CN114621122A - Process for the preparation of a cyclic sulphonone metabolite - Google Patents
Process for the preparation of a cyclic sulphonone metabolite Download PDFInfo
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- CN114621122A CN114621122A CN202011471696.8A CN202011471696A CN114621122A CN 114621122 A CN114621122 A CN 114621122A CN 202011471696 A CN202011471696 A CN 202011471696A CN 114621122 A CN114621122 A CN 114621122A
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- metabolite
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- 239000002207 metabolite Substances 0.000 title claims abstract description 63
- 238000000034 method Methods 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 230000008569 process Effects 0.000 title abstract description 15
- 125000004122 cyclic group Chemical group 0.000 title abstract description 5
- IUQAXCIUEPFPSF-UHFFFAOYSA-N tembotrione Chemical class ClC1=C(COCC(F)(F)F)C(S(=O)(=O)C)=CC=C1C(=O)C1C(=O)CCCC1=O IUQAXCIUEPFPSF-UHFFFAOYSA-N 0.000 claims abstract description 142
- 238000006243 chemical reaction Methods 0.000 claims abstract description 55
- 239000005620 Tembotrione Substances 0.000 claims abstract description 48
- 239000012752 auxiliary agent Substances 0.000 claims abstract description 37
- -1 cyclic sultone Chemical class 0.000 claims abstract description 31
- 239000007800 oxidant agent Substances 0.000 claims abstract description 29
- 239000002994 raw material Substances 0.000 claims abstract description 29
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 19
- 230000001590 oxidative effect Effects 0.000 claims abstract description 15
- 150000007513 acids Chemical group 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- 230000001035 methylating effect Effects 0.000 claims abstract description 3
- 239000000047 product Substances 0.000 claims description 49
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- 238000005406 washing Methods 0.000 claims description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 35
- 239000000203 mixture Substances 0.000 claims description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 24
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 22
- 238000000926 separation method Methods 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- 239000012043 crude product Substances 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 16
- 230000011987 methylation Effects 0.000 claims description 16
- 238000007069 methylation reaction Methods 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 14
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 claims description 13
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- 235000010265 sodium sulphite Nutrition 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 11
- 239000007795 chemical reaction product Substances 0.000 claims description 11
- 239000003638 chemical reducing agent Substances 0.000 claims description 11
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims description 8
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 8
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 7
- 239000012022 methylating agents Substances 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 235000011181 potassium carbonates Nutrition 0.000 claims description 7
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 7
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- 235000011054 acetic acid Nutrition 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- 229940102396 methyl bromide Drugs 0.000 claims description 6
- 150000002978 peroxides Chemical group 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- XYPISWUKQGWYGX-UHFFFAOYSA-N 2,2,2-trifluoroethaneperoxoic acid Chemical compound OOC(=O)C(F)(F)F XYPISWUKQGWYGX-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000002535 acidifier Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 150000007514 bases Chemical class 0.000 claims description 4
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical compound [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 claims description 4
- 238000005755 formation reaction Methods 0.000 claims description 4
- 229940050176 methyl chloride Drugs 0.000 claims description 4
- XCRBXWCUXJNEFX-UHFFFAOYSA-N peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 claims description 4
- FHHJDRFHHWUPDG-UHFFFAOYSA-N peroxysulfuric acid Chemical compound OOS(O)(=O)=O FHHJDRFHHWUPDG-UHFFFAOYSA-N 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000000575 pesticide Substances 0.000 abstract description 15
- 238000005580 one pot reaction Methods 0.000 abstract description 8
- MKMGKCALCCOODL-GVPWJHIJSA-N Metabolite M6 Chemical compound CC(C)(C)N=C(O)[C@H]1CNCCN1C[C@@H](O)C[C@H](C(O)=N[C@@H]1C2=CC=CC=C2C[C@@H]1O)CC1=CC=CC=C1 MKMGKCALCCOODL-GVPWJHIJSA-N 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 150000008053 sultones Chemical class 0.000 abstract description 3
- 238000001914 filtration Methods 0.000 description 32
- 238000001035 drying Methods 0.000 description 25
- 238000004321 preservation Methods 0.000 description 21
- 239000000463 material Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 15
- 239000008346 aqueous phase Substances 0.000 description 9
- 239000012535 impurity Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 239000004557 technical material Substances 0.000 description 9
- 238000009825 accumulation Methods 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 241000196324 Embryophyta Species 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 238000000643 oven drying Methods 0.000 description 7
- 230000004060 metabolic process Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000001276 controlling effect Effects 0.000 description 5
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000020477 pH reduction Effects 0.000 description 4
- 239000000447 pesticide residue Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 230000002147 killing effect Effects 0.000 description 3
- 235000011007 phosphoric acid Nutrition 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 230000002110 toxicologic effect Effects 0.000 description 3
- 231100000027 toxicology Toxicity 0.000 description 3
- XKLPBDMZJSWRBL-UHFFFAOYSA-N 3-benzoylcyclohexane-1,2-dione Chemical compound C=1C=CC=CC=1C(=O)C1CCCC(=O)C1=O XKLPBDMZJSWRBL-UHFFFAOYSA-N 0.000 description 2
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical class [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 230000003405 preventing effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000002689 soil Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- YGMJOCQCLVNPOD-UHFFFAOYSA-N 2-chloro-4-methylsulfonyl-3-(2,2,2-trifluoroethoxymethyl)benzoic acid Chemical compound CS(=O)(=O)C1=CC=C(C(O)=O)C(Cl)=C1COCC(F)(F)F YGMJOCQCLVNPOD-UHFFFAOYSA-N 0.000 description 1
- BHQCUGRUQURCJB-UHFFFAOYSA-N 2-chloro-4-methylsulfonyl-3-(2,2,2-trifluoroethoxymethyl)phenol Chemical compound CS(=O)(=O)c1ccc(O)c(Cl)c1COCC(F)(F)F BHQCUGRUQURCJB-UHFFFAOYSA-N 0.000 description 1
- 108010000700 Acetolactate synthase Proteins 0.000 description 1
- 239000005504 Dicamba Substances 0.000 description 1
- 239000005562 Glyphosate Substances 0.000 description 1
- 241000720991 Illicium Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 235000005775 Setaria Nutrition 0.000 description 1
- 241000232088 Setaria <nematode> Species 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
- 101100339555 Zymoseptoria tritici HPPD gene Proteins 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- IWEDIXLBFLAXBO-UHFFFAOYSA-N dicamba Chemical compound COC1=C(Cl)C=CC(Cl)=C1C(O)=O IWEDIXLBFLAXBO-UHFFFAOYSA-N 0.000 description 1
- 239000002359 drug metabolite Substances 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- XDDAORKBJWWYJS-UHFFFAOYSA-N glyphosate Chemical compound OC(=O)CNCP(O)(O)=O XDDAORKBJWWYJS-UHFFFAOYSA-N 0.000 description 1
- 229940097068 glyphosate Drugs 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000003328 mesylation reaction Methods 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- FBBDOOHMGLLEGJ-UHFFFAOYSA-N methane;hydrochloride Chemical compound C.Cl FBBDOOHMGLLEGJ-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of a tembotrione metabolite, which comprises the following steps: reacting the tembotrione, an oxidant and an auxiliary agent to obtain a tembotrione metabolite M1 and a tembotrione metabolite M6; the auxiliary agent is an acidic compound or an alkaline compound; according to the method, a cyclic sultone original drug is used as an initial raw material, a cyclic sultone metabolite M1 and a cyclic sultone metabolite M6 with high yield and high purity can be obtained through a one-step reaction in the presence of an oxidant and an auxiliary agent, the cyclic sultone metabolite M6 and a methylating reagent can be subjected to a one-step reaction to obtain a cyclic sultone metabolite M7, the raw materials are easy to obtain, the steps are simple, the operation is convenient, the experimental process is controllable, a harsh reaction environment is not needed, the conditions are mild, the process is easy to achieve, the large-scale preparation of the three cyclic sultone metabolites is realized, and the sample quantity requirements of the cyclic sultone metabolites in pesticide registration are fully met.
