CN115806530A - Preparation method of isoxadifen - Google Patents
Preparation method of isoxadifen Download PDFInfo
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- CN115806530A CN115806530A CN202111075108.3A CN202111075108A CN115806530A CN 115806530 A CN115806530 A CN 115806530A CN 202111075108 A CN202111075108 A CN 202111075108A CN 115806530 A CN115806530 A CN 115806530A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- ITGSCCPVERXFGN-UHFFFAOYSA-N isoxadifen Chemical compound C1C(C(=O)O)=NOC1(C=1C=CC=CC=1)C1=CC=CC=C1 ITGSCCPVERXFGN-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 239000002253 acid Substances 0.000 claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 239000003513 alkali Substances 0.000 claims abstract description 27
- XXRCUYVCPSWGCC-UHFFFAOYSA-N Ethyl pyruvate Chemical compound CCOC(=O)C(C)=O XXRCUYVCPSWGCC-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229940117360 ethyl pyruvate Drugs 0.000 claims abstract description 17
- 150000002443 hydroxylamines Chemical class 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 12
- 238000007259 addition reaction Methods 0.000 claims abstract description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 23
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- 239000000706 filtrate Substances 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical group Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 230000020477 pH reduction Effects 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 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 5
- 238000005406 washing Methods 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 4
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 4
- ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- FTTATHOUSOIFOQ-UHFFFAOYSA-N 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine Chemical compound C1NCCN2CCCC21 FTTATHOUSOIFOQ-UHFFFAOYSA-N 0.000 claims description 3
- ZNBNBTIDJSKEAM-UHFFFAOYSA-N 4-[7-hydroxy-2-[5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]-5-methyloxolan-2-yl]-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-2-methyl-3-propanoyloxypentanoic acid Chemical compound C1C(O)C(C)C(C(C)C(OC(=O)CC)C(C)C(O)=O)OC11OC(C)(C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CC1 ZNBNBTIDJSKEAM-UHFFFAOYSA-N 0.000 claims description 3
- 229910000378 hydroxylammonium sulfate Inorganic materials 0.000 claims description 3
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 3
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 2
- GJFNRSDCSTVPCJ-UHFFFAOYSA-N 1,8-bis(dimethylamino)naphthalene Chemical compound C1=CC(N(C)C)=C2C(N(C)C)=CC=CC2=C1 GJFNRSDCSTVPCJ-UHFFFAOYSA-N 0.000 claims description 2
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- MWKVXOJATACCCH-UHFFFAOYSA-N isoxadifen-ethyl Chemical group C1C(C(=O)OCC)=NOC1(C=1C=CC=CC=1)C1=CC=CC=C1 MWKVXOJATACCCH-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 abstract description 10
- 239000012965 benzophenone Substances 0.000 abstract description 10
- 238000007086 side reaction Methods 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 6
- -1 ethyl 4-chloro-4, 4-diphenyl-2-oxobutyrate Chemical compound 0.000 description 22
- 239000000047 product Substances 0.000 description 12
- 230000002363 herbicidal effect Effects 0.000 description 8
- 239000004009 herbicide Substances 0.000 description 8
- 239000007791 liquid phase Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 7
- 238000001816 cooling Methods 0.000 description 5
- ZMYIIHDQURVDRB-UHFFFAOYSA-N 1-phenylethenylbenzene Chemical group C=1C=CC=CC=1C(=C)C1=CC=CC=C1 ZMYIIHDQURVDRB-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- VUPXKQHLZATXTR-UHFFFAOYSA-N 2,4-diphenyl-1,3-oxazole Chemical compound C=1OC(C=2C=CC=CC=2)=NC=1C1=CC=CC=C1 VUPXKQHLZATXTR-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 238000003747 Grignard reaction Methods 0.000 description 2
- FHKYMEGVIVZQAD-UHFFFAOYSA-N [N].ON Chemical group [N].ON FHKYMEGVIVZQAD-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000005650 intramolecular substitution reaction Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- FTDCPKMMOZXFFO-UHFFFAOYSA-N (2-chloro-2-hydroxyiminoethyl) acetate Chemical compound CC(=O)OCC(Cl)=NO FTDCPKMMOZXFFO-UHFFFAOYSA-N 0.000 description 1
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- 229940075522 antidotes Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000000447 pesticide residue Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- BXQYQBFZTKKPHI-UHFFFAOYSA-M sodium;nitrite;hydrochloride Chemical compound [Na+].Cl.[O-]N=O BXQYQBFZTKKPHI-UHFFFAOYSA-M 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention provides a preparation method of isoxadifen. The invention uses benzophenone and ethyl pyruvate to prepare 4-chloro-4, 4-diphenyl-2-oxo ethyl butyrate through addition reaction under the action of a catalyst, and then obtains the bisbenzoxazole acid through cyclization reaction with hydroxylamine salt under the action of alkali. The preparation method is simple, safe, environment-friendly and low in cost; the used raw materials are stable, the reaction selectivity is high, the side reaction is less, and the yield and the purity of the target product are high.
