H] + )。
EXAMPLE 4 preparation of Ethyl [4- (5- (3, 5-dichlorophenyl) -5- (trifluoromethyl) -4, 5-dihydro-isoxazol-3-yl) -2-methylbenzamide ] glycinate, a compound of formula V
To a three-necked flask, the compound of formula IV (60.0 g,1.0 eq), obtained in example 3, NCS (33.4 g,1.1 eq) and 300ml DMF were added, the temperature was raised to 40℃for 1h, the ice bath was cooled to below 10℃and 1, 3-dichloro-5- (1-trifluoromethyl-vinyl) benzene (54.8 g,1.0 eq) and triethylamine (27.9 g,1.2 eq) were added, followed by warming to room temperature for 5h. Ethyl acetate and water were added, the layers were stirred, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to give 107.6g of a solid. 200ml of isopropanol are added for recrystallization, 94.8g of white solid, i.e. the compound of formula V, are obtained, the yield is 82.9% and the chromatographic purity is 98.9%. The resulting solid was detected by mass spectrometry.
EIMS m/z 503.1([M+H] + )。
Example 5 preparation of fluorine Lei Lana
The compound of formula V (80.0 g,1.0 eq) obtained in example 4 was dissolved in 400ml of tetrahydrofuran, and 80ml of an aqueous solution of sodium hydroxide (19.1 g,3.0 eq) was added thereto, reacted at room temperature for 3.5 hours, and the tetrahydrofuran was removed by concentration under reduced pressure. Adding ethyl acetate and acid water, regulating pH to acidity, separating an organic layer, washing with water, washing with saline solution, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain 75.7g oily substance, namely the compound VI, wherein the yield is calculated as 100%, and the compound VI is directly subjected to the next reaction without purification;
compound VI (75.7 g,1.0 eq) obtained in the previous step was dissolved in 400ml DMF and CDI (31.8 g,1.5 eq) was added and the mixture was heated to 40℃for activation for 2h. Trifluoroethylamine hydrochloride (28.0 g,1.3 eq) was added and reacted at 40℃for 3 hours. Ethyl acetate and acid water were added, and the mixture was stirred and separated. The organic layer was washed with acid water, brine 1 time each, dried over anhydrous sodium sulfate, and concentrated to give 82.8g of an oil. Adding 80ml of ethyl acetate to heat and dissolve, adding 240ml of n-heptane while the mixture is hot to precipitate solid, cooling to crystallization, filtering and drying to obtain 74.6 white solid, namely fluorine Lei Lana, wherein the yield of 2 steps is 84.4%, and the chromatographic purity is 99.2%. The obtained solid is detected by nuclear magnetic resonance and mass spectrum.
1 H-NMR(400MHz，DMSO-d6)：δ8.66-8.63ppm(2H)，7.80-7.52ppm(6H)，4.43-4.30ppm(2H)，4.02-3.93ppm(4H)，2.43ppm(3H)。
EIMS m/z 556.0([M+H] + )。
Example 6 preparation of isopropyl (2-methyl-4-bromo-benzoyl) glycine, a compound of formula i:
2-methyl-4-bromobenzoic acid (50.0 g,1.0 eq), 150ml DMF and CDI (56.5 g,1.5 eq) were added to a three-necked flask and activated for 1h at room temperature. Isopropyl glycinate hydrochloride (50.0 g,1.4 eq) was added and reacted at room temperature for 16h. Adding ethyl acetate and water, stirring and layering, washing an ethyl acetate layer with saline solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 72.6g of reddish brown solid, wherein the yield is 99.4%, and the chromatographic purity is 97.8%, namely the compound of the formula I. The resulting solid was detected by mass spectrometry.
