CN114685471A - Preparation method of isoxazoline compound - Google Patents
Preparation method of isoxazoline compound Download PDFInfo
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- CN114685471A CN114685471A CN202011621419.0A CN202011621419A CN114685471A CN 114685471 A CN114685471 A CN 114685471A CN 202011621419 A CN202011621419 A CN 202011621419A CN 114685471 A CN114685471 A CN 114685471A
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- isoxazoline
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- -1 isoxazoline compound Chemical class 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 150000002443 hydroxylamines Chemical class 0.000 claims abstract description 17
- 150000007942 carboxylates Chemical class 0.000 claims abstract description 13
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Natural products C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006116 polymerization reaction Methods 0.000 claims abstract description 11
- 238000005580 one pot reaction Methods 0.000 claims abstract description 9
- 239000000337 buffer salt Substances 0.000 claims abstract description 7
- 150000002547 isoxazolines Chemical class 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 239000003112 inhibitor Substances 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 229910052783 alkali metal Chemical group 0.000 claims description 6
- 150000001340 alkali metals Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000001188 haloalkyl group Chemical group 0.000 claims description 5
- 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 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- AZBRJNVNGXAMHL-UHFFFAOYSA-N n-ethylhydroxylamine;sulfuric acid Chemical compound CCNO.OS(O)(=O)=O AZBRJNVNGXAMHL-UHFFFAOYSA-N 0.000 claims description 4
- IZPZQLMZLAGOIR-UHFFFAOYSA-N n-methylhydroxylamine;sulfuric acid Chemical compound CNO.OS(O)(=O)=O IZPZQLMZLAGOIR-UHFFFAOYSA-N 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000011591 potassium Chemical group 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- 229910052701 rubidium Chemical group 0.000 claims description 3
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical group [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 2
- OFAVNWPVFVGSAR-UHFFFAOYSA-N C(C)(=O)O.ONC Chemical compound C(C)(=O)O.ONC OFAVNWPVFVGSAR-UHFFFAOYSA-N 0.000 claims description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 2
- MVQLHEHHTOVDCJ-UHFFFAOYSA-N P(=O)(O)(O)O.CNO Chemical compound P(=O)(O)(O)O.CNO MVQLHEHHTOVDCJ-UHFFFAOYSA-N 0.000 claims description 2
- 159000000021 acetate salts Chemical class 0.000 claims description 2
- FTSZEKRHIRVJKW-UHFFFAOYSA-N acetic acid;n-ethylhydroxylamine Chemical compound CC[NH2+]O.CC([O-])=O FTSZEKRHIRVJKW-UHFFFAOYSA-N 0.000 claims description 2
- 239000007853 buffer solution Substances 0.000 claims description 2
- HVYUMCAYFNLXOA-UHFFFAOYSA-N dihydrogen phosphate;ethyl(hydroxy)azanium Chemical compound CC[NH2+]O.OP(O)([O-])=O HVYUMCAYFNLXOA-UHFFFAOYSA-N 0.000 claims description 2
- RGZRSLKIOCHTSI-UHFFFAOYSA-N hydron;n-methylhydroxylamine;chloride Chemical group Cl.CNO RGZRSLKIOCHTSI-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 9
- 238000000034 method Methods 0.000 abstract description 19
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000000354 decomposition 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
- 238000007086 side reaction Methods 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 78
- WEGYGNROSJDEIW-UHFFFAOYSA-N 3-Acetylpyridine Chemical compound CC(=O)C1=CC=CN=C1 WEGYGNROSJDEIW-UHFFFAOYSA-N 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 12
- 239000012071 phase Substances 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
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000012488 sample solution Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000000605 extraction Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000002390 rotary evaporation Methods 0.000 description 7
- 238000005406 washing Methods 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
- 239000008346 aqueous phase Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- DHTJFQWHCVTNRY-OEMAIJDKSA-N pyrisoxazole Chemical compound C1([C@@]2(C)CC(ON2C)C=2C=CC(Cl)=CC=2)=CC=CN=C1 DHTJFQWHCVTNRY-OEMAIJDKSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 150000001734 carboxylic acid salts Chemical class 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- WGGLDBIZIQMEGH-UHFFFAOYSA-N 1-bromo-4-ethenylbenzene Chemical compound BrC1=CC=C(C=C)C=C1 WGGLDBIZIQMEGH-UHFFFAOYSA-N 0.000 description 2
- VDNKJMUNLKAGAM-UHFFFAOYSA-N 1-pyridin-3-ylpropan-1-one Chemical compound CCC(=O)C1=CC=CN=C1 VDNKJMUNLKAGAM-UHFFFAOYSA-N 0.000 description 2
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-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