Description
Technical Field
The invention relates to a preparation method of isoxadifen, belonging to the technical field of pesticide chemical industry.
Background
Herbicide safeners (safeners), also known as antidotes and protectants, are used to protect crops from herbicide hazards, thereby increasing herbicide safety and improving weed control. The herbicide safener can enhance the selectivity of the herbicide for removing weeds, improve the drug resistance of crops and protect the crops from being damaged by pesticide residues. The bisbenzoxazole acid (I) is an important herbicide safener, the chemical name of the bisbenzoxazole acid is 4, 5-dihydro-5, 5-diphenyl-isoxazole-3-ethyl formate, the CAS number is [163520-33-0], the bisbenzoxazole acid is a herbicide safener researched and developed by an Andont company, the bisbenzoxazole acid is used for being compounded with the herbicide to prevent and kill weeds growing in corn fields for one year and all the year around, the bisbenzoxazole acid is widely applied to related products of Bayer and DuPont companies, the market is wide, and therefore research and optimization of synthesis of the bisbenzoxazole acid are of great significance.
For the preparation of bisbenzoxazoic acid, it is now predominantly obtained by 1, 3-dipolar cycloaddition reaction using 1, 1-diphenylethylene and 2-chloro-2-oximinoethyl acetate. The patent DE4331448, chinese patent CN103709113A, CN 103172582A, CN1133038A, CN108440435A and pesticide, 2012, 51 (11) 792-793, 810 all use 2-chloro-2-oximidoethyl acetate and 1, 1-diphenylethylene to prepare the bisbenzoxazole acid under the action of different solvents and different acid-binding agents (reaction route 1), the one-step yield difference of the cycloaddition is large, and the reported yield is 64-90%.
The raw materials of 1, 1-diphenylethylene and 2-chloro-2-oximidoethyl acetate used in the method are not easy to obtain and have higher cost. The 1, 1-diphenylethylene is prepared by carrying out Grignard reaction on bromobenzene to obtain phenyl magnesium bromide, then carrying out addition reaction on the phenyl magnesium bromide and acetophenone, and dehydrating. The 2-chloro-2-oximidoethyl acetate is prepared by esterifying 2-aminoacetic acid to prepare 2-aminoacetic acid ethyl ester hydrochloride and then reacting with sodium nitrite-hydrochloric acid. The whole route is long, the Grignard reaction and the diazotization reaction are involved, the operation safety is poor, and the wastewater amount is large. In addition, the 2-chloro-2-oximidoethyl acetate has poor stability, poor reaction selectivity, more impurities, high content of non-cyclic impurities and difficult purification, and is not beneficial to green industrial production.
In conclusion, the development of the industrial preparation method of the diphenyloxazole acid, which is simple, safe and environment-friendly, high in reaction selectivity, less in side reaction, high in yield and purity, has important significance for the preparation, popularization and use of the diphenyloxazole acid.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of bisbenzoxazole acid. The preparation method is simple, safe, environment-friendly and low in cost; the used raw materials are stable, the reaction selectivity is high, the side reaction is less, and the yield and the purity of the target product are high.
