CN114685471B - Preparation method of isoxazoline compound - Google Patents
Preparation method of isoxazoline compound Download PDFInfo
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- CN114685471B CN114685471B CN202011621419.0A CN202011621419A CN114685471B CN 114685471 B CN114685471 B CN 114685471B CN 202011621419 A CN202011621419 A CN 202011621419A CN 114685471 B CN114685471 B CN 114685471B
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- toluene
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- isoxazoline
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- -1 isoxazoline compound Chemical class 0.000 title abstract description 33
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims abstract description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 90
- WEGYGNROSJDEIW-UHFFFAOYSA-N 3-Acetylpyridine Chemical compound CC(=O)C1=CC=CN=C1 WEGYGNROSJDEIW-UHFFFAOYSA-N 0.000 claims description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 16
- 239000012071 phase Substances 0.000 claims description 10
- 239000008346 aqueous phase Substances 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 8
- 238000002390 rotary evaporation Methods 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 150000002547 isoxazolines Chemical class 0.000 claims description 7
- 230000007935 neutral effect Effects 0.000 claims description 7
- 229940040526 anhydrous sodium acetate Drugs 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- WGGLDBIZIQMEGH-UHFFFAOYSA-N 1-bromo-4-ethenylbenzene Chemical compound BrC1=CC=C(C=C)C=C1 WGGLDBIZIQMEGH-UHFFFAOYSA-N 0.000 claims description 3
- WGLVLKABEGHUBH-UHFFFAOYSA-N CC1(CC(=NO1)C2=CC=CC=C2)C3=CN=CC=C3 Chemical compound CC1(CC(=NO1)C2=CC=CC=C2)C3=CN=CC=C3 WGLVLKABEGHUBH-UHFFFAOYSA-N 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 31
- 238000000034 method Methods 0.000 abstract description 15
- 150000007942 carboxylates Chemical class 0.000 abstract description 13
- 150000002443 hydroxylamines Chemical class 0.000 abstract description 12
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Natural products C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 abstract description 9
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 abstract description 9
- 238000006116 polymerization reaction Methods 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 7
- 239000000337 buffer salt Substances 0.000 abstract description 6
- 238000000354 decomposition reaction Methods 0.000 abstract description 6
- 238000005580 one pot reaction Methods 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 3
- 238000007086 side reaction Methods 0.000 abstract description 3
- 239000001632 sodium acetate Substances 0.000 abstract description 2
- 235000017281 sodium acetate Nutrition 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 150000007530 organic bases Chemical class 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 125000000217 alkyl group Chemical group 0.000 description 10
- KTZVZZJJVJQZHV-UHFFFAOYSA-N 1-chloro-4-ethenylbenzene Chemical compound ClC1=CC=C(C=C)C=C1 KTZVZZJJVJQZHV-UHFFFAOYSA-N 0.000 description 8
- 239000005740 Boscalid Substances 0.000 description 8
- 229940118790 boscalid Drugs 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000012488 sample solution Substances 0.000 description 8
- WYEMLYFITZORAB-UHFFFAOYSA-N boscalid Chemical compound C1=CC(Cl)=CC=C1C1=CC=CC=C1NC(=O)C1=CC=CN=C1Cl WYEMLYFITZORAB-UHFFFAOYSA-N 0.000 description 7
- 125000005843 halogen group Chemical group 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 229910052783 alkali metal Chemical group 0.000 description 4
- 150000001340 alkali metals Chemical group 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 125000001188 haloalkyl group Chemical group 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- AZBRJNVNGXAMHL-UHFFFAOYSA-N n-ethylhydroxylamine;sulfuric acid Chemical compound CCNO.OS(O)(=O)=O AZBRJNVNGXAMHL-UHFFFAOYSA-N 0.000 description 3
- IZPZQLMZLAGOIR-UHFFFAOYSA-N n-methylhydroxylamine;sulfuric acid Chemical compound CNO.OS(O)(=O)=O IZPZQLMZLAGOIR-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Chemical group 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- VDNKJMUNLKAGAM-UHFFFAOYSA-N 1-pyridin-3-ylpropan-1-one Chemical compound CCC(=O)C1=CC=CN=C1 VDNKJMUNLKAGAM-UHFFFAOYSA-N 0.000 description 2
- XESZUVZBAMCAEJ-UHFFFAOYSA-N 4-tert-butylcatechol Chemical compound CC(C)(C)C1=CC=C(O)C(O)=C1 XESZUVZBAMCAEJ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229910052701 rubidium Chemical group 0.000 description 2