- 241000894006 Bacteria Species 0.000 description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 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
- 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
- 229940079593 drug Drugs 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- MROAQUNKLFXYQN-UHFFFAOYSA-N methanamine;sulfuric acid Chemical compound NC.OS(O)(=O)=O MROAQUNKLFXYQN-UHFFFAOYSA-N 0.000 description 2
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 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
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- XTGVRZKBSFJWPZ-UHFFFAOYSA-N 1,3-dioxourea Chemical group O=NC(=O)N=O XTGVRZKBSFJWPZ-UHFFFAOYSA-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
- 238000012935 Averaging Methods 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 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
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 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
- QPOWUYJWCJRLEE-UHFFFAOYSA-N dipyridin-2-ylmethanone Chemical class C=1C=CC=NC=1C(=O)C1=CC=CC=N1 QPOWUYJWCJRLEE-UHFFFAOYSA-N 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052740 iodine 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
- 239000007788 liquid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture 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
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 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
- 238000000926 separation method Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- JBJWASZNUJCEKT-UHFFFAOYSA-M sodium;hydroxide;hydrate Chemical compound O.[OH-].[Na+] JBJWASZNUJCEKT-UHFFFAOYSA-M 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 150000003440 styrenes Chemical class 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 compounds, in particular to a preparation method of isoxazoline compounds. The pyridyl ketone compound, the substituted styrene compound and the hydroxylamine salt react in a one-step method in carboxylate serving as buffer salt to prepare the isoxazoline compound; wherein the carboxylate is an organic base. According to the invention, the isoxazoline compound is prepared by one-step reaction, on one hand, the process flow is simple, the negative effect of nitrosketone intermediate decomposition on the reaction is avoided, on the other hand, sodium acetate is introduced as buffer salt, and strong alkaline substances such as sodium methoxide and the like are not used, so that side reactions such as polymerization and decomposition of nitrosketone 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 compounds, in particular to a preparation method of isoxazoline compounds.
Background
At present, few reports are reported on the research of the synthesis method of the isoxazoline compound, and when the known synthesis route is used for synthesizing the isoxazoline compound, specifically the following reaction formulas (1) and (2) need to pass through an intermediate containing a nitrosoketone structure, and the intermediate is unstable, so that the yield of the finally synthesized isoxazoline compound is low.
(1) Nitrone synthesis
(2) Isoxazolines
The method for synthesizing the pyrisoxazole under the reflux condition by taking C, N-dimethyl- (3-pyridyl) nitrone and p-chlorostyrene as raw materials and toluene as a solvent has the reaction formulas 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 synthesis yield of the pyridinconazole oxazole is only about 20 percent due to easy self-polymerization of the p-chlorostyrene, and the product is difficult to separate. Then, an improved synthesis method suitable for industrialization is provided, and a pyridine bacterium oxazole product is synthesized by taking C, N-dimethyl- (3-pyridyl) nitrone and p-chlorostyrene as raw materials, acetic acid as a [3+2] cyclization catalyst and p-tert-butyl catechol as a polymerization inhibitor. The method has the advantages that due to the introduction of the catalyst and the polymerization inhibitor, the synthesis yield of the pyrisoxazole is greatly improved, the yield is still low although the yield reaches about 80%, and meanwhile, an intermediate-nitrosketone needs to be independently synthesized and treated, the thermal stability of the nitrosketone is poor, and the nitrosketone is easy to decompose during treatment, so that the synthesis yield of the pyrisoxazole cannot be further improved, and the content of the pyrisoxazole product is low.
Disclosure of Invention
The present invention provides a method for preparing isoxazoline compounds to solve the above technical problems.
In order to realize the problems, the invention adopts the technical scheme that:
a preparation method of isoxazoline compounds comprises the step of reacting pyridylketone compounds, substituted styrene compounds and hydroxylamine salts in carboxylate serving as buffer salt in a one-step method to obtain the isoxazoline compounds.