Description of terms:
a compound of formula II: benzophenone;
a compound of formula III, ethyl 4-chloro-4, 4-diphenyl-2-oxobutyrate;
a compound of formula I: bisbenzoxazole acid;
in the specification, the compound number is completely consistent with the structural formula number, has the same reference relationship, and is based on the structural formula.
The technical scheme of the invention is as follows:
a preparation method of bisbenzoxazole acid comprises the following steps:
(1) In a solvent A, under the action of a catalyst, a compound shown in a formula II and ethyl pyruvate are subjected to addition reaction and hydrochloric acid acidification to prepare a compound shown in a formula III;
(2) In a solvent B, under the action of alkali, carrying out cyclization reaction on a compound shown in a formula III and hydroxylamine salt to obtain a bisbenzoxazole acid I;
according to the invention, preferably, the solvent A in the step (1) is one or a combination of more than two of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, acetonitrile, 1, 2-dichloroethane, alkane with 6 to 8 carbon atoms, benzene, toluene or xylene; the mass ratio of the solvent A to the compound of the formula II is 2-7.
Preferably, in step (1), the catalyst is one or a combination of two or more of piperidine, 4-dimethylaminopyridine, tri-n-butylamine, 1, 8-diazabicycloundec-7-ene (DBU), 1, 4-diazabicyclo [2, 2] octane (DABCO), 1, 8-bisdimethylaminonaphthalene, tetramethylguanidine, sodium methoxide, sodium ethoxide, or potassium tert-butoxide; the mass of the catalyst is 0.5-5.0% of that of the compound shown in the formula II.
According to the invention, in the step (1), the molar ratio of the ethyl pyruvate to the compound of the formula II is (1.0-1.3): 1.
According to a preferred embodiment of the invention, in step (1), the addition reaction temperature is between 50 and 120 ℃ and preferably between 60 and 100 ℃. The addition reaction time is 2-10 hours.
Preferably, in step (1), the acidification is carried out by using hydrochloric acid to adjust the pH value of the acidification system to 1-3. Preferably, the mass concentration of the hydrochloric acid is 20-35%.
Preferably, in step (1), the ethyl pyruvate is added dropwise to a system containing the solvent A, the catalyst and the compound of formula II.
Preferably, in step (1), the method for post-treating the reaction solution obtained by the addition reaction of the compound of formula II and ethylpyruvate comprises the following steps: adding water and dichloromethane into the reaction solution, adjusting the pH value of the system to 1-3 with hydrochloric acid, demixing, extracting the water layer with dichloromethane, combining the organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, distilling the filtrate and recovering the solvent to obtain the compound shown in the formula III.
Preferably, in step (2), the solvent B is one or a combination of two or more of methanol, ethanol, a saturated monohydric alcohol having 3 to 5 carbon atoms, dichloromethane, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide, or water; the mass ratio of the solvent B to the compound of the formula III is 3-8.
Preferably, in step (2), the base is one or a combination of two or more of sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, triethylamine, isopropyldiethylamine, diisopropylethylamine, or pyridine.
Preferably, in step (2), the hydroxylamine salt is hydroxylamine hydrochloride or hydroxylamine sulfate.
According to the invention, in step (2), the molar ratio of the hydroxylamine salt, the base and the compound of formula III is (0.5-1.8): 1.0-3.0): 1.
Preferably, according to the invention, in step (2), the cyclisation reaction temperature is between 20 and 80 ℃, preferably between 30 and 60 ℃ and most preferably between 40 and 55 ℃. The cyclization reaction time is 2-8 hours.
Preferably, according to the present invention, in the step (2), the base is added to the reaction system in portions; preferably, the base is added to the reaction system in two portions.
According to the present invention, in the step (2), the preparation method of the bisbenzoxazole acid I comprises the steps of: dissolving a compound shown in a formula III, hydroxylamine salt and alkali 1 in a solvent B, and performing cyclization reaction at 20-80 ℃; then adding alkali 2, and continuing to perform cyclization reaction at 20-80 ℃ to obtain the isoxadifen I; the alkali 1 and the alkali 2 are both selected from one or a combination of more than two of sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, triethylamine, isopropyl diethylamine, diisopropyl ethylamine or pyridine, the types of the alkali 1 and the alkali 2 are the same or different, the molar ratio of the alkali 1 to the alkali 2 is 1.