EIMS m/z 314.2([M+H] + )。
Example 7 preparation of compound of formula ii (2-methyl-4-cyano-benzoyl) glycine isopropyl ester:
the compound of formula I (72.0 g,1.0 eq) obtained in example 6 was dissolved in 450ml DMSO, cuprous cyanide (41.0 g,2.0 eq) was added and the reaction was carried out at 120℃for 16h. Ethyl acetate and ammonia water are added, stirred, filtered and insoluble matters are removed. The filtrate was separated from the organic layer, which was washed 1 time with 10% aqueous ammonia, 1 time with brine, dried over sodium sulfate, and concentrated to a gray solid of 55.6 g. The mixture was recrystallized from 110ml isopropyl acetate, and 46.7g of an off-white solid was filtered and dried to give 78.2% yield and 97.2% chromatographic purity, i.e. the compound of formula II. The obtained solid is detected by nuclear magnetic resonance and mass spectrum.
1 H-NMR(400MHz，DMSO-d6)δ8.93-8.89ppm(1H)，7.78-7.74ppm(2H)，7.50-7.47ppm(1H)，4.91ppm(1H)，4.15-4.11ppm(2H)，2.37ppm(3H)，1.25-1.19ppm(6H)。
EIMS m/z 261.2([M+H] + )。
Example 8 preparation of isopropyl (4- (benzaldoxime) -2-methylbenzoyl) glycine, a compound of formula IV:
a three-necked flask was charged with the compound of the formula II obtained in example 7 (45.0 g,1.0 eq), anhydrous stannous chloride (81.9 g,2.5 eq) and 600ml of ethyl acetate, and the mixture was stirred at room temperature for 6 hours by introducing a dry hydrogen chloride gas. 400ml of water was added thereto and stirred, followed by delamination. The ethyl acetate layer was washed with acid water, brine and concentrated under reduced pressure to give 47.7g of a brown oil, the yield was calculated as 100%, which was the compound of formula III and was used in the next step without purification. The obtained sample is detected by nuclear magnetic resonance and mass spectrum.
1 H-NMR(400MHz，DMSO-d6)δ9.89(1H)，8.90-8.87ppm(1H)，7.75-7.70ppm(2H)，7.48-7.45ppm(1H)，4.93ppm(1H)，4.17-4.12ppm(2H)，2.39ppm(3H)，1.23-1.18ppm(6H)。
EIMS m/z 264.2([M+H] + )。
The compound of formula III (47.4 g,1.0 eq) obtained in the previous step is dissolved in 120ml of isopropanol, hydroxylamine hydrochloride (14.4 g,1.2 eq) is added, the temperature is raised to 60 ℃ for reaction for 3 hours, then the temperature is reduced to-10 to 0 ℃ for crystallization for 2 hours, filtration and drying are carried out, 41.2g of white solid, namely the compound of formula IV, is obtained, the yield of two steps is 85.6%, and the chromatographic purity is 98.5%. The obtained solid is detected by nuclear magnetic resonance and mass spectrum.
1 H-NMR(400MHz，DMSO-d6)：δ11.33(1H)，8.75-8.70ppm(1H)，8.15ppm(1H)，7.48-7.38ppm(3H)，4.93ppm(1H)，3.99-3.95ppm(2H)，2.38ppm(3H)，1.24-1.20ppm(6H)。
EIMS m/z 279.1([M+H] + )。
Example 9 preparation of benzyl (2-methyl-4-bromo-benzoyl) glycinate, compound of formula i:
2-methyl-4-bromobenzoic acid (50.0 g,1.0 eq), 150ml DMF and CDI (56.5 g,1.5 eq) were added to a three-necked flask and activated for 1h at room temperature. Benzyl glycine hydrochloride (65.6 g,1.4 eq) was added and reacted at room temperature for 18h. Adding ethyl acetate and water, stirring and layering, washing an ethyl acetate layer with saline solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 83.7g of reddish brown solid, wherein the yield is 99.4%, and the chromatographic purity is 98.0%, namely the compound of the formula I. The resulting solid was detected by mass spectrometry.
