CN115124440B - Preparation method of prothioconazole intermediate - Google Patents
Preparation method of prothioconazole intermediate Download PDFInfo
- Publication number
- CN115124440B CN115124440B CN202210735493.8A CN202210735493A CN115124440B CN 115124440 B CN115124440 B CN 115124440B CN 202210735493 A CN202210735493 A CN 202210735493A CN 115124440 B CN115124440 B CN 115124440B
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- reacting
- prothioconazole
- inorganic base
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 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 38
- 239000005825 Prothioconazole Substances 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 54
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 18
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 17
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 15
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 10
- 229940106681 chloroacetic acid Drugs 0.000 claims abstract description 10
- 239000000460 chlorine Chemical group 0.000 claims abstract description 8
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- 125000002252 acyl group Chemical group 0.000 claims abstract description 6
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 50
- 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 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 15
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- 238000004321 preservation Methods 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical group CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 239000012320 chlorinating reagent Substances 0.000 claims description 7
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 7
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 230000002140 halogenating effect Effects 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 claims description 2
- NPNPZTNLOVBDOC-UHFFFAOYSA-N 1,1-difluoroethane Chemical compound CC(F)F NPNPZTNLOVBDOC-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- ZFDLFHQAGYPRBY-UHFFFAOYSA-N chloro acetate Chemical compound CC(=O)OCl ZFDLFHQAGYPRBY-UHFFFAOYSA-N 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000007818 Grignard reagent Substances 0.000 abstract description 12
- 150000004795 grignard reagents Chemical class 0.000 abstract description 12
- 238000005888 cyclopropanation reaction Methods 0.000 abstract description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 abstract description 4
- 238000006114 decarboxylation reaction Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 3
- 229910052794 bromium Inorganic materials 0.000 abstract description 3
- 229910052731 fluorine Inorganic materials 0.000 abstract description 3
- 239000011737 fluorine Substances 0.000 abstract description 3
- 125000001153 fluoro group Chemical group F* 0.000 abstract description 3
- 239000011630 iodine Chemical group 0.000 abstract description 3
- 229910052740 iodine Chemical group 0.000 abstract description 3
- 230000007062 hydrolysis Effects 0.000 abstract description 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- -1 2-chloro-1-chlorocyclopropylethanone Chemical compound 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 241001530056 Athelia rolfsii Species 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 230000003301 hydrolyzing effect 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
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 1
- BASMANVIUSSIIM-UHFFFAOYSA-N 1-chloro-2-(chloromethyl)benzene Chemical compound ClCC1=CC=CC=C1Cl BASMANVIUSSIIM-UHFFFAOYSA-N 0.000 description 1
- CAXVRUHWRJPHLX-UHFFFAOYSA-N 2-(2-chlorophenyl)-1-cyclopropylethanone Chemical compound ClC1=CC=CC=C1CC(=O)C1CC1 CAXVRUHWRJPHLX-UHFFFAOYSA-N 0.000 description 1
- NHWQMJMIYICNBP-UHFFFAOYSA-N 2-chlorobenzonitrile Chemical compound ClC1=CC=CC=C1C#N NHWQMJMIYICNBP-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-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
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 241000221785 Erysiphales Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000000911 decarboxylating effect Effects 0.000 description 1
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical class [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- PKAHQJNJPDVTDP-UHFFFAOYSA-N methyl cyclopropanecarboxylate Chemical compound COC(=O)C1CC1 PKAHQJNJPDVTDP-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 238000007344 nucleophilic reaction Methods 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- WWTULTKUWBKVGV-UHFFFAOYSA-M potassium;3-methoxy-3-oxopropanoate Chemical compound [K+].COC(=O)CC([O-])=O WWTULTKUWBKVGV-UHFFFAOYSA-M 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C241/00—Preparation of compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C241/02—Preparation of hydrazines
-
- 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
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a prothioconazole intermediate, which comprises the following steps: (1) Subjecting o-chloroacetic acid to an acyl chlorination reaction to produce a compound I, wherein X is selected from fluorine, chlorine, bromine or iodine; (2) Reacting dimethyl malonate with an inorganic base to form a compound ii; (3) Reacting the compound I with the compound II to generate a compound III; (4) The compound III is subjected to cyclopropanation reaction to generate a compound IV, and then is subjected to hydrolysis decarboxylation reaction to generate a compound V; (5) And (3) performing chlorination reaction on the compound V to generate the prothioconazole intermediate. The preparation method avoids the use of Grignard reagent, does not need to be carried out under the harsh anhydrous and anaerobic condition, and reduces the potential safety hazard of production; the preparation method provided by the invention has the advantages that the raw materials used are low in price, the preparation cost of the prothioconazole intermediate is reduced, and the preparation method is suitable for industrial production.