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical group [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- WCGUUGGRBIKTOS-GPOJBZKASA-N (3beta)-3-hydroxyurs-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C WCGUUGGRBIKTOS-GPOJBZKASA-N 0.000 description 1
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical class C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OFAVNWPVFVGSAR-UHFFFAOYSA-N C(C)(=O)O.ONC Chemical compound C(C)(=O)O.ONC OFAVNWPVFVGSAR-UHFFFAOYSA-N 0.000 description 1
- SUGQOBJJVXPRMY-UHFFFAOYSA-N CC1(CN=C(O1)C2=CC=CC=C2)C3=CN=CC=C3 Chemical compound CC1(CN=C(O1)C2=CC=CC=C2)C3=CN=CC=C3 SUGQOBJJVXPRMY-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- MVQLHEHHTOVDCJ-UHFFFAOYSA-N P(=O)(O)(O)O.CNO Chemical compound P(=O)(O)(O)O.CNO MVQLHEHHTOVDCJ-UHFFFAOYSA-N 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- FTSZEKRHIRVJKW-UHFFFAOYSA-N acetic acid;n-ethylhydroxylamine Chemical compound CC[NH2+]O.CC([O-])=O FTSZEKRHIRVJKW-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 125000006003 dichloroethyl group Chemical group 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- HVYUMCAYFNLXOA-UHFFFAOYSA-N dihydrogen phosphate;ethyl(hydroxy)azanium Chemical compound CC[NH2+]O.OP(O)([O-])=O HVYUMCAYFNLXOA-UHFFFAOYSA-N 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- RGZRSLKIOCHTSI-UHFFFAOYSA-N hydron;n-methylhydroxylamine;chloride Chemical group Cl.CNO RGZRSLKIOCHTSI-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention relates to preparation of a compound, in particular to a preparation method of an isoxazoline compound. The method comprises the steps of reacting a pyridyl ketone compound with a substituted styrene compound and hydroxylamine salt in carboxylate serving as buffer salt in a one-step method to prepare the isoxazoline compound; wherein the carboxylate is an organic base. According to the invention, the isoxazoline compound is prepared by a one-step reaction, on one hand, the process flow is simple, the negative effect of nitrone intermediate decomposition on the reaction is avoided, and on the other hand, sodium acetate is introduced as buffer salt, strong alkaline substances such as sodium methoxide are not used, the side reactions such as polymerization and decomposition of nitrone under alkaline conditions are avoided, the reaction yield is improved, and the raw material cost is reduced.
Description
Technical Field
The invention relates to preparation of a compound, in particular to a preparation method of an isoxazoline compound.
Background
At present, few researches on the synthesis method of the isoxazolines are reported, and when the isoxazolines are synthesized by a known synthesis route, particularly the following reaction formulas (1) and (2) are needed to pass through an intermediate containing a nitrone structure, and the intermediate is unstable, so that the yield of the finally synthesized isoxazolines is low.
(1) Nitrone synthesis
(2) Isoxazolines
The method for synthesizing the boscalid by using C, N-dimethyl- (3-pyridyl) nitrone and p-chlorostyrene as raw materials and toluene as a solvent under the condition of reflux has the reaction formula shown in the formulas (1) and (2). The method has the advantages of few reaction steps, easily obtained raw material p-chlorostyrene and mild reaction conditions, but the synthetic yield of the boscalid is only about 20% due to easy self-polymerization of the p-chlorostyrene, and the product separation is difficult. After that, an improved synthesis method suitable for industrialization is provided, wherein C, N-dimethyl- (3-pyridyl) nitrone and p-chlorostyrene are used as raw materials, acetic acid is used as a [3+2] cyclization catalyst, and p-tert-butylcatechol is used as a polymerization inhibitor, so that a boscalid oxazole product is synthesized. The method has the advantages that the synthesis yield of the boscalid is greatly improved due to the introduction of the catalyst and the polymerization inhibitor, the yield of the boscalid reaches about 80 percent, but is still lower, meanwhile, the intermediate-nitrone needs to be independently synthesized and treated, the nitrone has poor thermal stability, and the nitrone is easy to decompose during the treatment, so that the synthesis yield of the boscalid cannot be further improved, and the content of the boscalid product is lower.