Preferably, in step (2), the method for post-treating the reaction solution obtained by cyclizing the compound of formula III and the hydroxylamine salt comprises the steps of: filtering the reaction solution, washing filter cakes with an organic solvent, combining the filtrates, distilling the filtrate to recover the organic solvent, and recrystallizing the remainder to obtain the isoxadifen acid I.
The process of the present invention is described as the following reaction scheme:
the invention has the technical characteristics and beneficial effects that:
1. the invention uses benzophenone and ethyl pyruvate to prepare 4-chloro-4, 4-diphenyl-2-oxo ethyl butyrate through addition reaction under the action of a catalyst, and then performs cyclization reaction with hydroxylamine salt under the action of alkali to obtain the bisbenzoxazole acid. The raw materials are cheap and easy to obtain, the process is simple and safe, the target product can be obtained by only two steps, the three wastes are less in generation amount, and the method is green and environment-friendly; the used raw materials and intermediate products are stable, the reaction selectivity is high, the side reaction is less, the impurity generation is less, the yield and the purity of the target product are high, the yield can reach 88 percent, the purity can reach 99.9 percent, the product cost is low, and the method is favorable for green industrial production of the bisbenzoxazole acid.
2. The invention utilizes the characteristic that ethyl pyruvate is easy to form carbanions under the action of an alkaline catalyst, the formed carbanions and benzophenone are subjected to addition reaction to obtain 4-hydroxy-4, 4-diphenyl-2-oxoethyl butyrate, 4-hydroxy is typical benzyl tertiary alcohol, and is extremely easy to be converted into chlorine atoms by acidification with hydrochloric acid, so that the 4-chloro-4, 4-diphenyl-2-oxoethyl butyrate is obtained, the reaction activity is high, the selectivity is specific, and the high purity and the high yield of the 4-chloro-4, 4-diphenyl-2-oxoethyl butyrate are essentially ensured by the reaction.
3. The invention utilizes the high activity of the 2-carbonyl of the 4-chloro-4, 4-diphenyl-2-oxoethyl butyrate to react with hydroxylamine obtained by alkali free hydroxylamine salt, and then intramolecular substitution is carried out under the action of alkali to complete cyclization reaction. The alkali is preferably added in batches, and the alkali sequentially neutralizes hydroxylamine salt and hydrogen chloride generated by intramolecular substitution, so that not only is enough alkalinity provided, but also a 4-chlorine hydrolysis side reaction and a hydroxylamine nitrogen atom substitution side reaction caused by excessive alkali are avoided, the selectivity is high, and the high purity and the high yield of the bisbenzoxazole acid are ensured.
Detailed Description
The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.
The raw materials and reagents used in the examples are all commercially available products.
In the examples, "%" is a mass percentage unless otherwise specified. The yields stated in the examples are all molar yields.
Example 1: preparation of ethyl 4-chloro-4, 4-diphenyl-2-oxobutyrate (III)
400 g of tetrahydrofuran, 182.2 g (1 mol) of benzophenone and 5.0 g of DBU were put into a 2000 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a constant pressure dropping funnel, heated, and a mixed solution of 139.5 g (1.2 mol) of ethyl pyruvate and 200 g of tetrahydrofuran was dropped from the constant pressure dropping funnel at 60 to 65 ℃ for 3 hours. Thereafter, the reaction was stirred at 60-65 ℃ for 3 hours. Cooling to 20-25 deg.c, adding 300 g of water and 400 g of dichloromethane, adjusting the system pH to 2 with 30% hydrochloric acid, separating the layers, extracting the water layer twice with dichloromethane, 200 g each time, combining the organic phases, drying with 20 g of anhydrous sodium sulfate for 4 hours, filtering, distilling the filtrate to recover dichloromethane and tetrahydrofuran to obtain 293.4 g of ethyl 4-chloro-4, 4-diphenyl-2-oxobutyrate (iii) with a liquid phase purity of 99.6% and a yield of 92.6%.