Further, the isoxazoline compound shown in the formula (I) is prepared by one-step reaction of the pyridylketone compound shown in the formula (II), the substituted styrene compound shown in the formula (III) and the 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 is1、R3Each independently is methyl, ethyl or propyl; n is a positive integer of 1-5; r2Independently selected from (C)1-C3) Alkyl, (C)1-C3) Alkoxy group, (C)1-C3) A haloalkyl group, a halogen atom or a cyano group; r4Is (C)1-C12) An alkyl group; t is ammonium ion or alkali metal.
The hydroxylamine salt is an inorganic acid salt or an acetate salt of hydroxylamine.
The hydroxylamine salt is N-methylhydroxylamine hydrochloride, N-methylhydroxylamine acetate, N-methylhydroxylamine phosphate, N-methylhydroxylamine sulfate, N-ethylhydroxylamine hydrochloride, N-ethylhydroxylamine acetate, N-ethylhydroxylamine phosphate or N-ethylhydroxylamine sulfate.
In the reaction formula, R1、R3Each independently is methyl, ethyl or propyl; n is a positive integer of 1-5; r is2Independently selected from halogen atoms; r4Is (C)1-C4) An alkyl group; t is an alkali metal.
In the reaction formula, R1、R3Each independently methyl, ethyl or propyl; n is 1; r2Independently selected from halogen atoms; r4Is (C)1-C4) An alkyl group; t is sodium, potassium or rubidium.
The R is2Is positioned at the para position of the vinyl.
The pyridylketone compound of formula (II), the substituted styrene compound of formula (III), the hydroxylamine salt of formula (IV) and the carboxylic acid salt of formula (V) are added in a molar ratio of 1: 1.5-5: 1-2: 1-3.
The reaction temperature is 70-150 ℃, preferably 110-135 ℃.
A polymerization inhibitor can be added in the one-step reaction, and the adding 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 one-step reaction, on one hand, the process flow is simple, the negative effect of nitrosketone intermediate decomposition on the reaction is avoided, on the other hand, sodium acetate is introduced as buffer salt, and strong alkaline substances such as sodium methoxide and the like are not used, so that side reactions such as polymerization and decomposition of nitrosketone under alkaline conditions are avoided, the reaction yield is improved, and the raw material cost is reduced. The synthesis yield of the pyridine bacteria oxazole compound prepared by the method can reach more than 88 percent, and the synthesis yield of the isoxazoline compound is improved; meanwhile, the method of the invention 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, as necessary.
The method adopts one-step reaction, introduces buffer salt, avoids side reactions such as polymerization and decomposition of nitrone under the alkaline condition, and the like, and improves the synthesis yield of the isoxazoline compound.
Specifically, the method comprises the following steps: the method comprises the following steps of reacting a pyridylketone compound with a structure shown in a formula (II), a substituted styrene compound with a structure shown in a formula (III), a hydroxylamine salt with a structure shown in a formula (IV) and carboxylate with a structure shown in a formula (V) in a one-step method to obtain an isoxazoline compound with a structure shown in a formula (I), wherein the reaction is as follows:
wherein R is1、R3Each independently is methyl, ethyl or propyl; n is a positive integer of 1-5; for different n, R2Independently selected from (C)1-C3) Alkyl, (C1-C)3) Alkoxy group, (C)1-C3) One of a haloalkyl group, a halogen atom, or a cyano group; r4Is (C)1-C12) An alkyl group; t is ammonium ion or alkali metal.
The one-pot method of the invention can promote the reaction of the hydroxylamine salt with the structure of the formula (IV) and the pyridylketone compound with the formula (II) because the carboxylate with the structure of the formula (V) is introduced as a buffer salt and reacts with the hydroxylamine salt with the structure of the formula (IV). Meanwhile, after the carboxylate with the structure of the formula (V) reacts with the hydroxylamine salt with the structure of the formula (IV), weak acid is generated, and a weak acid environment is provided, so that the substituted styrene compound with the structure of the formula (III) is promoted to participate in the reaction, and the compound with the structure of the formula (I) is directly generated.
Furthermore, the carboxylate with the structure of the formula (V) reacts with the sulfuric acid on the formula (IV) to promote the reaction of the formula (IV) and the formula (II), and the carboxylate reacts with the sulfuric acid to generate acetic acid, so that a weak acid environment is provided, the formula (III) can be promoted to participate in the reaction, and the product (I) is directly generated, so that the processes of generating and purifying intermediates are not needed. Moreover, the carboxylic acid salt used is relatively weak in basicity, and does not cause decomposition of raw materials and products, thereby improving the yield.