Description
Technical Field
The invention belongs to the technical field of organic compound preparation, relates to a preparation method of a tembotrione metabolite, and particularly relates to a preparation method of tembotrione metabolites M1, M6 and M7.
Background
The pesticide is an important agricultural input product, the use of the pesticide is directly related to the quality safety and ecological environment of agricultural products, the new 'pesticide management regulations' puts higher requirements on pesticide management work, the difficulty of the registration of the original pesticide is improved, and the increase of test items is mainly reflected. The requirements for the original drug metabolites are embodied in an environment part and a residual part, the environment part is additionally provided with tests of soil aerobic metabolism, soil anaerobic metabolism, water-sediment system aerobic metabolism and the like, and the residual part is additionally provided with tests of plant metabolism, animal metabolism, environment metabolism, pesticide metabolite residue in agricultural product processing and the like. At least more than 2 kilograms of samples are needed to be prepared for completing the corresponding toxicological test of the metabolite, so that a large number of samples are extremely difficult to separate from the plant body, reports that enough quantity meeting the toxicological test needs can not be obtained through separation are not seen at present, a few chemical methods are used for synthesis, the synthesis process is complex, and the synthesis efficiency is low. Meanwhile, the problem of pesticide residue is always a civil problem which is focused on by all countries in the world, the quantity of various pesticide residues in all countries in the world is limited and standard, the export trade of agricultural products is influenced by the pesticide residue exceeding, and the preparation of high-quality metabolite standards is inevitable for detecting the residue quantity. Therefore, the research on synthesis of pesticide metabolites is an urgent need in the fields of pesticide registration, pesticide residue quality inspection and scientific research, and has great social application value.
The Tembotrione (Tembotrione) has the chemical name of 2- (2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonylbenzoyl) cyclohexane-1, 3 dione and the CAS number of 335104-84-2, is a triketone HPPD inhibitor herbicide developed by Bayer company in 2007, is mainly used for preventing and killing gramineous and latifolious weeds in corn fields and paddy fields, has a killing effect on various weeds, and also has a higher preventing and killing effect on cross-spectrum weeds (such as setaria and illicium) and weeds resistant to glyphosate, acetolactate synthase inhibitor and dicamba. The recent market performance of the tembotrione is excellent, related pesticide products are concerned, registration of pesticides is one of important works of many enterprises at present, and therefore, a large amount of tembotrione metabolites need to be prepared for toxicological tests.
The European Union food safety agency reports on cycliophenone metabolites, and documents Conclusion on the peer review of the pharmaceutical lipid supplement of the active substention tembotrione (EFSA Journal 2013, 11, 3, 3131) disclose the production pathways and molecular structures of various cycliophenone metabolites, and Shenyang chemical research institute has also conducted a large number of studies on the metabolic pathways of cycliophenone in plants to confirm the existence of various cycliophenone metabolites, and M1, M6 and M7 are some of the reported metabolites.
The chemical name of the cyclazone metabolite M1 is 2-chloro-3- (2,2, 2-trifluoroethoxymethyl) -4-methylsulfonylphenol, and M7 is 2-chloro-3- (2,2, 2-trifluoroethoxymethyl) -4-methylsulfonylphenylmethyl ether, so that no relevant report on the chemical synthesis methods of the metabolites M1 and M7 exists at present.
M6 chemical name 2-chloro-3- (2,2, 2-trifluoroethoxymethyl) -4-methylsulfonylbenzoic acid, CN1323292A discloses a benzoyl cyclohexanedione and its preparation method, wherein M6 is one of intermediates for synthesizing the benzoyl cyclohexanedione, the preparation method has long process route and unsatisfactory product yield. CN104292137A discloses a preparation method of M6, which takes 2-chloro-6-toluene as an initial raw material and finally obtains M6 through a mesylation reaction, an acetylation reaction, an oxidation reaction, an esterification reaction, a bromination reaction and a coupling reaction; the method has complex synthetic route and low preparation efficiency.
Therefore, the development of a synthetic process of a cyclic sultone metabolite with simple steps and high preparation efficiency is an urgent problem to be solved in the field.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of a tembotrione metabolite, and particularly relates to a preparation method of tembotrione metabolites M1, M6 and M7, wherein a tembotrione raw pesticide is used as an initial raw material, the tembotrione metabolites M1 and M6 can be obtained through one-step reaction, the M6 can be used for obtaining the tembotrione metabolite M7 through one-step reaction, the synthetic route is simple, the conditions are mild, the tembotrione metabolite with high purity and high yield can be obtained, and the sample quantity requirement of the tembotrione metabolite in pesticide registration is fully met.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a method for preparing a tembotrione metabolite, the method comprising: reacting the tembotrione, an oxidant and an auxiliary agent to obtain a tembotrione metabolite M1 and a tembotrione metabolite M6; the auxiliary agent is an acidic compound or an alkaline compound; the reaction formula is as follows:
the preparation method provided by the invention takes the tembotrione original drug as the starting raw material, and can obtain the tembotrione metabolite M1 and the tembotrione metabolite M6 with high yield and high purity through one-step reaction in the presence of an oxidant and an auxiliary agent, the raw materials are easy to obtain, the steps are simple, a harsh reaction environment is not needed, the conditions are mild, the process is easy to realize, the mass preparation of the tembotrione metabolite is realized, and the requirement of pesticide registration on the mass sample amount of the metabolite can be fully met.
In the preparation method, the auxiliary agent can be an acidic compound or a basic compound. When the auxiliary agent is an acidic compound, the reaction product is a mixture of a tembotrione metabolite M1 and a tembotrione metabolite M6, and the ratio of the two reaction products can be adjusted by screening the types of the acidic compound and regulating and controlling the process parameters, so that the yield of the tembotrione metabolite M1 is 20-45%, and the yield of the tembotrione metabolite M6 is 45-65%. When the auxiliary agent is an alkaline compound, the reaction product is more than the cyclic sulfoketone metabolite M6, the yield reaches more than 85%, and the proportion of the cyclic sulfoketone metabolite M1 in the product is even lower than 1%.
Preferably, the oxidizing agent is a peroxide-based oxidizing agent.
Preferably, the peroxide-based oxidant comprises any one of hydrogen peroxide, peroxyacetic acid, peroxytrifluoroacetic acid, peroxybenzoic acid, 3-chloroperoxybenzoic acid or peroxysulfuric acid or a combination of at least two of the hydrogen peroxide, the peroxyacetic acid, the peroxytrifluoroacetic acid, the peroxybenzoic acid, the 3-chloroperoxybenzoic acid and the peroxysulfuric acid.
The molar ratio of the tembotrione to the oxidizing agent is preferably 1 (1.5 to 5), and may be, for example, 1:1.6, 1:1.8, 1:2, 1:2.2, 1:2.5, 1:2.8, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:4.2, 1:4.5, or 1:4.8, and more preferably 1 (3 to 3.5).
Preferably, the auxiliary is an acidic compound, the molar ratio of the tembotrione to the auxiliary is 1 (1.5-4), and the molar ratio may be, for example, 1:1.6, 1:1.8, 1:2, 1:2.2, 1:2.5, 1:2.8, 1:3, 1:3.2, 1:3.5, or 1:3.8, and more preferably 1 (3-3.5).
Preferably, the acidic compound comprises any one of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, formic acid or phosphoric acid or a combination of at least two thereof.