Of the resulting product 1 HNMR data (400MHz, DMSO-d) 6 ) The following were used:
1.33(t,3H),4.17(s,2H),4.31(q,2H),7.23-7.38(m,10H).
example 2: preparation of ethyl 4-chloro-4, 4-diphenyl-2-oxobutyrate (III)
300 g of N, N-dimethylformamide, 182.2 g (1 mol) of benzophenone and 6.5 g of 1, 4-diazabicyclo [2, 2] octane were added to a 2000 ml four-neck flask equipped with a stirrer, a thermometer, a reflux condenser and a constant pressure dropping funnel, heated, and a mixed solution of 139.5 g (1.2 mol) of ethyl pyruvate and 200 g of N, N-dimethylformamide was dropped from the constant pressure dropping funnel at 90 to 95 ℃ for 3 hours. Thereafter, the reaction was stirred at 95-100 ℃ for 2 hours. Cooling to 20-25 deg.c, adding 300 g of water, 400 g of dichloromethane, adjusting the system pH to 2 with 30% hydrochloric acid, separating the layers, extracting the aqueous layer twice with dichloromethane, 200 g each time, combining the organic phases, drying with 20 g of anhydrous sodium sulfate for 4 hours, filtering, distilling the filtrate to recover dichloromethane and N, N-dimethylformamide to obtain 302.6 g of ethyl 4-chloro-4, 4-diphenyl-2-oxobutyrate (iii) with a liquid phase purity of 99.2% and a yield of 95.5%.
Example 3: preparation of bisbenzoxazole acid (I)
To a 2000 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a constant pressure dropping funnel were added 500 g of N, N-dimethylformamide, 158.5 g (0.5 mol) of ethyl 4-chloro-4, 4-diphenyl-2-oxobutanoate (III) obtained in example 1, 47.5 g (0.68 mol) of hydroxylamine hydrochloride and 40.0 g of potassium carbonate (0.29 mol), and the mixture was heated and reacted at 40 to 45 ℃ with stirring for 3 hours. 55.5 g of potassium carbonate (0.4 mol) is added, and the reaction is stirred for 2 hours at the temperature of between 50 and 55 ℃. Cooled to 20-25 ℃, filtered, and the filter cake washed twice with 100 g of N, N-dimethylformamide each time. The filtrates were combined, the filtrate was distilled to recover N, N-dimethylformamide, and the residue was recrystallized from 350 g of methyl-t-butyl ether to give 132.8 g of isoxadifen (i), with a liquid phase purity of 99.9% and a yield of 89.9%.
Of the resulting product 1 HNMR data (400MHz, DMSO-d) 6 ) The following were used:
1.36(t,3H),3.28(s,2H),4.33(q,2H),7.22-7.37(m,10H).
example 4: preparation of bisbenzoxazole acid (I)
To a 2000 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a constant pressure dropping funnel were added 500 g of ethanol, 158.5 g (0.5 mol) of ethyl 4-chloro-4, 4-diphenyl-2-oxobutanoate (III) obtained in example 2, 57.5 g (0.35 mol) of hydroxylamine sulfate, 41.5 g (0.3 mol) of potassium carbonate, and the mixture was heated and stirred at 40 to 45 ℃ for reaction for 3 hours. Adding 55.5 g of potassium carbonate (0.4 mol), stirring and reacting at 50-55 ℃ for 2 hours, cooling to 20-25 ℃, filtering, washing a filter cake twice by using ethanol, and 150 g of ethanol each time. The filtrates were combined, the filtrate was distilled to recover ethanol, and the residue was recrystallized from 350 g of methyl-t-butyl ether to give 135.6 g of isoxadifen (I), with a liquid phase purity of 99.6% and a yield of 91.8%.