EIMS m/z 362.1([M+H] + )。
Example 10 preparation of compound (2-methyl-4-cyano-benzoyl) glycine benzyl ester of formula ii:
the compound of formula I (83.0 g,1.0 eq) obtained in example 9 was dissolved in 500ml DMSO, cuprous cyanide (47.3 g,2.0 eq) was added and the reaction was carried out at 120℃for 18h. Ethyl acetate and ammonia water are added, stirred, filtered and insoluble matters are removed. The filtrate was separated from the organic layer, which was washed 1 time with 10% aqueous ammonia, 1 time with brine, dried over sodium sulfate, and concentrated to 65.5g of a gray solid. The mixture was recrystallized from 130ml isopropyl acetate, and 66.1g of an off-white solid was filtered and dried to give a yield of 81.1% and a chromatographic purity of 98.3%, i.e., the compound of formula II. The obtained solid is detected by nuclear magnetic resonance and mass spectrum.
1 H-NMR(400MHz，DMSO-d6)δ8.92-8.88ppm(1H)，7.78-7.72ppm(2H)，7.45-7.33ppm(6H)，5.13ppm(2H)，4.16-4.10ppm(2H)，2.36ppm(3H)。
EIMS m/z 308.2([M+H] + )。
Example 11 preparation of benzyl (4- (benzaldoxime) -2-methylbenzoyl) glycinate, compound of formula IV:
the compound (65.0 g,1.0 eq) of the formula II obtained in example 10, anhydrous stannous chloride (100.0 g,2.5 eq) and 600ml of ethyl acetate were charged into a three-necked flask, and dried hydrogen chloride gas was introduced and the mixture was stirred at room temperature for 6 hours. 400ml of water was added thereto and stirred, followed by delamination. The ethyl acetate layer was washed with acid water, brine and concentrated under reduced pressure to give 68.7g of a brown oil, the yield was calculated as 100%, which was the compound of formula III, and the next step was carried out without purification. The obtained sample is detected by nuclear magnetic resonance and mass spectrum.
1 H-NMR(400MHz，DMSO-d6)δ9.88ppm(1H),8.88-8.82ppm(1H)，7.75-7.70ppm(2H)，7.46-7.33ppm(6H)，5.15ppm(2H)，4.16-4.08ppm(2H)，2.38ppm(3H)。
EIMS m/z 312.2([M+H] + )。
The compound of formula III (68.5 g,1.0 eq) obtained in the previous step is dissolved in 120ml of isopropanol, hydroxylamine hydrochloride (17.6 g,1.2 eq) is added, the temperature is raised to 60 ℃ for reaction for 3 hours, then the temperature is reduced to-10 to 0 ℃ for crystallization for 3 hours, filtration and drying are carried out, 59.4g of white solid, namely the compound of formula IV, is obtained, the two-step yield is 86.3%, and the chromatographic purity is 98.6%.
1 H-NMR(400MHz，DMSO-d6)：δ11.32(1H)，8.75-8.71ppm(1H)，8.13ppm(1H)，7.48-7.36ppm(8H)，5.15ppm(2H)，4.15-4.08ppm(2H)，2.36ppm(3H)。
EIMS m/z 327.2([M+H] + )。
Although the invention has been described herein with reference to illustrative embodiments thereof, it should be understood that numerous other modifications and embodiments can be devised by those skilled in the art that will fall within the scope and spirit of the principles of this disclosure. More specifically, various variations and modifications may be made to the component parts and/or arrangements of the subject combination arrangement within the scope of the disclosure. In addition to variations and modifications in the component parts and/or arrangements, other uses will be apparent to those skilled in the art.
Claims (12)
1. An intermediate compound having a structure according to formula ii:
wherein R1 is selected from C1-C12 alkyl.
2. An intermediate compound of formula II according to claim 1, wherein R1 is selected from C1-C8 alkyl.
3. An intermediate compound of formula II according to claim 2, wherein R1 is selected from C2-C7 alkyl.
4. A process for the preparation of a compound of formula ii according to claim 1, comprising the steps of:
step 1: reacting 2-methyl-4-bromobenzoic acid with glycine ester derivatives of the formula VIII, wherein the substituent R1 is defined as in claim 1;
step 2: the compound of formula I reacts with cyanating agent to obtain the compound of formula II.
