CN113788797A - Desulfurized prothioconazole impurity and synthetic method and application thereof - Google Patents
Desulfurized prothioconazole impurity and synthetic method and application thereof Download PDFInfo
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- MNHVNIJQQRJYDH-UHFFFAOYSA-N 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2-dihydro-1,2,4-triazole-3-thione Chemical compound N1=CNC(=S)N1CC(C1(Cl)CC1)(O)CC1=CC=CC=C1Cl MNHVNIJQQRJYDH-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 239000005825 Prothioconazole Substances 0.000 title claims abstract description 17
- 239000012535 impurity Substances 0.000 title claims abstract description 14
- 238000010189 synthetic method Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000001953 recrystallisation Methods 0.000 claims abstract description 4
- 238000000746 purification Methods 0.000 claims abstract description 3
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 238000010438 heat treatment Methods 0.000 claims description 17
- 238000001816 cooling Methods 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 150000003852 triazoles Chemical class 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-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
- 239000002904 solvent Substances 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 239000011230 binding agent Substances 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 claims description 4
- KVNYFPKFSJIPBJ-UHFFFAOYSA-N 1,2-diethylbenzene Chemical compound CCC1=CC=CC=C1CC KVNYFPKFSJIPBJ-UHFFFAOYSA-N 0.000 claims description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000543 intermediate Substances 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- ZMCUDHNSHCRDBT-UHFFFAOYSA-M caesium bicarbonate Chemical compound [Cs+].OC([O-])=O ZMCUDHNSHCRDBT-UHFFFAOYSA-M 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 claims description 2
- AWDMDDKZURRKFG-UHFFFAOYSA-N potassium;propan-1-olate Chemical compound [K+].CCC[O-] AWDMDDKZURRKFG-UHFFFAOYSA-N 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 claims description 2
- RCOSUMRTSQULBK-UHFFFAOYSA-N sodium;propan-1-olate Chemical compound [Na+].CCC[O-] RCOSUMRTSQULBK-UHFFFAOYSA-N 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 10
- 238000001514 detection method Methods 0.000 abstract description 8
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 238000005457 optimization Methods 0.000 abstract description 2
- 238000001914 filtration Methods 0.000 description 18
- 239000012065 filter cake Substances 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- 238000001035 drying Methods 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 239000012043 crude product Substances 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 239000012265 solid product Substances 0.000 description 6
- -1 1- (2-chloro-phenyl) -3- [1, 2, 4] triazol-1-yl-2- (1- [1, 2, 4] triazol-1-yl-cyclopropyl) -propan-2-ol Chemical compound 0.000 description 4
- 238000010606 normalization Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 206010039509 Scab Diseases 0.000 description 3
- 241000209140 Triticum Species 0.000 description 3
- 235000021307 Triticum Nutrition 0.000 description 3
- 238000003760 magnetic stirring Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 241000252212 Danio rerio Species 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 206010027146 Melanoderma Diseases 0.000 description 2
- 241000221662 Sclerotinia Species 0.000 description 2
- 235000013339 cereals Nutrition 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000012502 risk assessment Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- JRDJNOICNOXLRB-UHFFFAOYSA-N 1-bromo-2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)propan-2-ol Chemical compound OC(CC(C=CC=C1)=C1Cl)(CBr)C1(CC1)Cl JRDJNOICNOXLRB-UHFFFAOYSA-N 0.000 description 1
- LGNKJFHEXZRYDM-UHFFFAOYSA-N 1-chloro-2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)propan-2-ol Chemical compound C1CC1(Cl)C(CCl)(O)CC1=CC=CC=C1Cl LGNKJFHEXZRYDM-UHFFFAOYSA-N 0.000 description 1
- IKKKLHQSHUAIMM-UHFFFAOYSA-N 2-(1-chlorocyclopropyl)-2-[(2-chlorophenyl)methyl]oxirane Chemical compound ClC1=CC=CC=C1CC1(C2(Cl)CC2)OC1 IKKKLHQSHUAIMM-UHFFFAOYSA-N 0.000 description 1
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000018262 Arachis monticola Nutrition 0.000 description 1
- 241001530056 Athelia rolfsii Species 0.000 description 1
- 235000010149 Brassica rapa subsp chinensis Nutrition 0.000 description 1
- 235000000536 Brassica rapa subsp pekinensis Nutrition 0.000 description 1
- 241000499436 Brassica rapa subsp. pekinensis Species 0.000 description 1
- 241000221785 Erysiphales Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 1
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- 241000233647 Phytophthora nicotianae var. parasitica Species 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- HHUQPWODPBDTLI-UHFFFAOYSA-N Prothioconazole-desthio Chemical compound C1=NC=NN1CC(C1(Cl)CC1)(O)CC1=CC=CC=C1Cl HHUQPWODPBDTLI-UHFFFAOYSA-N 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 210000000750 endocrine system Anatomy 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 230000008686 ergosterol biosynthesis Effects 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000036244 malformation Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 210000004994 reproductive system Anatomy 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 231100000378 teratogenic Toxicity 0.000 description 1