Example 5: preparation of bisbenzoxazole acid (I)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel having a constant pressure, 150 g of ethanol, 31.7 g (0.1 mol) of ethyl 4-chloro-4, 4-diphenyl-2-oxobutanoate (III) obtained in example 2, 10.5 g (0.15 mol) of hydroxylamine hydrochloride and 12.0 g (0.12 mol) of triethylamine were charged, heated, and stirred at 40 to 45 ℃ for reaction for 3 hours. Adding 15.0 g (0.11 mol) of potassium carbonate, stirring and reacting at 50-55 ℃ for 2 hours, cooling to 20-25 ℃, filtering, washing a filter cake twice by using ethanol, and each time washing 30 g of ethanol. The filtrates were combined, the filtrate was distilled to recover ethanol, and the residue was recrystallized from 120 g of methyl-t-butyl ether to give 27.2 g of isoxadifen (I), with a liquid phase purity of 99.8% and a yield of 92.1%.
Example 6: preparation of ethyl 4-chloro-4, 4-diphenyl-2-oxobutanoate (III)
To a 2000 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel having a constant pressure, 600 g of tetrahydrofuran, 182.2 g (1 mol) of benzophenone, 5.0 g of DBU, and 139.5 g (1.2 mol) of ethyl pyruvate were charged, heated, and reacted with stirring at 60 to 65 ℃ for 6 hours. Cooling to 20-25 deg.c, adding 300 g of water and 400 g of dichloromethane, adjusting the pH value of the system to 2 with 30% hydrochloric acid, separating the layers, extracting the water layer twice with dichloromethane, 200 g each time, combining the organic phases, drying with 20 g of anhydrous sodium sulfate for 4 hours, filtering, distilling the filtrate to recover dichloromethane and tetrahydrofuran to obtain 263.3 g of viscous liquid, wherein the content of benzophenone is 16.3%, the content of ethyl 4-chloro-4, 4-diphenyl-2-oxobutyrate (iii) is 73.7% and the external standard yield of liquid phase is 77.6% (calculated by benzophenone actually participating in the reaction) according to the analysis of an external standard method of liquid phase.
It can be seen from this example that the addition of ethyl pyruvate affects the yield and product purity in this step, and if ethyl pyruvate is added at one time, a self-condensation reaction of ethyl pyruvate under the action of an alkaline catalyst occurs, which reduces the conversion rate of benzophenone, reduces the reaction selectivity, and reduces the product yield and purity.
Example 7: preparation of bisbenzoxazole acid (I)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel having a constant pressure, 150 g of ethanol, 31.7 g (0.1 mol) of ethyl 4-chloro-4, 4-diphenyl-2-oxobutanoate (III) obtained in example 2, 10.5 g (0.15 mol) of hydroxylamine hydrochloride, 12.0 g (0.12 mol) of triethylamine and 15.0 g (0.11 mol) of potassium carbonate were charged, heated, stirred at 40 to 45 ℃ for reaction for 3 hours, then stirred at 50 to 55 ℃ for reaction for 2 hours, cooled to 20 to 25 ℃, filtered, and the filter cake was washed twice with ethanol, 30 g of ethanol each time. The filtrates were combined, the filtrate was distilled to recover ethanol, and the residue was recrystallized from 120 g of methyl-t-butyl ether to give 20.1 g of isoxadifen (I), with a liquid phase purity of 97.3% and a yield of 68.1%.
As can be seen from this example, the manner of addition of the base affects the yield and product purity of this step, and if the base is added at once, the remaining base, after neutralization of the hydroxylamine salt, causes a side reaction of hydrolysis of the 4-position chlorine atom and a side reaction of substitution of the hydroxylamine nitrogen atom, which is detrimental to the progress of the cyclization reaction, resulting in a decrease in the product yield and purity.