Preferably, the auxiliary agent is a basic compound, and the molar ratio of the tembotrione to the auxiliary agent is 1 (1.5-5), and may be, for example, 1:1.6, 1:1.8, 1:2, 1:2.2, 1:2.5, 1:2.8, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:4.2, 1:4.5, or 1: 4.8.
Preferably, the basic compound comprises any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate or a combination of at least two thereof.
Preferably, the auxiliary agent is any one or a combination of at least two of sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate, and the molar ratio of the auxiliary agent to the tembotrione is (3-5): 1, such as 3.1:1, 3.3:1, 3.5:1, 3.7:1, 3.9:1, 4:1, 4.1:1, 4.3:1, 4.5:1, 4.7:1 or 4.9:1, and more preferably (3.5-4): 1.
Preferably, the auxiliary agent is sodium carbonate and/or potassium carbonate, and the molar ratio of the auxiliary agent to the tembotrione is (1.5-2.5): 1, such as 1.6:1, 1.8:1, 2:1, 2.1:1, 2.2:1, 2.3:1 or 2.4: 1.
Preferably, the reaction is carried out in the presence of a solvent.
Preferably, the solvent is selected from any one of water, methanol, ethanol, isopropanol, acetonitrile, Dimethylformamide (DMF), Dimethylacetamide (DMAC) or Dimethylsulfoxide (DMSO), or a combination of at least two thereof, and more preferably acetonitrile.
Preferably, the amount of the solvent is 600-1500 mL, such as 700mL, 800mL, 900mL, 1000mL, 1100mL, 1200mL, 1300mL or 1400mL, based on 1mol of the tembotrione, and the specific values therebetween are limited by space and for the sake of brevity, and the invention is not exhaustive of the specific values included in the range.
Preferably, the temperature of the reaction is 30 to 90 ℃, for example, 32 ℃, 35 ℃, 38 ℃, 40 ℃, 42 ℃, 45 ℃, 48 ℃, 50 ℃, 52 ℃, 55 ℃, 58 ℃, 60 ℃, 62 ℃, 65 ℃, 68 ℃, 70 ℃, 72 ℃, 75 ℃, 78 ℃, 80 ℃, 82 ℃, 85 ℃ or 88 ℃, and the specific values therebetween are limited to space and conciseness, and the invention does not exhaustive list the specific values included in the range, and more preferably 40 to 50 ℃.
Preferably, the reaction time is 3 to 8 hours, such as 3.2 hours, 3.5 hours, 3.8 hours, 4 hours, 4.2 hours, 4.5 hours, 4.8 hours, 5 hours, 5.2 hours, 5.5 hours, 5.8 hours, 6 hours, 6.2 hours, 6.5 hours, 6.8 hours, 7 hours, 7.2 hours, 7.5 hours or 7.8 hours, and the specific values therebetween are limited by space and for the sake of brevity, and the invention is not exhaustive list of the specific values included in the range, and further preferably 4 to 6 hours.
Preferably, the reaction is completed further comprising isolation of the product.
Preferably, the auxiliary is an acidic compound, and the method for separating comprises the following steps: adding a reducing agent into the reaction product to consume the oxidizing agent, then carrying out salt forming reaction with an alkaline substance, and acidifying the generated salt until the pH value of the system is 4.5-5 to obtain a tembotrione metabolite M1; continuously acidifying until the pH value of the system is less than or equal to 2 to obtain the tembotrione metabolite M6.
As a preferable technical scheme of the invention, in the separation method, firstly a reducing agent (such as sodium sulfite) is added to destroy an oxidizing agent, then alkali is added to carry out salt formation reaction, and then the separation of the pure product of the tembotrion metabolite M1 and the pure product of the tembotrion metabolite M6 is realized by utilizing the alkali difference between the salt formed by the tembotrion metabolite M1 and the salt formed by the tembotrion metabolite M6 and regulating and controlling the pH value of a system.
In the acidification process, the pH value of the separated cyclosulfone metabolite M1 is controlled to be 4.5-5, for example, the pH value can be 4.55, 4.6, 4.65, 4.7, 4.75, 4.8, 4.85, 4.9 or 4.95. If the pH value is too high, the yield of M1 is low; if the pH is too low, the quality and purity of M1 decreases.
In the acidification process, the pH value of the separated tembotrione metabolite M6 is less than or equal to 2, for example, the pH value can be 1.95, 1.9, 1.85, 1.8, 1.75, 1.7, 1.65, 1.6, 1.55, 1.5, 1.4, 1.3, 1.2 or 1.1, etc. If the pH is too high, acidification is incomplete, affecting the yield of M6.
Preferably, the reducing agent comprises sodium sulfite.
Preferably, the method further comprises a desolventizing step after the oxidant is consumed.
Preferably, the alkaline substance comprises any one of sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate or a combination of at least two thereof.
Preferably, the molar ratio of the basic substance to the tembotrione is (3-4: 1), such as 3.1:1, 3.2:1, 3.3:1, 3.4:1, 3.5:1, 3.6:1, 3.7:1, 3.8:1 or 3.9: 1.
Preferably, the salt formation reaction is carried out in an aqueous solution.
Preferably, the acidifying agent comprises any one of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, formic acid or phosphoric acid or a combination of at least two thereof.
Preferably, acidifying until the pH value of the system is 3.5-4 to obtain a mixture of the cyclic sulfone metabolite M1/M6.
In a preferred embodiment of the present invention, the pH of the mixture of separated cyclosulfone metabolite M1/M6 is 3.5 to 4, for example, 3.55, 3.6, 3.65, 3.7, 3.75, 3.8, 3.85, 3.9, or 3.95. If the pH value is too high, the removal of M1 does not completely affect the quality of the subsequent M6; if the pH is too low, M6 loss increases; the mixture can be further separated and purified after accumulation.
Preferably, the auxiliary agent is an alkaline compound, and the separation method comprises the following steps: adding a reducing agent into the reaction product to consume the oxidizing agent, and then acidifying until the pH value of the system is 3.5-4 (for example, the pH value is 3.55, 3.6, 3.65, 3.7, 3.75, 3.8, 3.85, 3.9 or 3.95) to obtain a mixture of the cyclosulfoketone metabolite M1/M6; acidification is continued until the pH value of the system is less than or equal to 2 (for example, the pH value can be 1.95, 1.9, 1.85, 1.8, 1.75, 1.7, 1.65, 1.6, 1.55, 1.5, 1.4, 1.3, 1.2 or 1.1, etc.), and the cyclanone metabolite M6 is obtained.
Preferably, the acidifying agent comprises any one of hydrochloric acid, hydrobromic acid, sulphuric acid, acetic acid, formic acid or phosphoric acid, or a combination of at least two thereof.
As a preferred technical scheme of the invention, if the auxiliary agent in the reaction is an alkaline compound, no alkaline substance is required to be added for salt formation in the separation process, the product is mainly the tembotrione metabolite M6, and other separation steps and process parameters are as described above and are not described in detail.
After the separation step, the content of the obtained cyclosulfoketone metabolite M1 is more than 98.5%, and the content of the obtained cyclosulfoketone metabolite M6 is more than 98.0%.
Preferably, the preparation method specifically comprises: reacting the tembotrione, the peroxide oxidant and the auxiliary agent in a solvent at 30-90 ℃ for 3-8 h, and separating the obtained crude product to obtain a tembotrione metabolite M1 and a tembotrione metabolite M6; the molar ratio of the tembotrione to the oxidant is 1 (1.5-5).
The auxiliary agent is an acidic compound, and the molar ratio of the tembotrione to the auxiliary agent is 1 (1.5-4); the separation method comprises the following steps: adding a reducing agent into the reaction product to consume the oxidizing agent, then carrying out salt-forming reaction with an alkaline substance, and acidifying the generated salt until the pH value of the system is 4.5-5 to obtain a tembotrione metabolite M1; continuously acidifying until the pH value of the system is 3.5-4 to obtain a mixture of the tembotrione metabolite M1/M6; then acidifying until the pH value of the system is less than or equal to 2 to obtain the tembotrione metabolite M6.