- 230000003390 teratogenic effect Effects 0.000 description 1
- 231100000048 toxicity data Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- QPDUQKTYZRXRBC-UHFFFAOYSA-N triazole-4-thione Chemical compound S=C1C=NN=N1 QPDUQKTYZRXRBC-UHFFFAOYSA-N 0.000 description 1
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a desulfurized prothioconazole impurity and a synthesis method and application thereof, belonging to the technical field of organic synthesis. The invention provides impurities in a thioprothioconazole intermediate, which are shown in a formula (I):
the invention also provides a method for preparing the compound shown in the formula (I). The method has the advantages of mild and easily-controlled reaction, simple and convenient operation, easy product purification, direct recrystallization to obtain the product, high product quality and capability of providing a detection standard substance for subsequent process optimization.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a thioprothioconazole impurity and a synthesis method and application thereof.
Background
Prothioconazole (Prothioconazole), trade name Proline, is a triazolethione fungicide discovered, developed and produced by bayer crop science, and is an inhibitor of sterol demethylation (ergosterol biosynthesis); can provide good systemic action, excellent protection, treatment and eradication activity, long lasting period and safety to crops.
Prothioconazole is mainly used for preventing and treating various diseases of cereals, wheat and bean crops and the like. The prothioconazole almost has excellent control effect on all fungal diseases on the grains, such as powdery mildew, gibberellic disease, banded sclerotial blight, rust disease, glume blight, leaf spot, net blotch, sclerotinia, basic rot, mildew and the like; can effectively prevent and control soil-borne diseases (such as sclerotinia, and the like) of rape and peanut fields and main leaf diseases (such as gray mold, brown spot, black spot, rust disease, black shank, and the like); also can be used for preventing and treating black spot of Chinese cabbage.
At present, China is mainly used for controlling wheat scab. It is reported that prothioconazole is not only effective in preventing and treating wheat scab, but also can effectively inhibit toxins produced by the scab.
2- (1-chlorocyclopropyl) -1- (2-chlorophenyl) -3- (1H-1,2, 4-triazol-1-yl) propan-2-ol, an important intermediate of prothioconazole (thioprothioconazole), is shown in the work of St.p. enantioselective degradation behavior of prothioconazole and its metabolites in several ecosystems, published by john, the university of inner Mongolia, that desulfothioconazole has a long half-life, causes imbalance in the endocrine system by affecting the function of various nuclear hormone receptors, and further affects the development and reproductive systems of humans, that desulfothioconazole can induce oxidative stress produced by zebrafish, and that the acute toxicity in zebrafish is 3.5 times that of the mother. In addition, it is necessary to provide toxicological data of thioprothioconazole when it is registered after 2020 according to regulations. The us environmental protection agency (USEPA) mentions in the human health risk assessment report of prothioconazole released in 2007 that desulfothioconazole is teratogenic, resulting in malformation in young children. Therefore, in the case of the prothioconazole risk assessment, the risk of the thioprothioconazole cannot be ignored, but the structure of the compound of the invention is similar to that of the thioprothioconazole, and the research on the synthetic route and the preparation of a standard substance for qualitatively and quantitatively analyzing the content of the substance in the prothioconazole are crucial.
Disclosure of Invention
The invention mainly aims to provide a desulfurized prothioconazole impurity, a synthesis method and application thereof, so that an intermediate can be detected in the process of preparing prothioconazole, the source of impurities can be searched, the generation of impurities can be reduced, the utilization rate of raw materials can be improved, and the product quality can be improved.
A desulfotriazole impurity, the structure of which is shown in formula (I):
the compound of formula (I) is prepared as follows:
wherein X and Y are independently selected from Br or Cl;
the reaction process is as follows: taking a formula (II) or a formula (III) as a raw material, adding triazole in a solvent I, simultaneously adding an acid-binding agent, heating for reaction, cooling to room temperature after the reaction is finished, and carrying out post-treatment to obtain the formula (I).