Disclosure of Invention
The invention provides a preparation method of isoxazoline compounds for solving the technical problems.
In order to realize the problems, the invention adopts the technical scheme that:
the preparation method of the isoxazoline compound comprises the step of reacting a pyridyl ketone compound with a substituted styrene compound and hydroxylamine salt in carboxylate serving as buffer salt in a one-step method to obtain the isoxazoline compound.
Further, the isoxazolines compound shown in the formula (I) is prepared by a one-step reaction of a pyridyl ketone compound shown in the formula (II), a substituted styrene compound shown in the formula (III) and a hydroxylamine salt shown in the formula (IV) in a buffer system of carboxylate shown in the formula (V), and the reaction is as follows:
wherein R is 1 、R 3 Each independently is methyl, ethyl or propyl; n is a positive integer from 1 to 5; r is R 2 Independently selected from (C) 1 -C 3 ) Alkyl, (C) 1 -C 3 ) Alkoxy, (C) 1 -C 3 ) Haloalkyl, halogen atom or cyano; r is R 4 Is (C) 1 -C 12 ) An alkyl group; t is an ammonium ion or an alkali metal.
The hydroxylamine salt is an inorganic acid salt or an acetate salt of hydroxylamine.
The hydroxylamine salt is N-methyl hydroxylamine hydrochloride, N-methyl hydroxylamine acetate, N-methyl hydroxylamine phosphate, N-methyl hydroxylamine sulfate, N-ethyl hydroxylamine hydrochloride, N-ethyl hydroxylamine acetate, N-ethyl hydroxylamine phosphate or N-ethyl hydroxylamine sulfate.
In the reaction formula, R 1 、R 3 Each independently is methyl, ethyl or propyl; n is a positive integer from 1 to 5; r is R 2 Independently selected from halogen atoms; r is R 4 Is (C) 1 -C 4 ) An alkyl group; t is an alkali metal.
In the reaction formula, R 1 、R 3 Each independently is methyl, ethyl or propyl; n is 1; r is R 2 Independently selected from halogen atoms; r is R 4 Is (C) 1 -C 4 ) An alkyl group; t is sodium, potassium or rubidium.
The R is 2 Is positioned at the para position of the vinyl.
The molar ratio of the addition of the pyridyl ketone compound of the formula (II), the substituted styrene compound of the formula (III), the hydroxylamine salt of the formula (IV) and the carboxylate of the formula (V) is 1:1.5-5:1-2:1-3.
The reaction temperature is 70 ℃ to 150 ℃, preferably 110 ℃ to 135 ℃.
And a polymerization inhibitor can be added in the one-step reaction, and the addition amount of the polymerization inhibitor is 0.01% -1% of the weight of the substituted styrene compound.
Compared with the prior art, the technical scheme of the embodiment of the invention has the following beneficial effects:
according to the invention, the isoxazoline compound is prepared by a one-step reaction, on one hand, the process flow is simple, the negative effect of nitrone intermediate decomposition on the reaction is avoided, and on the other hand, sodium acetate is introduced as buffer salt, strong alkaline substances such as sodium methoxide are not used, the side reactions such as polymerization and decomposition of nitrone under alkaline conditions are avoided, the reaction yield is improved, and the raw material cost is reduced. The synthetic yield of the boscalid oxazole compound prepared by the method can reach more than 88%, and the synthetic yield of isoxazoline compounds is improved; meanwhile, the method is simple and convenient for subsequent separation.
Detailed Description
In order that those skilled in the art will better understand the present invention, a more detailed description is provided below with reference to specific embodiments, but the present invention is not limited thereto.
In the present invention, "optional" means optional or not, as required.
The invention adopts a one-step reaction, introduces buffer salt, avoids side reactions such as polymerization and decomposition of nitrone under alkaline conditions, and the like, and improves the synthesis yield of isoxazolines.