Claims (10)
1. A preparation method of bisbenzoxazole acid comprises the following steps:
(1) In a solvent A, under the action of a catalyst, a compound shown in a formula II and ethyl pyruvate are subjected to addition reaction and acidification to prepare a compound shown in a formula III;
(2) In a solvent B, under the action of alkali, carrying out cyclization reaction on a compound shown in a formula III and hydroxylamine salt to obtain isoxadifen acid I;
2. the process for preparing bisbenzoxazole acid according to claim 1, wherein step (1) comprises one or more of the following conditions:
i. the solvent A is one or the combination of more than two of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, acetonitrile, 1, 2-dichloroethane, alkane with 6 to 8 carbon atoms, benzene, toluene or xylene; the mass ratio of the solvent A to the compound shown in the formula II is 2-7;
ii. The catalyst is one or the combination of more than two of piperidine, 4-dimethylamino pyridine, tri-n-butylamine, 1, 8-diazabicycloundec-7-ene (DBU), 1, 4-diazabicyclo [2, 2] octane (DABCO), 1, 8-bisdimethylamino naphthalene, tetramethyl guanidine, sodium methoxide, sodium ethoxide or potassium tert-butoxide; the mass of the catalyst is 0.5-5.0% of that of the compound shown in the formula II;
iii the molar ratio of the ethyl pyruvate to the compound of the formula II is (1.0-1.3): 1;
iv, the temperature of the addition reaction is 50-120 ℃, preferably 60-100 ℃.
3. The method for preparing the bisbenzoxazole acid according to claim 1, wherein in step (1), the acidification is performed by using hydrochloric acid to acidify the system to a pH value of 1-3; preferably, the mass concentration of the hydrochloric acid is 20-35%.
4. The method for preparing bisbenzoxazolic acid according to claim 1, wherein in the step (1), the ethylpyruvate is added dropwise to a system comprising the solvent a, the catalyst and the compound of formula ii.
5. The method for preparing isoxadifen-ethyl according to claim 1, wherein in step (1), the method for post-treating the reaction solution obtained by the addition reaction of the compound of formula II and ethyl pyruvate comprises the following steps: adding water and dichloromethane into the reaction solution, adjusting the pH value of the system to 1-3 with hydrochloric acid, demixing, extracting the water layer with dichloromethane, combining the organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, distilling the filtrate and recovering the solvent to obtain the compound shown in the formula III.
6. The process for preparing bisbenzoxazole acid according to claim 1, wherein step (2) comprises one or more of the following conditions:
i. the solvent B is one or the combination of more than two of methanol, ethanol, saturated monohydric alcohol with 3 to 5 carbon atoms, dichloromethane, 1, 2-dichloroethane, acetonitrile, N-dimethylformamide or water; the mass ratio of the solvent B to the compound of the formula III is 3-8;
ii. The alkali is one or the combination of more than two of sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, triethylamine, isopropyl diethylamine, diisopropyl ethylamine or pyridine;
iii, the hydroxylamine salt is hydroxylamine hydrochloride or hydroxylamine sulfate;
iv, the molar ratio of the hydroxylamine salt, the alkali and the compound of the formula III is (0.5-1.8): 1.0-3.0): 1.
7. The process for preparing bisbenzoxazoic acid according to claim 1, wherein in step (2), the cyclization reaction temperature is in the range of 20 to 80 ℃, preferably 30 to 60 ℃, and most preferably 40 to 55 ℃.
8. The process for producing bisbenzoxazole acid according to claim 1, wherein in the step (2), the base is added to the reaction system in portions; preferably, the base is added to the reaction system in two portions.
9. The method for preparing isoxadifen-yl acid according to claim 1, wherein in step (2), the method for preparing isoxadifen-yl acid I comprises the steps of: dissolving a compound shown in a formula III, hydroxylamine salt and alkali 1 in a solvent B, and performing cyclization reaction at 20-80 ℃; then adding alkali 2, and continuing to perform cyclization reaction at 20-80 ℃ to obtain the isoxadifen I; the alkali 1 and the alkali 2 are respectively selected from one or a combination of more than two of sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, triethylamine, isopropyl diethylamine, diisopropylethylamine or pyridine, the types of the alkali 1 and the alkali 2 are the same or different, the molar ratio of the alkali 1 to the alkali 2 is 1.
10. The process for producing bisbenzoxazoic acid according to claim 1, wherein in step (2), the method for post-treating the reaction solution obtained by cyclizing the compound of formula iii and the hydroxylamine salt comprises the steps of: filtering the reaction liquid, washing filter cakes by using an organic solvent, combining the filter liquor, distilling the filter liquor to recover the organic solvent, and recrystallizing the remainder to obtain the isoxadifen I.
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