The auxiliary agent is an alkaline compound, and the molar ratio of the tembotrione to the auxiliary agent is 1 (1.5-5); the separation method comprises the following steps: adding a reducing agent into the reaction product to consume the oxidizing agent, and then acidifying until the pH value of the system is 3.5-4 to obtain a mixture of a cyclanone metabolite M1/M6; continuously acidifying until the pH value of the system is less than or equal to 2 to obtain the tembotrione metabolite M6.
In a second aspect, the present invention provides a preparation method of a tembotrione metabolite M7, the preparation method comprising: reacting a raw material of a cyclic sulfoketone metabolite M1 with a methylating reagent to obtain a cyclic sulfoketone metabolite M7; the reaction formula is as follows:
wherein M is selected from H, Na or K; namely, the raw material of the tembotrion metabolite M1 is any one or the combination of at least two of tembotrion metabolite M1, M1 sodium salt or M1 potassium salt.
According to the preparation method of the tembotrion metabolite M7, the tembotrion metabolite M1 or salts thereof are used as raw materials, a target product with high purity and high yield can be obtained through one-step reaction, the process is simple, the operation is convenient, and the yield of the tembotrion metabolite M7 can reach 78-95%.
Preferably, the methylating agent comprises any one of dimethyl sulphate, methyl iodide, methyl bromide or methyl chloride or a combination of at least two thereof.
Preferably, the molar ratio of the raw material of the tembotrione metabolite M1 to the methylating agent is 1 (1-5), and may be, for example, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2, 1:2.2, 1:2.5, 1:2.8, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:4.2, 1:4.5 or 1: 4.8.
Preferably, the methylation reagent is dimethyl sulfate and/or methyl iodide, and the molar ratio of the methylation reagent to the raw material of the cyclic sultone metabolite M1 is (1-2): 1, such as 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1 or 1.9:1, and more preferably (1.1-1.3): 1.
Preferably, the methylation reagent is methyl bromide and/or methyl chloride, and the molar ratio of the methylation reagent to the raw material of the tembotrione metabolite M1 is (1.5-5): 1, such as 1.6:1, 1.8:1, 2:1, 2.2:1, 2.5:1, 2.8:1, 3:1, 3.2:1, 3.5:1, 3.8:1, 4:1, 4.2:1, 4.5:1 or 4.8:1, and more preferably (2-2.5): 1.
Preferably, the reaction is carried out in the presence of a solvent.
Preferably, the solvent comprises any one of dichloroethane, toluene, acetonitrile, Dimethylformamide (DMF), Dimethylacetamide (DMAC) or Dimethylsulfoxide (DMSO), or a combination of at least two thereof.
Preferably, the amount of the solvent is 500-1500 mL based on 1mol of the raw material of the tembotrione metabolite M1, for example, 600mL, 700mL, 800mL, 900mL, 1000mL, 1100mL, 1200mL, 1300mL or 1400mL, and the specific values therebetween are not exhaustive, and for brevity, the invention does not list the specific values included in the range, and further preferably 1000-1200 mL.
Preferably, the temperature of the reaction is 50 to 150 ℃, for example, 55 ℃, 60 ℃, 62 ℃, 65 ℃, 68 ℃, 70 ℃, 72 ℃, 75 ℃, 78 ℃, 80 ℃, 82 ℃, 85 ℃, 88 ℃, 90 ℃, 95 ℃, 100 ℃, 105 ℃, 110 ℃, 115 ℃, 120 ℃, 125 ℃, 130 ℃, 135 ℃, 140 ℃ or 145 ℃, and the specific values therebetween are limited by space and in the interest of conciseness, and the invention does not exhaust the specific values included in the range, and more preferably is 60 to 80 ℃.
Preferably, the reaction time is 6-10 h, for example, 6.2h, 6.5h, 6.8h, 7h, 7.2h, 7.5h, 7.8h, 8h, 8.2h, 8.5h, 8.8h, 9h, 9.2h, 9.5h or 9.8h, and the specific values therebetween are limited by space and simplicity, and the invention does not exhaust the specific values included in the range, and more preferably 7-8 h.
Preferably, the reaction is completed and further comprises the post-treatment of the product.
Preferably, the post-treatment comprises desolventizing, recrystallizing and washing.
Preferably, the agent for recrystallization comprises methanol.
Preferably, the recrystallization temperature is-5 to 10 ℃, for example, -4 ℃, -3 ℃, -2 ℃, -1 ℃, 0 ℃, 1 ℃,2 ℃,3 ℃, 4 ℃, 5 ℃, 6 ℃, 7 ℃, 8 ℃ or 9 ℃.
Preferably, the cyclic sultone metabolite M1 raw material is prepared by the preparation method as described in the first aspect.
Preferably, the preparation method specifically comprises the following steps: reacting a raw material of a cyclic sulfoketone metabolite M1 with a methylating agent in a solvent at 50-150 ℃ for 6-10 h, and desolventizing, recrystallizing and washing an obtained crude product to obtain the cyclic sulfoketone metabolite M7; the methylation reagent is dimethyl sulfate, and the molar ratio of the methylation reagent to the raw material of the cyclic sulfoketone metabolite M1 is (1-2): 1; the methylation reagent is any one or combination of at least two of methyl iodide, methyl bromide or methyl chloride, and the molar ratio of the methylation reagent to the raw material of the cyclic sultone metabolite M1 is (1.5-5): 1.
Compared with the prior art, the invention has the following beneficial effects:
in the preparation method of the tembotrione metabolite, a tembotrione metabolite M1 and a tembotrione metabolite M6 with high yield and high purity can be obtained by taking a tembotrione original drug as an initial raw material and carrying out one-step reaction in the presence of an oxidant and an auxiliary agent, wherein the purity of the tembotrione metabolite M1 is more than or equal to 98.7 percent, and the purity of M6 is more than or equal to 98.2 percent; the tembotrione metabolite M6 and a methylating agent are subjected to one-step reaction to obtain a tembotrione metabolite M7, and the purity of the product is more than or equal to 98%. The preparation method has the advantages of easily available raw materials, simple steps, convenient operation, controllable experimental process, no need of harsh reaction environment, mild conditions and easy realization of the process, realizes the mass preparation of the tembotrion metabolite, and can fully meet the sample quantity requirement of the tembotrion metabolite in pesticide registration.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
The quantitative contents (purities) in the following examples of the present invention were measured by high performance liquid chromatography (HPLC, LC-20AT, Shimadzu corporation, Japan) external standard method.
Example 1
A method for preparing a tembotrione metabolite comprises the following specific steps:
267g of tembotrione technical material (purity 99%, 0.6mol), 700mL of acetonitrile and 182.5g of concentrated hydrochloric acid (purity 36%, 1.8mol) are added into a 2L three-mouth bottle, stirring is started, the temperature of the system is raised to 40 ℃, 238g of hydrogen peroxide (purity 30%, 2.1mol) is dripped in about 1h, and the temperature of the system is controlled to be 40-45 ℃ after dripping is finished, and reaction is carried out for 5 h. And (3) stopping the reaction when the heat preservation is finished and the residual material of the central control tembotrione is less than 0.2%, then adding 53g of sodium sulfite (with the purity of 99 percent and the mol of 0.416mol) to destroy hydrogen peroxide, and then carrying out negative pressure desolventizing to obtain M1 and M6 crude products. To the crude product, 750g of water and 80g of sodium hydroxide (96% pure, 1.92mol) were added to make M1 and M6 into the corresponding salts, followed by extraction with 200mL of dichloroethane to remove impurities, and the aqueous phases obtained by separation were acidified with 10% dilute hydrochloric acid to separate M1 and M6; when the mixture is acidified to a pH value of 4.5, a large amount of products are separated out, and 69g of pure tembotrione metabolite M1 product is obtained through filtration, water washing and drying, the quantitative content is 98.9%, and the yield is 35.8%; further acidifying until pH is 3.5, separating out a small amount of solid, filtering, washing with water, oven drying to obtain 11g of mixture of cyclanone metabolite M1/M6, and purifying again after accumulation; and then, when the pH value is further acidified to be 2, a large amount of products are separated out, and 104.5g of the pure product of the tembotrione metabolite M6 is obtained through filtration, washing and drying, the quantitative content is 98.2 percent, and the yield is 49.4 percent.