Specifically: reacting a pyridyl ketone compound with a structure of formula (II), a substituted styrene compound with a structure of formula (III), a hydroxylamine salt with a structure of formula (IV) and a carboxylate with a structure of formula (V) in a one-step method to obtain an isoxazoline compound with a structure of formula (I), wherein the reaction is as follows:
wherein R is 1 、R 3 Each independently is methyl, ethyl or propyl; n is a positive integer from 1 to 5; r for different n 2 Independently selected from (C) 1 -C 3 ) Alkyl, (C1-C) 3 ) Alkoxy, (C) 1 -C 3 ) One of a haloalkyl group, a halogen atom, or a cyano group; r is R 4 Is (C) 1 -C 12 ) An alkyl group; t is an ammonium ion or an alkali metal.
According to the one-pot method, the carboxylate of the structure of the formula (V) is introduced as the buffer salt, and reacts with the hydroxylamine salt of the structure of the formula (IV), so that the reaction of the hydroxylamine salt of the structure of the formula (IV) with the pyridylketone compound of the formula (II) can be promoted. Meanwhile, carboxylate with the structure of formula (V) reacts with hydroxylamine salt with the structure of formula (IV) to generate weak acid, and weak acid environment is provided, so that substituted styrene compound with the structure of formula (III) is promoted to participate in the reaction, and further the compound with the structure of formula (I) is directly generated.
Further, the carboxylate with the structure of the formula (V) reacts with sulfuric acid on the formula (IV) to promote the reaction of the formula (IV) and the formula (II), and acetic acid is generated after the carboxylate reacts with the sulfuric acid, so that a weak acidic environment is provided, the formula (III) can be promoted to participate in the reaction, and the product (I) can be directly generated, thereby avoiding the process of generating and purifying intermediates. In addition, the alkali of the adopted carboxylate is weaker, the decomposition of raw materials and products is avoided, and the yield can be improved.
In a specific embodiment of the present invention, R 2 Is (C) 1 -C 3 ) Alkyl refers to a group containing 1 to 3 carbon atoms and includes straight or branched chain forms such as: methyl, ethyl, n-propyl or isopropyl; r is R 2 Is (C) 1 -C 3 ) Alkoxy refers to a group containing 1 to 3 carbon atoms, including straight or branched chain forms, such as: methoxy, ethoxy, n-propoxy or isopropoxy; r is R 2 Is (C) 1 -C 3 ) Haloalkyl refers to a halogen atom containing 1 to 3 carbon atoms and having 1 or more, for example: chloromethyl, bromomethyl, dichloromethyl, dichloroethyl, trichloromethyl, etc.; r is R 2 Halogen atoms, for example: fluorine, chlorine, bromine or iodine atoms; in a specific embodiment of the invention, R for different n, R 2 Independently selected from (C) 1 -C 3 ) Alkyl, (C) 1 -C 3 ) Alkoxy, (C) 1 -C 3 ) One of haloalkyl, halogen atom, or cyano, when n is 2, 3, 4, or 5, R 2 Which may be the same or different, preferably n is 1, i.e. R 2 Is monosubstituted. The R is 2 May be located in the ortho, meta or para position of the vinyl group, preferably in the para position of the vinyl group.
In a specific embodiment of the present invention, R 4 Is (C) 1 -C 12 ) Alkyl means having from 1 to 12 carbon atoms, including straight or branched chain forms; further, R 4 Preferably (C) 1 -C 4 ) Alkyl groups such as: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. An alkali metal, the alkali ion comprising: sodium, potassium or rubidium, preferably sodium or potassium.
The invention provides a specific embodiment of a preparation method of an isoxazoline compound, which further comprises the following steps: mixing the pyridylketone compound with a substituted styrene compound, a carboxylate and optionally a polymerization inhibitor, such as p-tert-butylcatechol, to form a mixture; and adding the hydroxylamine salt to the mixture to effect the cycloaddition reaction.
In particular embodiments of the invention, the reaction time may generally be selected from 1 hour to 10 hours, for example 2, 4, 6, 8 or 10 hours, preferably from 6 hours to 8 hours.