The feeding molar ratio of the formula (II) or the formula (III) to the triazole is 1: 2-10.
The feeding molar ratio of the formula (II) or the formula (III) to the acid binding agent is 1: 2-10.
The heating temperature is 80-170 ℃, and the reaction time is 1-10 h.
The acid-binding agent comprises sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium propoxide, potassium propoxide, sodium butoxide and potassium butoxide.
The first solvent is one or more selected from dimethyl sulfoxide, N-dimethylformamide, N-methylpyrrolidone, N-dimethylacetamide, acetonitrile, propionitrile, butyronitrile, acetone and butanone.
The reaction process also comprises a refining process, and a solvent is used for carrying out recrystallization treatment on the compound shown in the formula (I).
The second solvent comprises one or more of benzene, toluene, xylene, trimethylbenzene, ethylbenzene, diethylbenzene, chlorobenzene, methanol, ethanol, propanol, isopropanol, dichloromethane, dichloroethane and chloroform.
The compound of formula (I) of the invention is used as an impurity reference when synthesizing prothioconazole intermediates.
The invention has the beneficial effects that:
the compound of formula (I) is prepared by reacting a compound of formula (II) or formula (III) as a raw material with triazole in the presence of an acid-binding agent. The method has the advantages of mild and easily-controlled reaction, simple and convenient operation, easy product purification, direct recrystallization to obtain the product, high product quality and capability of providing a detection standard substance for subsequent process optimization.
Drawings
In order to more clearly illustrate the embodiments or technical solutions in the prior art of the present invention, the drawings used in the description of the embodiments or prior art will be briefly described below, and it is obvious for those skilled in the art that other drawings can be obtained based on these drawings without creative efforts.
FIG. 1 is an HPLC chromatogram of the product prepared in example 1 of the present invention.
FIG. 2 is an MS spectrum of a product prepared in example 1 of the present invention.
FIG. 3 shows the preparation of the product of example 1 of the present invention1HNMR atlas.
Detailed Description
In order to make those skilled in the art better understand the technical solution of the present invention, the technical solution in the embodiment of the present invention will be clearly and completely described below with reference to the drawings in the embodiment of the present invention, and it is obvious that the described embodiment is only a part of the embodiment 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.
Example 1
Preparation of 1- (2-chloro-phenyl) -3- [1, 2, 4] triazol-1-yl-2- (1- [1, 2, 4] triazol-1-yl-cyclopropyl) -propan-2-ol (formula I)
28.6g (0.1mol, 1eq) of 2- (2-chlorobenzyl) -2- (1-bromocyclopropyl) oxirane, 20.7g (0.3mol, 3eq) of triazole, 34.5g (0.25mol, 2.5eq) of potassium carbonate and 100ml of N, N-Dimethylformamide (DMF) are put into a four-neck flask heated by a thermometer, a magnetic stirrer, a reflux condenser and an oil bath, the temperature is raised to 120 ℃, and the temperature is kept for 5 hours. And after the reaction is finished, cooling to room temperature, beginning to dropwise add 1000ml of water, filtering after dropwise adding is finished, drying a filter cake at 70 ℃ for 10 hours to obtain a light brown solid crude product, adding 80ml of toluene, heating to reflux, filtering insoluble substances while hot, slowly cooling the filtrate to 0-5 ℃, preserving heat for 0.5 hour, filtering, washing the filter cake with 20ml of toluene, and drying at 70 ℃ for 5 hours to obtain 25.6g of a white solid product, wherein the yield is 72.6%, and the HPLC detection area normalization content is 97.6%.