And (3) structure detection:
cyclic sultone metabolite M1: ultra-high liquid chromatography-mass spectrometry UHPLC-MS (m/z, ESI)-)：316.98448(M-H)-(ii) a Theoretical value: 316.9862 (negative ions).
1H-NMR(CDCl3，300MHz)：δ3.17(s,3H,CH3)，4.00-4.06(q,J＝6.0Hz,2H,CH2)，5.30(s,2H,CH2)，6.34(s,1H,OH)，7.20(d,J＝6.0Hz,1H,ArH)，8.02(d,J＝6.0Hz,1H,ArH)。
Cyclic sultone metabolite M6: UHPLC-MS (m/z, ESI)-)：344.97949(M-H)-(ii) a Theoretical value: 344.9812 (negative ion).
1H-NMR(CDCl3，300MHz)：δ3.36(s,4H,CH3,RCOOH)，4.26-4.32(q,J＝6.0Hz,2H,CH2)，5.24(s,2H,CH2)，7.94(d,J＝6.0Hz,1H,ArH)，8.07(d,J＝6.0Hz,1H,ArH)。
The method of the embodiment is used for amplification preparation, and 2.5kg of tembotrione metabolite M1 is obtained, and the quantitative content is 99.1%; 3.7kg of tembotrione metabolite M6 was obtained, with a quantitative content of 98.6%.
Example 2
A method for preparing a tembotrione metabolite comprises the following specific steps:
267g of tembotrione technical material (purity 99%, 0.6mol), 800mL of acetonitrile and 212.9g of concentrated hydrochloric acid (purity 36%, 2.1mol) are added into a 2L three-mouth bottle, stirring is started, the temperature of the system is raised to 40 ℃, 238g of hydrogen peroxide (purity 30%, 2.1mol) is dripped in about 1h, and the temperature of the system is controlled to be 40-45 ℃ after dripping is finished, and reaction is carried out for 5 h. And (3) stopping the reaction when the heat preservation is finished and the residual material of the central control tembotrione is less than 0.2%, then adding sodium sulfite to destroy hydrogen peroxide, and then performing negative pressure desolventizing to obtain M1 and M6 crude products. To the crude product, 750g of water and 85g of sodium hydroxide (96% pure, 2.04mol) were added to make M1 and M6 into the corresponding salts, followed by extraction with 200mL of dichloroethane to remove impurities, and the aqueous phases obtained by separation were acidified with 10% dilute hydrochloric acid to separate M1 and M6; when the mixture is acidified to a pH value of 4.5, a large amount of products are separated out, and 67.5g of pure tembotrione metabolite M1 product is obtained through filtration, water washing and drying, the quantitative content is 98.8%, and the yield is 35.0%; further acidifying until pH is 3.5, separating out a small amount of solid, filtering, washing with water, and oven drying to obtain 10.6g mixture of cyclanone metabolite M1/M6, and purifying again after accumulation; and then, when the pH value is further acidified to be 2, a large amount of products are separated out, and 108.2g of the pure product of the tembotrione metabolite M6 is obtained through filtration, water washing and drying, the quantitative content is 98.4 percent, and the yield is 51.2 percent.
Example 3
A method for preparing a tembotrione metabolite comprises the following specific steps:
267g of tembotrione technical material (purity 99%, 0.6mol), 700mL of acetonitrile and 182.5g of concentrated hydrochloric acid (purity 36%, 1.8mol) are added into a 2L three-mouth bottle, stirring is started, the temperature of the system is raised to 40 ℃, 161.2g of peroxyacetic acid (purity 30%, 2.1mol) is dripped in about 1h, the temperature of the system is controlled to be 40-45 ℃ after dripping, and reaction is carried out for 6 h. And (3) stopping the reaction when the heat preservation is finished and the residual material of the central control tembotrione is less than 0.2%, then adding sodium sulfite to destroy peroxyacetic acid, and then performing negative pressure desolventizing to obtain M1 and M6 crude products. To the crude product, 750g of water and 80g of sodium hydroxide (96% pure, 1.92mol) were added to make M1 and M6 into the corresponding salts, followed by extraction with 200mL of dichloroethane to remove impurities, and the aqueous phases obtained by separation were acidified with 10% dilute hydrochloric acid to separate M1 and M6; when the mixture is acidified to a pH value of 4.5, a large amount of products are separated out, and 80.5g of pure tembotrione metabolite M1 product with the quantitative content of 99.0% and the yield of 41.8% is obtained through filtration, washing and drying; further acidifying until pH is 3.5, separating out a small amount of solid, filtering, washing with water, and oven drying to obtain 10.7g mixture of cyclanone metabolite M1/M6, and purifying again after accumulation; and then, when the pH value is further acidified to be 2, a large amount of products are separated out, and 96.2g of pure product M6 of the tembotrione metabolite M6 is obtained through filtration, water washing and drying, the quantitative content is 98.6 percent, and the yield is 45.6 percent.
Example 4
A method for preparing a tembotrione metabolite comprises the following specific steps:
267g of tembotrione technical material (purity 99%, 0.6mol), 800mL of methanol and 212.9g of concentrated hydrochloric acid (purity 36%, 2.1mol) are added into a 2L three-mouth bottle, stirring is started, the temperature of the system is raised to 40 ℃, 204g of hydrogen peroxide (purity 30%, 1.8mol) is dripped in about 1h, the temperature of the system is controlled to be 40-45 ℃ after dripping, and reaction is carried out for 5 h. And (3) stopping the reaction when the heat preservation is finished and the residual material of the central control tembotrione is less than 0.2%, then adding sodium sulfite to destroy hydrogen peroxide, and then performing negative pressure desolventizing to obtain M1 and M6 crude products. To the crude product, 750g of water and 134.4g of potassium hydroxide (85% pure, 2.04mol) were added to make M1 and M6 into the corresponding salts, followed by extraction with 200mL of dichloroethane to remove impurities, and the aqueous phases obtained by separation were acidified with 10% dilute hydrochloric acid to separate M1 and M6; when the mixture is acidified to a pH value of 4.5, a large amount of products are separated out, and 48.5g of pure tembotrione metabolite M1 product is obtained through filtration, water washing and drying, the quantitative content is 98.7%, and the yield is 25.1%; further acidifying until pH is 3.5, separating out a small amount of solid, filtering, washing with water, and oven drying to obtain 10.5g mixture of cyclanone metabolite M1/M6, and purifying again after accumulation; and then, when the pH value is further acidified to be 2, a large amount of products are separated out, and 121.6g of pure tembotrione metabolite M6 product is obtained through filtration, water washing and drying, the quantitative content is 98.4%, and the yield is 57.5%.