In a specific embodiment of the present invention, the pyridinone compound of the structure of formula (II), the substituted styrene compound of the structure of formula (III), the hydroxylamine salt of the structure of formula (IV), and the carboxylate of the structure of formula (V) may be added in a molar ratio of 1:1.5-5:1-2:1-3, e.g., 1:2:1:0.5, 1:2:1.5:1.5, 1:3:2:2.
In particular embodiments of the invention, the temperature of the reaction may be from 70 ℃ to 150 ℃, for example: 90. 100, 110, 115, 120, 125, 130, 135 or 140 ℃, preferably 110-135 ℃.
In a specific embodiment of the present invention, after the reaction is finished, the method may further include purifying the obtained output material containing the isoxazoline compound of formula (I) by adopting an extraction manner, and as a specific example, the method may be as follows: adding water; regulating pH to be less than 1, standing and layering to separate a para-olefin organic phase; then, extracting the water phase by using an organic solvent, and combining and recycling the organic solvent layer and the para-olefin organic phase; adjusting the pH of the remaining water layer to 12-14, extracting with organic solvent for one or more times, mixing organic phases, and washing with water to neutrality; removing the organic solvent by rotary evaporation to obtain a crude product. The organic solvent includes toluene, xylene, etc. The aqueous phase refers to a phase mainly taking water as a medium, and the amount of water can be more than 50wt%, 60wt%, 70wt%, 80wt%, 90wt%, 95wt% of the total amount of the medium, or even the whole medium is water; the adjustment of the pH to <1 is achieved with mineral acids, which are generally added in the form of aqueous solutions, for example dropwise, and which specifically include, for example: one or any combination of hydrochloric acid, sulfuric acid or phosphoric acid; the pH is adjusted to 12-14 with an inorganic base, which is generally added in the form of an aqueous solution, such as dropwise addition, and specifically includes, for example, sodium hydroxide, potassium hydroxide or sodium carbonate.
The following description of embodiments of the present invention will be made clearly and fully with reference to the accompanying drawings, in which it is shown, however, only some, but not all embodiments of the invention are shown. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Description of the sources of the raw materials
Main experiment reagent
HPLC test method description
High performance liquid chromatography (Agilent 1200 with variable UV detector), agilent chromatography workstation, and 50 μl microinjector were used for sample injection. The operating conditions were as follows:
chromatographic column: 250mm×4.6mm (i.d) stainless steel column, filled with C18 filler, and particle size of 5 μm; mobile phase: methanol: water=80: 20, a step of; flow rate: 0.8mL/min; wavelength: 236nm; temperature: room temperature, wherein methanol is chromatographically pure, and water is double distilled water.
The solvent was formulated as follows:
standard solution: weighing 0.020 g-0.025 g (accurate to 0.0002 g) of standard sample E and Z of raw medicine respectively, putting into a 100mL volumetric flask, adding 10mL of methanol, oscillating for 5min on an ultrasonic cleaner, cooling to room temperature, diluting to scale with methanol, and shaking uniformly.
Sample solution: weighing 0.030 g-0.035 g of crude drug sample (0.0002 g) into a 100mL volumetric flask, adding 10mL of methanol, oscillating for 5min on an ultrasonic cleaner, cooling to room temperature, diluting to scale with methanol, and shaking uniformly.
And then, under the operation condition, after the base line of the chromatograph is stable, continuously injecting a plurality of needles of standard sample solutions, calculating the response value of each needle, and measuring according to the sequence of the standard sample solution, the sample solution and the standard sample solution when the response value change of two adjacent needles is less than 1.2 percent.
The peak areas in the two-needle sample solution and the two-needle standard sample solution before and after the sample were measured and averaged, respectively. The mass fraction X (%) of the product is calculated according to the following formula:
wherein:
A 1 -an average value of the z/e peak area in the standard solution;
A 2 -an average value of peak areas in the sample solution;
m 1 -mass of standard z/e in grams (g);
m 2 -mass of the sample in grams (g);
mass fraction of P-standard z/e.
Yield calculation method
Some typical compounds of formula (I) according to the invention are listed in Table 1, but are not limiting to the invention.
TABLE 1 partial exemplary Compounds of formula (I) of the invention
The following examples illustrate the invention in detail.