In a particular embodiment of the invention, R2Is (C)1-C3) Alkyl, meaning containing 1 to 3 carbon atoms, including straight or branched chain forms, such as: methyl, ethyl, n-propyl or isopropyl; r2Is (C)1-C3) Alkoxy, means containing 1 to 3 carbon atoms, including straight or branched chain forms, such as: methoxy, ethoxy, n-propoxy or iso-propoxyA propoxy group; r2Is (C)1-C3) Haloalkyl, means containing 1 to 3 carbon atoms and having 1 or more halogen atoms, such as: chloromethyl, bromomethyl, dichloromethyl, dichloroethyl, trichloromethyl, or the like; r2Is a halogen atom, for example: a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; in a particular embodiment of the invention, R is different for different n2Independently selected from (C)1-C3) Alkyl, (C)1-C3) Alkoxy group, (C)1-C3) One of haloalkyl, halogen atom, or cyano, R is when n is 2, 3, 4, or 52Which may be the same or different, preferably n is 1, i.e. R2Is monosubstituted. The R is2It may be in the ortho, meta or para position with respect to the vinyl group, preferably in the para position with respect to the vinyl group.
In a particular embodiment of the invention, R4Is (C)1-C12) Alkyl, meaning containing from 1 to 12 carbon atoms, including straight or branched chain forms; further, R4Is preferably (C)1-C4) Alkyl groups, for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. Alkali metals, the alkali ions comprising: sodium, potassium or rubidium, preferably sodium or potassium.
In a specific embodiment of the method for preparing an isoxazoline compound provided by the present invention, the method further comprises: mixing the pyridinone compound with a substituted styrene compound, a carboxylate and optionally a polymerization inhibitor, such as p-tert-butylcatechol, to form a mixed material; and adding the hydroxylamine salt to the mixture to perform the cycloaddition reaction.
In a particular embodiment of the invention, the time of the reaction may generally be chosen to be between 1 hour and 10 hours, such as between 2, 4, 6, 8 or 10 hours, preferably between 6 hours and 8 hours.
In a specific embodiment of the present invention, the pyridinone compound of formula (II), the substituted styrene compound of formula (III), the hydroxylamine salt of formula (IV), and the carboxylic acid salt of formula (V) may be added in a molar ratio of 1: 1.5-5: 1-2: 1-3, such as 1:2:1:0.5, 1:2:1.5:1.5, 1:3:2: 2.
In a particular embodiment of the invention, the temperature of the reaction may be in the range of 70 ℃ to 150 ℃, for example: 90. 100, 110, 115, 120, 125, 130, 135 or 140 ℃, preferably 110 ℃ to 135 ℃.
In the embodiment of the present invention, after the reaction is finished, the obtained output material containing the isoxazoline compound with the structure of formula (I) may be further purified by extraction, which may be as follows as specific examples: adding water; adjusting the pH value to be less than 1, standing for layering, and separating out a para-olefin organic phase; then, extracting the water phase by using an organic solvent, and combining an organic solvent layer and the p-alkene organic phase and recovering; adjusting the pH value of the remaining water layer to 12-14, extracting with organic solvent once or more times, combining organic phases, and washing with water to neutrality; rotary evaporation is carried out to remove the organic solvent to obtain a crude product. The organic solvent includes toluene or xylene, etc. The aqueous phase refers to a phase mainly taking water as a medium, and the amount of water can be more than 50 wt%, 60 wt%, 70 wt%, 80 wt%, 90 wt%, 95 wt% of the total amount of the medium, or even all the media are water; adjusting the pH to <1 is achieved with mineral acids, which are typically added in the form of an aqueous solution, e.g. dropwise, and specifically include, for example: one or any combination of hydrochloric acid, sulfuric acid or phosphoric acid; the pH is adjusted to 12 to 14 using an inorganic base, which is generally added in the form of an aqueous solution, for example dropwise, and specifically includes, for example, sodium hydroxide, potassium hydroxide or sodium carbonate.