The structure of the prepared product is confirmed and detected, and the results are as follows:
1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.46(s,1H),8.10(s,1H),7.86(s,1H),7.64(dd,J＝7.9,1.9Hz,1H),7.31–7.18(m,3H),6.01(s,1H),4.97(d,J＝14.4Hz,1H),4.84(d,J＝14.5Hz,1H),3.28(d,J＝14.2Hz,1H),3.05(d,J＝13.9Hz,1H),0.98–0.88(m,1H),0.88–0.77(m,1H),0.48–0.34(m,2H)。
MS[M+H]+1:345.12/347.12。
example 2
24.3g (0.1mol, 1eq) of 2- (2-chlorobenzyl) -2- (1-chlorocyclopropyl) oxirane, 27.6g (0.4mol, 4eq) of triazole, 12g (0.3mol, 3eq) of sodium hydroxide and 150ml of N, N-dimethylacetamide are put into a four-neck flask with a thermometer, a magnetic stirring device, a reflux condenser and an oil bath for heating, heating to 130 ℃, preserving heat for 3 hours, cooling to room temperature after the reaction is finished, adding 1200ml of water dropwise, filtering at room temperature after the dropwise addition is finished, drying a filter cake at 70 ℃ for 10 hours to obtain a light brown solid crude product, adding 60ml of xylene, heating to reflux, filtering insoluble substances while the solution is hot, slowly cooling the filtrate to 0-5 ℃, preserving heat for 0.5 hour, filtering, washing the filter cake with 20ml of xylene, drying the filter cake at 70 ℃ for 5 hours to obtain 26.5g of a white solid product, wherein the yield is 74.7%, and the HPLC detection area normalization content is 97.0%.
Example 3
Putting 36.8g (0.1mol, 1eq) of 1-bromo-2- (1-bromocyclopropyl) -3- (2-chlorophenyl) propan-2-ol, 20.7g (0.3mol, 3eq) of triazole, 42.4g (0.4mol, 4eq) of sodium carbonate and 200ml of dimethyl sulfoxide into a four-neck flask with a thermometer, a mechanical stirrer, a reflux condenser and oil bath heating, heating to 150 ℃, preserving heat for 5h, sampling for HPLC detection, cooling to room temperature after reaction is finished, adding 1500ml of water dropwise, filtering at room temperature after dropwise addition, drying a filter cake at 70 ℃ for 10h to obtain a crude product, adding 50ml of isopropanol, heating to reflux, filtering insoluble substances while hot, slowly cooling the filtrate to 0-5 ℃, preserving heat for 0.5h, filtering, washing the filter cake with 5ml of isopropanol, drying at 70 deg.C for 5h to obtain 23.7g of white solid product, yield 68.0%, and HPLC detection area normalization content 98.8%.
Example 4
Putting 32.4g (0.1mol, 1eq) of 1-chloro-2- (1-bromocyclopropyl) -3- (2-chlorophenyl) propan-2-ol, 34.5g (0.5mol, 5eq) of triazole, 25g (0.25mol, 2.5eq) of potassium bicarbonate and 200ml of acetonitrile into a four-neck flask heated by a thermometer, a magnetic stirring pipe, a reflux condenser pipe and an oil bath, heating up and refluxing, preserving heat for 10 hours, cooling to room temperature after the reaction is finished, filtering, washing a filter cake with 20ml of acetonitrile, merging filtrate, desolventizing to obtain a crude product, adding 100ml of dichloroethane, heating to reflux, filtering insoluble substances while hot, slowly cooling the filtrate to 0-5 ℃, preserving heat for 0.5 hours, filtering, washing the filter cake with 20ml of dichloroethane, drying at 70 ℃ to obtain 23.0g of a white-like solid product, wherein the yield is 65.1%, and the HPLC detection area is up to 97.4%.
Example 5
27.9g (0.1mol, 1eq) of 1-chloro-2- (1-chloro-cyclopropyl) -3- (2-chlorophenyl) propan-2-ol, 34.5g (0.5mol, 5eq) of triazole, 31.8g (0.3mol, 3eq) of sodium carbonate and 100ml of N, N-dimethylformamide are put into a four-neck flask heated by a thermometer, a magnetic stirrer, a reflux condenser and an oil bath, heating to 120 ℃, preserving heat for 4 hours, cooling to room temperature after the reaction is finished, adding 1100ml of water dropwise, filtering at room temperature after the dropwise addition is finished, drying a filter cake at 70 ℃ for 10 hours to obtain a crude product, adding 60ml of toluene, heating to reflux, filtering insoluble substances while the solution is hot, slowly cooling the filtrate to 0-5 ℃, preserving heat for 0.5 hour, filtering, washing the filter cake with 20ml of toluene, drying at 70 ℃ for 5 hours to obtain 25.3g of a white solid product, wherein the yield is 71.1%, and the HPLC detection area normalization content is 96.7%.