Example 1
N-methyl-3- (4-chloro) phenyl-5-methyl-5-pyridin-3-yl-isoxazoline
3-acetylpyridine (0.1 mol), 4-chlorostyrene (0.2 mol), anhydrous sodium acetate (0.1 mol) and N-mevalonate sulfate (0.1 mol) are added in sequence, the temperature is raised to 115 ℃, and the reaction is carried out for 7 hours until the conversion of the 3-acetylpyridine is complete.
Adding 30ml of water, dropwise adding 30% hydrochloric acid until the pH value is less than 1, standing for layering, adjusting the pH value of the lower aqueous solution to be more than 12 by using 30% NaOH aqueous solution, adding 50ml of toluene for extraction, extracting the aqueous phase once by using toluene, combining toluene phases, washing with water to be neutral, and removing the toluene by rotary evaporation to obtain the N-methyl-3- (4-chloro) phenyl-5-methyl-5-pyridin-3-yl-isoxazoline, wherein the quantitative content of HPLC is 95 percent, and the yield is 90 percent.
Example 2
N-methyl-3- (4-bromo) phenyl-5-methyl-5-pyridin-3-yl-isoxazoline
3-acetylpyridine (0.1 mol), 4-bromostyrene (0.15 mol), anhydrous sodium acetate (0.15 mol) and N-mevalonate sulfate (0.1 mol) are added in sequence, the temperature is raised to 110 ℃, and the reaction is carried out for 6 hours until the conversion of the 3-acetylpyridine is complete.
Adding 30ml of water, dropwise adding 30% hydrochloric acid until the pH value is less than 1, standing for layering, adjusting the pH value of the lower aqueous solution to be more than 12 by using 30% NaOH aqueous solution, adding 50ml of toluene for extraction, extracting the aqueous phase once by using toluene, combining toluene phases, washing with water to be neutral, and removing the toluene by rotary evaporation to obtain the N-methyl-3- (4-bromine) phenyl-5-methyl-5-pyridine-3-yl-isoxazoline, wherein the quantitative content of HPLC is 95 percent and the yield is 92 percent.
Example 3
N-ethyl-3- (4-chloro) phenyl-5-methyl-5-pyridin-3-yl-isoxazoline
3-acetylpyridine (0.1 mol), 4-chlorostyrene (0.2 mol), anhydrous sodium acetate (0.2 mol) and N-ethylhydroxylamine sulfate (0.2 mol) are added in sequence, the temperature is raised to 120 ℃, and the reaction is carried out for 8 hours until the conversion of the 3-acetylpyridine is complete.
Adding 30ml of water, dropwise adding 30% hydrochloric acid until the pH value is less than 1, standing for layering, regulating the pH value of the lower aqueous solution to be more than 12 by using 30% NaOH aqueous solution, adding 50ml of toluene for extraction, extracting the aqueous phase once by using toluene, combining toluene phases, washing with water to be neutral, and removing the toluene by rotary evaporation to obtain the N-ethyl-3- (4-chloro) phenyl-5-methyl-5-pyridin-3-yl-isoxazoline, wherein the quantitative content of HPLC is 92%, and the yield is 88%.
Example 4
N-ethyl-3- (4-chloro) phenyl-5-methyl-5-pyridin-3-yl-isoxazoline
3-acetylpyridine (0.1 mol), 4-chlorostyrene (0.2 mol), anhydrous sodium acetate (0.15 mol) and N-ethylhydroxylamine sulfate (0.15 mol) are added in sequence, the temperature is raised to 130 ℃, and the reaction is carried out for 5 hours until the conversion of the 3-acetylpyridine is complete.
Adding 30ml of water, dropwise adding 30% hydrochloric acid until the pH value is less than 1, standing for layering, adjusting the pH value of the lower aqueous solution to be more than 12 by using 30% NaOH aqueous solution, adding 50ml of toluene for extraction, extracting the aqueous phase once by using toluene, combining toluene phases, washing with water to be neutral, and removing the toluene by rotary evaporation to obtain the N-ethyl-3- (4-chloro) phenyl-5-methyl-5-pyridin-3-yl-isoxazoline, wherein the quantitative content of HPLC is 95 percent, and the yield is 90 percent.