The following will clearly and completely describe the technical solutions of the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Description of the sources of the raw materials
Main experimental reagent
Description of HPLC test method
Sample introduction was performed using a 50 μ l microinjector using a high performance liquid chromatograph (Agilent 1200 with variable uv detector), Agilent chromatography workstation. The operating conditions were as follows:
a chromatographic column: a 250mm × 4.6mm (i.d) stainless steel column filled with C18 filler and having a particle size of 5 μm; mobile phase: methanol: 80 parts of water: 20; flow rate: 0.8 mL/min; wavelength: 236 nm; temperature: at room temperature, wherein the methanol is chromatographic pure, and the water is double distilled water.
The solvent was formulated as follows:
standard solution: weighing 0.020 g-0.025 g (accurate to 0.0002g) of the E body and the Z body of the original drug standard sample respectively into a 100mL volumetric flask, adding 10mL of methanol, oscillating for 5min on an ultrasonic cleaner, cooling to room temperature, diluting with the methanol to a scale, and shaking uniformly.
Sample solution: weighing 0.030 g-0.035 g (accurate to 0.0002g) of original drug sample in a 100mL volumetric flask, adding 10mL of methanol, oscillating for 5min on an ultrasonic cleaner, cooling to room temperature, diluting with methanol to scale, and shaking up.
Then, under the above operating conditions, after the baseline of the chromatograph is stabilized, a plurality of needles of standard sample solution are continuously injected, the response value of each needle is calculated, and when the response value of two adjacent needles is changed by less than 1.2%, the measurement is carried out according to the sequence of the standard sample solution, the sample solution and the standard sample solution.
And respectively averaging the peak areas in the two measured needle sample solutions and the two measured needle standard sample solutions before and after the sample. The product mass fraction X (%) is calculated according to the following formula:
in the formula:
A1-average value of the z/e peak area in the standard solution;
A2-average value of peak area in the sample solution;
m1-mass of standard z/e in grams (g);
m2-mass of the sample in grams (g);
p-mass fraction of z/e of standard.
Method for calculating yield
Some representative compounds of formula (I) of the present invention are listed in Table 1, but not limiting the invention.
TABLE 1 partial typical compounds of the formula (I) according to the invention
The following examples illustrate the invention in detail.
Example 1
N-methyl-3- (4-chloro) phenyl-5-methyl-5-pyridin-3 yl-isoxazolines
Sequentially adding 3-acetylpyridine (0.1mol), 4-chlorostyrene (0.2mol), anhydrous sodium acetate (0.1mol) and N-methylamine sulfate (0.1mol), heating to 115 ℃, and reacting 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-layer 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 the toluene, combining toluene phases, washing 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%, and the yield is 90%.
Example 2
N-methyl-3- (4-bromo) phenyl-5-methyl-5-pyridin-3 yl-isoxazolines
Sequentially adding 3-acetylpyridine (0.1mol), 4-bromostyrene (0.15mol), anhydrous sodium acetate (0.15mol) and N-methylamine sulfate (0.1mol), heating to 110 ℃, and reacting 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-layer 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 the toluene, combining toluene phases, washing to be neutral, and removing the toluene by rotary evaporation to obtain the N-methyl-3- (4-bromo) phenyl-5-methyl-5-pyridin-3-yl-isoxazoline, wherein the quantitative content of HPLC is 95%, and the yield is 92%.
Example 3
N-ethyl-3- (4-chloro) phenyl-5-methyl-5-pyridin-3 yl-isoxazolines
Sequentially adding 3-acetylpyridine (0.1mol), 4-chlorostyrene (0.2mol), anhydrous sodium acetate (0.2mol) and N-ethylhydroxylamine sulfate (0.2mol), heating to 120 ℃, and reacting 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, adjusting the pH value of the lower-layer 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 the toluene, combining toluene phases, washing 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-isoxazolines
Sequentially adding 3-acetylpyridine (0.1mol), 4-chlorostyrene (0.2mol), anhydrous sodium acetate (0.15mol) and N-ethylhydroxylamine sulfate (0.15mol), heating to 130 ℃, and reacting 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-layer water solution to be more than 12 by using 30% NaOH water solution, adding 50ml of toluene for extraction, extracting the water phase once by using the toluene, combining toluene phases, washing to be neutral, and performing rotary evaporation to remove the toluene to obtain the N-ethyl-3- (4-chloro) phenyl-5-methyl-5-pyridin-3-yl-isoxazoline, wherein the HPLC quantitative content is 95%, and the yield is 90%.