Example 5
A method for preparing a tembotrione metabolite comprises the following specific steps:
267g of tembotrione technical material (purity 99%, 0.6mol), 800mL of DMF and 182.5g of concentrated hydrochloric acid (purity 36%, 1.8mol) are added into a 2L three-mouth bottle, stirring is started, the temperature of the system is raised to 40 ℃, 204g of hydrogen peroxide (purity 30%, 1.8mol) is added dropwise after the temperature is raised to 40 ℃ for 1 hour, the temperature of the system is controlled to be 40-45 ℃ after the dropwise addition, and the reaction is carried out for 5 hours. And (3) stopping the reaction when the heat preservation is finished and the residual material of the central control tembotrione is less than 0.2%, then adding sodium sulfite to destroy hydrogen peroxide, and then performing negative pressure desolventizing to obtain M1 and M6 crude products. To the crude product, 750g of water and 126.5g of potassium hydroxide (85% pure, 1.92mol) were added to make M1 and M6 into the corresponding salts, followed by extraction with 200mL of dichloroethane to remove impurities, and the aqueous phases obtained by separation were acidified with 10% dilute hydrochloric acid to separate M1 and M6; when the mixture is acidified to a pH value of 4.5, a large amount of products are separated out, and 39g of a pure product of the tembotrione metabolite M1 is obtained through filtering, washing and drying, the quantitative content is 98.9%, and the yield is 21.2%; further acidifying until pH is 3.5, separating out a small amount of solid, filtering, washing with water, oven drying to obtain 9.9g of mixture of cyclanone metabolite M1/M6, and purifying again after accumulation; and then, when the pH value is further acidified to be 2, a large amount of products are separated out, and 132.6g of pure product M6 of the tembotrione metabolite M6 is obtained through filtration, water washing and drying, the quantitative content is 98.6 percent, and the yield is 62.9 percent.
Example 6
A method for preparing a tembotrione metabolite comprises the following specific steps:
267g of tembotrione technical material (purity 99%, 0.6mol), 900mL of water and 87.5g of sodium hydroxide (purity 96%, 2.1mol) are added into a 2L three-mouth bottle, stirring is started, the temperature of the system is raised to 40 ℃, 238g of hydrogen peroxide (purity 30%, 2.1mol) is dripped in about 1h, and the temperature of the system is controlled to be 40-45 ℃ after dripping is finished, and reaction is carried out for 4 h. After heat preservation is finished, stopping reaction when the residual material of the central control tembotrion is less than 0.2%, then adding sodium sulfite to destroy hydrogen peroxide to obtain aqueous solutions of corresponding salts of M1 and M6, then extracting with 200mL of dichloroethane to remove impurities, and acidifying and separating the aqueous phase obtained by layering by using 10% of dilute hydrochloric acid to separate M1 and M6; when the mixture is acidified to a pH value of 3.5, a small amount of solid is separated out, and 13.5g of a mixture of the cyclanone metabolite M1/M6 is obtained by filtering, washing and drying, and the mixture can be purified again after being accumulated; and (3) further acidifying until the pH value is 2, separating out a large amount of products, and filtering, washing and drying to obtain 182.9g of the pure product of the tembotrione metabolite M6, wherein the quantitative content is 98.4 percent, and the yield is 86.6 percent.
Example 7
A method for preparing a tembotrione metabolite comprises the following specific steps:
267g of tembotrione technical material (purity 99%, 0.6mol), 900mL of water and 146.5g of potassium carbonate (purity 99%, 1.05mol) are added into a 2L three-mouth bottle, stirring is started, the temperature of the system is raised to 40 ℃, 238g of hydrogen peroxide (purity 30%, 2.1mol) is dripped in about 1h, and the temperature of the system is controlled to be 40-45 ℃ after dripping is finished, and reaction is carried out for 5 h. After heat preservation is finished, stopping reaction when the residual material of the central control tembotrion is less than 0.2%, then adding sodium sulfite to destroy hydrogen peroxide to obtain aqueous solutions of corresponding salts of M1 and M6, then extracting with 200mL of dichloroethane to remove impurities, and acidifying and separating the aqueous phase obtained by layering by using 10% of dilute hydrochloric acid to separate M1 and M6; when the mixture is acidified to a pH value of 3.5, a small amount of solid is separated out, and 14.7g of a mixture of the cyclanone metabolite M1/M6 is obtained by filtering, washing and drying, and the mixture can be purified again after being accumulated; when the solution is further acidified to a pH value of 2, a large amount of products are separated out, and 184.4g of the pure product of the tembotrione metabolite M6, with the quantitative content of 98.3% and the yield of 87.2%, is obtained after filtration, washing and drying.
Example 8
A method for preparing a tembotrione metabolite M7 comprises the following specific steps:
161.4g of cyclamate metabolite M1 (purity 98.5%, 0.5mol), 500mL of dichloroethane and 77.1g of dimethyl sulfate (purity 98%, 0.6mol) are added into a 2L three-necked flask, stirring is started, and the system is controlled to 60-65 ℃ for reaction for 7 hours under heat preservation. And (3) stopping the reaction when the heat preservation is finished and the residual material of the intermediate control M1 is less than 0.5%, then removing the solvent by desolventizing, adding 100mL of methanol, heating to dissolve, slowly cooling to 0 ℃ for crystallization, and then filtering, washing and drying to obtain 146.2g of the sample of the M7 of the cyclanone metabolite, wherein the quantitative content is 98.8% and the yield is 87.0%.
And (3) structure detection: UHPLC-MS (m/z, ESI)+)：333.01671(M+H)+(ii) a Theoretical value: 333.0175 (positive ions).
1H-NMR(CDCl3，400MHz)：δ3.186(s,3H,CH3)，4.000(s,3H,CH3)，4.001-4.067(q,J＝8.8Hz,2H,CH2)，5.355(s,2H,CH2)，7.062(d,J＝8.8Hz,1H,ArH)，8.079(d,J＝8.8Hz,1H,ArH)。
Example 9
A method for preparing a tembotrione metabolite M7 comprises the following specific steps:
161.4g of cyclanone metabolite M1 (purity 98.5%, 0.5mol), 600mL of toluene and 83.6g of dimethyl sulfate (purity 98%, 0.65mol) are added into a 2L three-necked bottle, stirring is started, and the system is controlled to 70-75 ℃ for heat preservation reaction for 6 h. And (3) stopping the reaction when the heat preservation is finished and the residual material of the intermediate control M1 is less than 0.5%, then removing the solvent by desolventizing, adding 100mL of methanol, heating to dissolve, slowly cooling to 0 ℃ for crystallization, and then filtering, washing and drying to obtain 144.9g of a sample of the M7 of the cyclanone metabolite, wherein the quantitative content is 98.5%, and the yield is 86.0%.
Example 10
A method for preparing a tembotrione metabolite M7 comprises the following specific steps:
adding 180.7g of cyclazone metabolite M1 potassium salt (purity 98.5%, 0.5mol) and 600mL of acetonitrile into a 2L pressure kettle, adding 86.1g of methyl iodide (purity 99%, 0.6mol), sealing the system, starting stirring, controlling the temperature of the system to 60-65 ℃, and carrying out heat preservation reaction for 6 hours. And (3) stopping the reaction when the heat preservation is finished and the residual material of the intermediate control M1 is less than 0.5%, then removing the solvent by desolventizing, adding 100mL of methanol, heating to dissolve, slowly cooling to 0 ℃ for crystallization, and then filtering, washing and drying to obtain 156.1g of a sample of the M7 of the cyclanone metabolite, wherein the quantitative content is 98.9% and the yield is 93.0%.
Example 11
A method for preparing a tembotrione metabolite M7 comprises the following specific steps:
adding 180.7g of cyclazone metabolite M1 potassium salt (purity 98.5%, 0.5mol) and 600mL of acetonitrile into a 2L pressure kettle, introducing 63.8g of methane chloride (purity 99%, 1.25mol), sealing the system, starting stirring, controlling the temperature of the system to 80-85 ℃, and carrying out heat preservation reaction for 8 hours. And (3) stopping the reaction when the heat preservation is finished and the residual material of the intermediate control M1 is less than 0.5%, then removing the solvent by desolventizing, adding 100mL of methanol, heating to dissolve, slowly cooling to 0 ℃ for crystallization, and then filtering, washing and drying to obtain 154.8g of a sample of the M7 of the cyclanone metabolite, wherein the quantitative content is 99.0% and the yield is 92.3%.