Example 5
N-methyl-3- (4-chloro) phenyl-5-ethyl-5-pyridin-3-yl-isoxazoline
3-propionylpyridine (0.1 mol), 4-chlorostyrene (0.3 mol), anhydrous sodium acetate (0.2 mol) and N-methyl hydroxylamine sulfate (0.2 mol) are added in sequence, the temperature is raised to 115 ℃, and the reaction is carried out for 10 hours until the conversion of the 3-acetylpyridine is complete.
Adding 30ml of water, dropwise adding 30% hydrochloric acid until the pH value is less than 1, standing for layering, regulating the pH value of the lower aqueous solution to be more than 12 by using 30% NaOH aqueous solution, adding 50ml of toluene for extraction, extracting the aqueous phase once by using toluene, combining toluene phases, washing the aqueous phase to be neutral by water, and removing the toluene by rotary evaporation to obtain the N-methyl-3- (4-chloro) phenyl-5-ethyl-5-pyridin-3-yl-isoxazoline, wherein the quantitative content of HPLC is 94.5 percent and the yield is 89 percent.
Example 6
N-methyl-3- (4-bromo) phenyl-5-methyl-5-pyridin-3-yl-isoxazoline
3-acetylpyridine (0.1 mol), 4-bromostyrene (0.2 mol), anhydrous ammonium acetate (0.15 mol) and N-methyl hydroxylamine sulfate (0.1 mol) are added in sequence, the temperature is raised to 120 ℃, and the reaction is carried out for 7 hours until the conversion of the 3-acetylpyridine is complete.
Adding 30ml of water, dropwise adding 30% hydrochloric acid until the pH value is less than 1, standing for layering, adjusting the pH value of the lower aqueous solution to be more than 12 by using 30% NaOH aqueous solution, adding 50ml of toluene for extraction, extracting the aqueous phase once by using toluene, combining toluene phases, washing with water to be neutral, and removing the toluene by rotary evaporation to obtain the N-methyl-3- (4-bromine) phenyl-5-methyl-5-pyridine-3-yl-oxazoline, wherein the quantitative content of HPLC is 92 percent, and the yield is 89 percent.
Although the present invention is disclosed above, the present invention is not limited thereto. Various changes and modifications may be made by one skilled in the art without departing from the spirit and scope of the invention, and the scope of the invention should be assessed accordingly to that of the appended claims.
Claims (1)
1. A preparation method of isoxazoline compounds is characterized in that:
the preparation method comprises the following steps: adding 0.1mol of 3-acetylpyridine, 0.15mol of 4-bromostyrene, 0.15mol of anhydrous sodium acetate and 0.1mol of N-mevalonate into the mixture in sequence, heating the mixture to 110 ℃, and reacting the mixture for 6 hours until the 3-acetylpyridine is completely converted;
adding 30ml of water, dropwise adding 30% hydrochloric acid until the pH value is less than 1, standing for layering, adjusting the pH value of the lower aqueous solution to be more than 12 by using 30% NaOH aqueous solution, adding 50ml of toluene for extraction, extracting the aqueous phase once by using toluene, combining toluene phases, washing with water to be neutral, and removing the toluene by rotary evaporation to obtain the N-methyl-3- (4-bromine) phenyl-5-methyl-5-pyridine-3-yl-isoxazoline.
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| CN1280767A (en) * | 1999-07-14 | 2001-01-24 | 沈阳化工研究院 | Heterocycle substituted isoxazoline compounds used as disinfectant |
| CN105061304A (en) * | 2015-06-05 | 2015-11-18 | 沈阳科创化学品有限公司 | Method for preparing isoxazoline compound and intermediate thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1280767A (en) * | 1999-07-14 | 2001-01-24 | 沈阳化工研究院 | Heterocycle substituted isoxazoline compounds used as disinfectant |
| CN105061304A (en) * | 2015-06-05 | 2015-11-18 | 沈阳科创化学品有限公司 | Method for preparing isoxazoline compound and intermediate thereof |
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| Title |
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| 程春生 等.1,3-偶极环加成法合成异噁唑啉新化合物及其生物活性的研究.《有机化学》.第25卷(第11期),第1392-1397页. * |
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