Example 6
Putting 32.4g (0.1mol, 1eq) of 1-bromo-2- (1-chlorocyclopropyl) -3- (2-chlorophenyl) propan-2-ol, 20.7g (0.3mol, 3eq) of triazole, 24.3g (0.45mol, 4.5eq) of sodium methoxide and 100ml of butyronitrile into a four-neck flask heated by a thermometer, magnetic stirring, a reflux condenser tube and an oil bath, heating to 110 ℃, preserving heat for 8 hours, cooling to room temperature after reaction, filtering, washing a filter cake with 20ml of butyronitrile, merging filtrate, desolventizing to obtain a crude product, adding 120ml of dichloromethane, heating to reflux, filtering insoluble substances while hot, slowly cooling the filtrate to 0-5 ℃, preserving heat for 0.5 hours, filtering, washing the filter cake with 20ml of dichloromethane, drying for 4 hours at 70 ℃ to obtain 24.8g of a white-like solid product, obtaining a yield of 69.3%, and detecting an area by HPLC (HPLC) to obtain a content of 96.1.1%.
Although the present invention has been described in detail by referring to the drawings in connection with the preferred embodiments, the present invention is not limited thereto. Various equivalent modifications or substitutions can be made on the embodiments of the present invention by those skilled in the art without departing from the spirit and scope of the present invention, and these modifications or substitutions are within the scope of the present invention/any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (10)
1. A desulfothioconazole impurity represented by formula (i):
2. a process for preparing the des-thioprothioconazole impurity of claim 1, characterized by the following reaction formula:
wherein X and Y are independently selected from Br or Cl;
the reaction process is as follows: taking a compound of a formula (II) or a compound of a formula (III) as a raw material, adding an acid binding agent into triazole in a solvent I, heating for reaction, cooling to room temperature after the reaction is finished, and carrying out post-treatment to obtain the compound of the formula (I).
3. The method of claim 2, wherein the feeding molar ratio of the compound of formula (II) or the compound of formula (III) to triazole is 1: 2-10.
4. The method according to claim 2, wherein the feeding molar ratio of the compound of formula (II) or the compound of formula (III) to the acid-binding agent is 1: 2-10.
5. The method of claim 2, wherein the heating temperature is 80-170 ℃ and the reaction time is 1-10 h.
6. The method of claim 2, wherein the acid-binding agent comprises sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium propoxide, potassium propoxide, sodium butoxide, potassium butoxide.
7. The method of claim 2, wherein the solvent one is selected from one or more of dimethylsulfoxide, N-dimethylformamide, N-methylpyrrolidone, N-dimethylacetamide, acetonitrile, propionitrile, butyronitrile, acetone, and butanone.
8. The method of claim 2, further comprising a purification process of subjecting formula (i) to a recrystallization process using a solvent.
9. The method of claim 8, wherein the second solvent comprises one or more of benzene, toluene, xylene, trimethylbenzene, ethylbenzene, diethylbenzene, chlorobenzene, methanol, ethanol, propanol, isopropanol, dichloromethane, dichloroethane, and chloroform.
10. Use of the desulphatoprothioconazole impurity of claim 1 as an impurity control in the synthesis of prothioconazole intermediates.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105949137A (en) * | 2016-07-15 | 2016-09-21 | 泸州东方农化有限公司 | Method for synthesizing prothioconazole and optical active body thereof and intermediate |
| CN106749057A (en) * | 2016-12-30 | 2017-05-31 | 南京工业大学 | Intermediate compound and method for synthesizing prothioconazole |
| CN108358860A (en) * | 2018-02-08 | 2018-08-03 | 盐城辉煌化工有限公司 | A kind of method of high yield synthesis prothioconazoles |
| CN111662240A (en) * | 2020-06-08 | 2020-09-15 | 山东潍坊润丰化工股份有限公司 | Preparation method of high-purity prothioconazole |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105949137A (en) * | 2016-07-15 | 2016-09-21 | 泸州东方农化有限公司 | Method for synthesizing prothioconazole and optical active body thereof and intermediate |
| CN106749057A (en) * | 2016-12-30 | 2017-05-31 | 南京工业大学 | Intermediate compound and method for synthesizing prothioconazole |
| CN108358860A (en) * | 2018-02-08 | 2018-08-03 | 盐城辉煌化工有限公司 | A kind of method of high yield synthesis prothioconazoles |
| CN111662240A (en) * | 2020-06-08 | 2020-09-15 | 山东潍坊润丰化工股份有限公司 | Preparation method of high-purity prothioconazole |
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