The amplification preparation was carried out by the method of this example to obtain 2.4kg total of the tembotrione metabolite M7 with a quantitative content of 99.0%.
Example 12
A method for preparing a tembotrione metabolite M7 comprises the following specific steps:
adding 172.6g of cyclazone metabolite M1 sodium salt (purity 98.5%, 0.5mol) and 500mL of DMF (dimethyl formamide) into a 2L pressure kettle, introducing 96.0g of monobromomethane (purity 99%, 1.0mol), sealing the system, starting stirring, controlling the temperature of the system to 70-75 ℃, and carrying out heat preservation reaction for 7 hours. And (3) stopping the reaction when the heat preservation is finished and the residual material of the intermediate control M1 is less than 0.5%, then removing the solvent by desolventizing, adding 100mL of methanol, heating to dissolve, slowly cooling to 0 ℃ for crystallization, and then filtering, washing and drying to obtain 155.3g of a sample of the M7 of the cyclanone metabolite, wherein the quantitative content is 98.7% and the yield is 92.3%.
Example 13
A method for preparing a tembotrione metabolite M7 comprises the following specific steps:
180.7g of cyclamate metabolite M1 potassium salt (98.5% in purity, 0.5mol), 750mL of DMSO and 38.3g of methyl chloride (99% in purity, 0.75mol) were placed in a 2L autoclave, the mixture was stirred, and the system was kept at 130 ℃ for 6 hours. And (3) stopping the reaction when the heat preservation is finished and the residual material of the intermediate control M1 is less than 0.5%, then desolventizing to remove the solvent, adding 150mL of methanol, heating to dissolve, slowly cooling to 0 ℃ for crystallization, and then filtering, washing and drying to obtain 133.9g of a sample of the M7 of the cyclanone metabolite, wherein the quantitative content is 97.5%, and the yield is 78.6% calculated by M1.
Example 14
A method for preparing a tembotrione metabolite M7 comprises the following specific steps:
180.7g of cyclazone metabolite M1 potassium salt (purity 98.5%, 0.5mol), 250mL of acetonitrile and 102g of methyl chloride (purity 99%, 2mol) were added to a 2L autoclave, and stirring was started, and the system was maintained at 55 ℃ for 10 hours. And (3) stopping the reaction when the heat preservation is finished and the residual material of the intermediate control M1 is less than 0.5%, then removing the solvent by desolventizing, adding 150mL of methanol, heating to dissolve, slowly cooling to 0 ℃ for crystallization, and then filtering, washing and drying to obtain 154.8g of a sample of the M7 of the cyclanone metabolite, wherein the quantitative content is 98.3% and the yield is 91.7%.
Example 15
A method for preparing a tembotrione metabolite comprises the following specific steps:
267g of tembotrione technical material (purity 99%, 0.6mol), 400mL of acetonitrile and 91.2g of concentrated hydrochloric acid (purity 36%, 0.9mol) are added into a 2L three-mouth bottle, stirring is started, the temperature of the system is raised to 40 ℃, 340g of hydrogen peroxide (purity 30%, 3mol) is added dropwise after about 1h, and the temperature of the system is controlled to be 75 ℃ after the dropwise addition, and the reaction is carried out for 3.5 h. And (3) stopping the reaction when the heat preservation is finished and the residual material of the central control tembotrione is less than 0.2%, then adding sodium sulfite to destroy hydrogen peroxide, and then performing negative pressure desolventizing to obtain M1 and M6 crude products. To the crude product, 750g of water and 85g of sodium hydroxide (96% pure, 2.04mol) were added to make M1 and M6 into the corresponding salts, followed by extraction with 200mL of dichloroethane to remove impurities, and the aqueous phases obtained by separation were acidified with 10% dilute hydrochloric acid to separate M1 and M6; when the mixture is acidified to a pH value of 4.3, a large amount of products are separated out, and 68.5g of pure tembotrione metabolite M1 product is obtained through filtration, water washing and drying, the quantitative content is 99.0 percent, and the yield is 35.5 percent; further acidifying until pH is 3.5, separating out a small amount of solid, filtering, washing with water, and oven drying to obtain 9.7g mixture of cyclanone metabolite M1/M6, and purifying again after accumulation; and then, when the pH value is further acidified to be 1.7, a large amount of products are separated out, and 110.4g of pure product of the tembotrione metabolite M6, with the quantitative content of 98.9% and the yield of 52.5%, is obtained through filtration, washing and drying.
Example 16
A method for preparing a tembotrione metabolite comprises the following specific steps:
267g of tembotrione technical material (purity 99%, 0.6mol), 700mL of acetonitrile, 200mL of DMSO and 243g of concentrated hydrochloric acid (purity 36%, 2.4mol) are added into a 2L three-mouth bottle, stirring is started, the temperature of the system is raised to 40 ℃, 115.2g of peroxyacetic acid (purity 99%, 1.5mol) is added dropwise after about 1h, and the temperature of the system is controlled to 40 ℃ after the dropwise addition, and the reaction is carried out for 7.5 h. And (3) stopping the reaction when the heat preservation is finished and the residual material of the central control tembotrione is less than 0.2%, then adding sodium sulfite to destroy peroxyacetic acid, and then performing negative pressure desolventizing to obtain M1 and M6 crude products. To the crude product, 750g of water and 100g of sodium hydroxide (96%, 2.4mol) were added to make M1 and M6 into the corresponding salts, followed by extraction with 200mL of dichloroethane to remove impurities, and the aqueous phases obtained by separation were acidified with 10% dilute hydrochloric acid to separate M1 and M6; when the mixture is acidified to a pH value of 4.5, a large amount of products are separated out, and 38.6g of pure tembotrione metabolite M1 product is obtained through filtration, water washing and drying, the quantitative content is 98.9 percent, and the yield is 20.0 percent; further acidifying until pH is 3.5, separating out a small amount of solid, filtering, washing with water, and oven drying to obtain 11.2g mixture of cyclanone metabolite M1/M6, and purifying again after accumulation; and then, when the pH value is further acidified to be 2, a large amount of products are separated out, and 125.8g of pure product of the tembotrione metabolite M6, with the quantitative content of 99.0 percent and the yield of 59.9 percent, are obtained through filtration, washing and drying.
The applicant states that the present invention is illustrated by the above examples to the preparation method of the cyclic sulfone metabolite of the present invention, but the present invention is not limited to the above examples, i.e., it does not mean that the present invention must be implemented by the above examples. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (10)
1. A method for preparing a cyclic sultone metabolite, comprising: reacting the tembotrione, an oxidant and an auxiliary agent to obtain a tembotrione metabolite M1 and a tembotrione metabolite M6; the auxiliary agent is an acidic compound or an alkaline compound; the reaction formula is as follows:
2. the production method according to claim 1, wherein the oxidizing agent is a peroxide-based oxidizing agent;
preferably, the peroxide oxidant comprises any one of hydrogen peroxide, peroxyacetic acid, peroxytrifluoroacetic acid, peroxybenzoic acid, 3-chloroperoxybenzoic acid or peroxysulfuric acid or a combination of at least two of the hydrogen peroxide, the peroxyacetic acid, the peroxytrifluoroacetic acid, the peroxybenzoic acid and the peroxysulfuric acid;
preferably, the molar ratio of the tembotrione to the oxidant is 1 (1.5-5).