5. An intermediate compound having a structure according to formula III:
wherein R1 is as defined in any one of claims 1 to 3.
6. The process for preparing a compound of the formula III as claimed in claim 5, wherein the compound of the formula II is prepared by dissolving a compound of the formula II in an organic solvent, adding anhydrous stannous chloride, and reacting by introducing a dry hydrogen chloride gas
Wherein R1 is as defined in any one of claims 1 to 3.
7. An intermediate compound having a structure according to formula iv:
wherein R1 is as defined in any one of claims 1 to 3.
8. The process for preparing a compound of the formula IV as claimed in claim 7, wherein the compound of the formula III is reacted with hydroxylamine or a salt thereof
Wherein R1 is as defined in any one of claims 1 to 3.
9. A process for preparing fluororalston from a compound of formula iv according to claim 7, comprising the steps of:
step 1: reacting a compound of formula IV with 1, 3-dichloro-5- (1-trifluoromethyl-vinyl) benzene to obtain an intermediate V compound;
step 2: hydrolyzing the intermediate in the formula V to obtain an intermediate in the formula VI;
step 3: reaction of the intermediate of formula VI with trifluoroethylamine or a salt thereof affords fluoro Lei Lana.
10. A process for preparing fluororalston from a compound of formula III according to claim 5 as an intermediate comprising the steps of:
step 1: reacting the intermediate of formula III with hydroxylamine or a salt thereof to form an intermediate of formula IV;
step 2: reacting the intermediate of formula IV with 1, 3-dichloro-5- (1-trifluoromethyl-vinyl) benzene to form an intermediate of formula V;
step 3: hydrolyzing the intermediate in the formula V to obtain an intermediate in the formula VI;
step 4: reaction of the intermediate of formula VI with trifluoroethylamine or a salt thereof affords fluoro Lei Lana.
11. A process for preparing fluororalston from a compound of formula ii as claimed in claim 1, comprising the steps of:
step 1: dissolving a compound of a formula II in an organic solvent, adding anhydrous stannous chloride, and introducing dry hydrogen chloride gas to react to prepare an intermediate of the formula III;
step 2: reacting the intermediate of formula III with hydroxylamine or a salt thereof to form an intermediate of formula IV;
step 3: reacting the intermediate of formula IV with 1, 3-dichloro-5- (1-trifluoromethyl-vinyl) benzene to form an intermediate of formula V;
step 4: hydrolyzing the intermediate in the formula V to obtain an intermediate in the formula VI;
step 5: reaction of the intermediate of formula VI with trifluoroethylamine or a salt thereof affords fluoro Lei Lana.
12. The preparation method of the fluororalreceived is characterized by comprising the following steps:
step 1: reacting commercially available 2-methyl-4-bromobenzoic acid with glycine ester derivatives of the compound of formula VIII to generate a compound of formula I; the substituent R1 in the glycine ester derivative is defined as in any one of claims 1 to 3;
step 2: reacting a compound of formula I with a cyanating agent to obtain a compound of formula II;
step 3: dissolving a compound of a formula II in an organic solvent, adding anhydrous stannous chloride, and introducing dry hydrogen chloride gas to react to prepare an intermediate of the formula III;
step 4: reacting the intermediate of formula III with hydroxylamine or a salt thereof to form an intermediate of formula IV;
step 5: reacting the intermediate of formula IV with 1, 3-dichloro-5- (1-trifluoromethyl-vinyl) benzene to form an intermediate of formula V;
step 6: hydrolyzing the intermediate in the formula V to obtain an intermediate in the formula VI;
step 7: reaction of the intermediate of formula VI with trifluoroethylamine or a salt thereof affords fluoro Lei Lana.
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| CN101765592A (en) * | 2007-06-26 | 2010-06-30 | 杜邦公司 | Naphthisoxazoline Invertebrate Pest Control Agent |
| JP2009108046A (en) * | 2007-10-10 | 2009-05-21 | Nissan Chem Ind Ltd | Insecticidal, miticidal, nematicidal, molluscicidal, sterilizing, or bactericidal composition and method for controlling pest |
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