Example 5
N-methyl-3- (4-chloro) phenyl-5-ethyl-5-pyridin-3 yl-isoxazolines
Adding 3-propionyl pyridine (0.1mol), 4-chlorostyrene (0.3mol), anhydrous sodium acetate (0.2mol) and N-methylhydroxylamine sulfate (0.2mol) in sequence, heating to 115 ℃, and reacting for 10 hours until the conversion of the 3-acetyl pyridine 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-layer 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 the toluene, combining toluene phases, washing to be neutral, 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%, and the yield is 89%.
Example 6
N-methyl-3- (4-bromo) phenyl-5-methyl-5-pyridin-3 yl-isoxazolines
Sequentially adding 3-acetylpyridine (0.1mol), 4-bromostyrene (0.2mol), anhydrous ammonium acetate (0.15mol) and N-methylhydroxylamine sulfate (0.1mol), heating to 120 ℃, and reacting 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-layer 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 the toluene, combining toluene phases, washing to be neutral, and removing the toluene by rotary evaporation to obtain the N-methyl-3- (4-bromo) phenyl-5-methyl-5-pyridine-3-yl-oxazoline, wherein the quantitative content of HPLC is 92% and the yield is 89%.
Although the present invention is disclosed above, the present invention is not limited thereto. Various changes and modifications may be effected by one skilled in the art without departing from the spirit and scope of the invention, as defined in the appended claims.
Claims (10)
1. A preparation method of isoxazoline compounds is characterized by comprising the following steps: the isoxazoline compound is prepared by one-step reaction of a pyridylketone compound, a substituted styrene compound and hydroxylamine salt in carboxylate serving as a buffer salt.
2. The method for producing an isoxazoline compound according to claim 1, characterized in that: the preparation method of the isoxazoline compound is characterized by comprising the following steps: the isoxazoline compound shown in the formula (I) is prepared by one-step reaction of a pyridylketone compound shown in the formula (II), a substituted styrene compound shown in the formula (III) and 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 is1、R3Each independently methyl, ethyl or propyl; n is a positive integer of 1-5; r2Independently selected from (C)1-C3) Alkyl, (C)1-C3) Alkoxy group, (C)1-C3) A haloalkyl group, a halogen atom or a cyano group; r4Is (C)1-C12) An alkyl group; t is ammonium ion or alkali metal.
3. The method for producing an isoxazoline compound according to claim 1, characterized in that: the hydroxylamine salt is an inorganic acid salt or an acetate salt of hydroxylamine.
4. The method for producing an isoxazoline compound according to claim 3, characterized in that: the hydroxylamine salt is N-methylhydroxylamine hydrochloride, N-methylhydroxylamine acetate, N-methylhydroxylamine phosphate, N-methylhydroxylamine sulfate, N-ethylhydroxylamine hydrochloride, N-ethylhydroxylamine acetate, N-ethylhydroxylamine phosphate or N-ethylhydroxylamine sulfate.
5. The method for producing an isoxazoline compound according to any one of claims 1 to 4, characterized in that: in the reaction formula, R1、R3Each independently is methyl, ethyl or propyl; n is a positive integer of 1-5; r is2Independently selected from halogen atoms; r4Is (C)1-C4) An alkyl group; t is an alkali metal.
6. The method for producing an isoxazoline compound according to claim 4, characterized in that: in the reaction formula, R1、R3Each independently methyl, ethyl or propyl; n is 1; r2Independently selected from halogen atoms; r4Is (C)1-C4) An alkyl group; t is sodium, potassium or rubidium.
7. The method for producing an isoxazoline compound according to claim 5, characterized in that: the R is2At the para position of the vinyl group.
8. The method for producing an isoxazoline compound according to claim 1, characterized in that: the pyridylketone compound of formula (II), the substituted styrene compound of formula (III), the hydroxylamine salt of formula (IV) and the carboxylate of formula (V) are added in a molar ratio of 1: 1.5-5: 1-2: 1-3.
9. The method for producing an isoxazoline compound according to claim 1, characterized in that: the reaction temperature is 70-150 ℃.
10. The method for producing isoxazolines according to claim 1, characterized by: and adding a polymerization inhibitor in the one-step reaction, wherein the addition amount of the polymerization inhibitor is 0.01-1% of the weight of the substituted styrene compound.
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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》, vol. 25, no. 11, pages 1392 - 1397 * |
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