3. The preparation method of the compound of claim 1 or 2, wherein the auxiliary is an acidic compound, and the molar ratio of the tembotrione to the auxiliary is 1 (1.5-4);
preferably, the acidic compound comprises any one of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, formic acid or phosphoric acid or a combination of at least two thereof;
preferably, the auxiliary agent is an alkaline compound, and the molar ratio of the tembotrione to the auxiliary agent is 1 (1.5-5);
preferably, the basic compound comprises any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate or a combination of at least two thereof;
preferably, the auxiliary agent is any one or a combination of at least two of sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate, and the molar ratio of the auxiliary agent to the tembotrione is (3-5): 1;
preferably, the auxiliary agent is sodium carbonate and/or potassium carbonate, and the molar ratio of the auxiliary agent to the tembotrione is (1.5-2.5): 1.
4. The production method according to any one of claims 1 to 3, wherein the reaction is carried out in the presence of a solvent;
preferably, the solvent is selected from any one of water, methanol, ethanol, isopropanol, acetonitrile, dimethylformamide, dimethylacetamide or dimethylsulfoxide or a combination of at least two thereof;
preferably, the dosage of the solvent is 600-1500 mL based on 1mol of the tembotrione;
preferably, the reaction temperature is 30-90 ℃, and more preferably 40-50 ℃;
preferably, the reaction time is 3-8 h, and further preferably 4-6 h.
5. The preparation method according to any one of claims 1 to 4, further comprising the step of separating a product after the reaction is completed;
preferably, the auxiliary is an acidic compound, and the method for separating comprises the following steps: adding a reducing agent into the reaction product to consume the oxidizing agent, then carrying out salt forming reaction with an alkaline substance, and acidifying the generated salt until the pH value of the system is 4.5-5 to obtain a tembotrione metabolite M1; continuously acidifying until the pH value of the system is less than or equal to 2 to obtain a tembotrione metabolite M6;
preferably, the reducing agent comprises sodium sulfite;
preferably, the method also comprises a desolventizing step after the oxidant is consumed;
preferably, the alkaline substance comprises any one or a combination of at least two of sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate;
preferably, the molar ratio of the alkaline substance to the tembotrione is (3-4): 1;
preferably, the salt formation reaction is carried out in an aqueous solution;
preferably, the acidifying agent comprises any one of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, formic acid or phosphoric acid, or a combination of at least two thereof;
preferably, acidifying until the pH value of the system is 3.5-4 to obtain a mixture of a tembotrione metabolite M1/M6;
preferably, the auxiliary agent is an alkaline compound, and the separation method comprises the following steps: adding a reducing agent into the reaction product to consume the oxidizing agent, then acidifying until the pH value of the system is 3.5-4 to obtain a mixture of a cyclic sulfoketone metabolite M1/M6, and continuously acidifying until the pH value of the system is less than or equal to 2 to obtain a cyclic sulfoketone metabolite M6;
preferably, the acidifying agent comprises any one of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, formic acid or phosphoric acid or a combination of at least two thereof.
6. The preparation method according to any one of claims 1 to 5, which specifically comprises: reacting the tembotrione, the peroxide oxidant and the auxiliary agent in a solvent at 30-90 ℃ for 3-8 h, and separating the obtained crude product to obtain a tembotrione metabolite M1 and a tembotrione metabolite M6; the molar ratio of the tembotrione to the oxidant is 1 (1.5-5);
the auxiliary agent is an acidic compound, and the molar ratio of the tembotrione to the auxiliary agent is 1 (1.5-4); the separation method comprises the following steps: adding a reducing agent into the reaction product to consume the oxidizing agent, then carrying out salt-forming reaction with an alkaline substance, and acidifying the generated salt until the pH value of the system is 4.5-5 to obtain a tembotrione metabolite M1; continuously acidifying until the pH value of the system is 3.5-4 to obtain a mixture of a tembotrione metabolite M1/M6; then acidifying until the pH value of the system is less than or equal to 2 to obtain a tembotrione metabolite M6;
the auxiliary agent is an alkaline compound, and the molar ratio of the tembotrione to the auxiliary agent is 1 (1.5-5); the separation method comprises the following steps: adding a reducing agent into the reaction product to consume the oxidizing agent, and then acidifying until the pH value of the system is 3.5-4 to obtain a mixture of a cyclanone metabolite M1/M6; continuously acidifying until the pH value of the system is less than or equal to 2 to obtain the tembotrione metabolite M6.
7. A preparation method of a tembotrione metabolite M7 is characterized by comprising the following steps: reacting a raw material of a cyclic sulfoketone metabolite M1 with a methylating reagent to obtain a cyclic sulfoketone metabolite M7; the reaction formula is as follows:
wherein M is selected from H, Na or K.
8. The method of claim 7, wherein the methylating agent comprises any one of dimethyl sulfate, methyl iodide, methyl bromide or methyl chloride or a combination of at least two thereof;
preferably, the molar ratio of the raw material of the tembotrione metabolite M1 to the methylating agent is 1 (1-5);
preferably, the methylation reagent is dimethyl sulfate and/or methyl iodide, and the molar ratio of the methylation reagent to the raw material of the cyclic sultone metabolite M1 is (1-2): 1;
preferably, the methylation reagent is methyl bromide and/or methyl chloride, and the molar ratio of the methylation reagent to the raw material of the tembotrione metabolite M1 is (1.5-5): 1;
preferably, the reaction is carried out in the presence of a solvent;
preferably, the solvent comprises any one of dichloroethane, toluene, acetonitrile, dimethylformamide, dimethylacetamide, or dimethylsulfoxide, or a combination of at least two thereof;
preferably, the dosage of the solvent is 500-1500 mL based on 1mol of the raw material of the tembotrione metabolite M1;
preferably, the reaction temperature is 50-150 ℃, and further preferably 60-80 ℃;
preferably, the reaction time is 6-10 h, and more preferably 7-8 h.
9. The method according to claim 7 or 8, wherein the reaction further comprises a post-treatment of the product after completion of the reaction;
preferably, the post-treatment comprises desolventizing, recrystallizing and washing;
preferably, the agent for recrystallization comprises methanol;
preferably, the temperature of recrystallization is-5 to 10 ℃;
preferably, the cyclic sulfoketone metabolite M1 raw material is prepared by the preparation method of any one of claims 1-6.
10. The preparation method according to any one of claims 7 to 9, characterized by specifically comprising the steps of: reacting a raw material of a cyclic sulfoketone metabolite M1 with a methylating agent in a solvent at 50-150 ℃ for 6-10 h, and desolventizing, recrystallizing and washing an obtained crude product to obtain the cyclic sulfoketone metabolite M7;
the methylation reagent is dimethyl sulfate, and the molar ratio of the methylation reagent to the raw material of the cyclic sulfoketone metabolite M1 is (1-2): 1;
the methylation reagent is any one or combination of at least two of methyl iodide, methyl bromide or methyl chloride, and the molar ratio of the methylation reagent to the raw material of the cyclic sultone metabolite M1 is (1.5-5): 1.
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| CN109678767A (en) * | 2018-12-27 | 2019-04-26 | 浙江中山化工集团股份有限公司 | A kind of synthesis technology of herbicide tembotrions |
| CN109761787A (en) * | 2017-11-09 | 2019-05-17 | 山东润博生物科技有限公司 | The preparation method of the chloro- 2 bromo toluene of 3,6- bis- and the preparation method of dicamba |
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| CN102942474A (en) * | 2012-11-26 | 2013-02-27 | 江苏扬农化工股份有限公司 | Synthetic process of herbicide dicamba |
| CN106008290A (en) * | 2016-05-16 | 2016-10-12 | 安徽久易农业股份有限公司 | Method for preparing tembotrions |
| CN109761787A (en) * | 2017-11-09 | 2019-05-17 | 山东润博生物科技有限公司 | The preparation method of the chloro- 2 bromo toluene of 3,6- bis- and the preparation method of dicamba |
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