Description
Technical Field
The invention particularly relates to a preparation method of a prothioconazole intermediate.
Background
The prothioconazole (prothioconazole) is a novel efficient spectral triazole fungicide developed by German Bayer company 1995, is mainly applied to cereal crops such as wheat and rice, and rape, peanut and beans, and has good control effects on powdery mildew, leaf rust, stripe rust, banded sclerotial blight, leaf spot, sclerotial blight and leaf streak. The synthesis of prothioconazole cannot bypass an important intermediate, and the chemical structural formula is as follows:
at present, three main methods for synthesizing prothioconazole intermediates are as follows:
One of them is disclosed in chinese patent CN110590499 a: in methyl tetrahydrofuran solution, 1 o-chlorochlorobenzene and magnesium generate Grignard reagent, and then nucleophilic reaction is carried out with 2-chloro-1-chlorocyclopropylethanone, thus obtaining an important intermediate of prothioconazole. The preparation method mainly has the following defects: (1) The Grignard reagent is needed for reaction, and is easy to be decomposed and exploded violently when meeting water and oxygen, and the reaction is more harsh under anhydrous and anaerobic conditions, thus being not beneficial to amplification experiments and safe production; (2) The method has high requirements on equipment, and certain potential safety hazards exist in the generation and storage of the Grignard reagent.
Second, as disclosed in patent US5146001 a: 1-chloro-2-chloromethylbenzene is used as a starting material to generate an organic zinc reagent (Grignard reagent) and then reacts with 1-chlorocyclopropane formyl chloride in a nucleophilic way to obtain the prothioconazole intermediate. The preparation method mainly has the following defects: (1) the method has the advantages of overlong steps and lower overall yield after being folded; (2) The Grignard reagent is needed in the reaction, the anhydrous and anaerobic condition is needed in the reaction, the reaction is more severe, and the amplification experiment and the safe production are not facilitated; (3) The method has high requirements on equipment, and certain potential safety hazards exist in the generation and storage of the Grignard reagent.
And thirdly, taking o-chlorobenzonitrile as a starting material, condensing with methyl cyclopropanecarboxylate to obtain an intermediate, hydrolyzing and decarboxylating, and finally introducing chlorine gas to obtain an important intermediate of prothioconazole. The preparation method mainly has the following defects: (1) The overall yield of the reaction is low (less than 50 percent), and the method is not suitable for industrial production; and (2) the raw materials are expensive and the production cost is high.
Disclosure of Invention
The invention aims to provide a preparation method of prothioconazole intermediate, which has low raw material price, does not need to use Grignard reagent and is suitable for industrial production.
In order to achieve the above purpose, the invention adopts the following technical scheme:
A method for preparing a prothioconazole intermediate, comprising the following steps: (1) The O-chloroacetic acid is subjected to acyl chlorination reaction to generate a compound I, wherein the structural formula of the compound I is The X is selected from fluorine, chlorine, bromine or iodine; (2) Reacting dimethyl malonate with an inorganic base to form a compound II of formula/>Wherein A is selected from sodium or potassium; (3) Reacting the compound I and the compound II to form a compound III, wherein the structural formula of the compound III is/>(4) The compound III is subjected to cyclopropanation reaction to generate a compound IV, and then is subjected to hydrolysis decarboxylation reaction to generate a compound V, wherein the structural formula of the compound IV is/>The structural formula of the compound V is/>(5) The compound V is subjected to chlorination reaction to generate the prothioconazole intermediate, and the structural formula of the prothioconazole intermediate is/>
Preferably, the step of reacting the compound I with the compound ii to form the compound iii comprises: reacting the compound II, alkali and magnesium chloride in the presence of an organic solvent, then adding the compound I into a reaction system for reaction, and then adding hydrochloric acid for reaction.
Further preferably, the specific step of reacting the compound I with the compound ii to form the compound iii comprises: and respectively adding the compound II, the organic solvent, the alkali and the magnesium chloride into a reactor, carrying out heat preservation reaction for 2-3 h at 15-25 ℃, then cooling to 0-10 ℃, adding the compound I in a dropwise manner, heating to 20-25 ℃ after the dropwise addition, carrying out heat preservation reaction for 16-17 h, then adding the hydrochloric acid, and heating to 40-50 ℃ for reaction for 1.5-2.5 h.
Still more preferably, the base is selected from triethylamine.
Still more preferably, the organic solvent in the step (3) includes one or more of acetonitrile, DMF (N, N-dimethylformamide), and methanol.
According to some preferred embodiments, the ratio of the mass of the compound II to the mass of the compound I is 1 (1.0-1.3), such as 1:1.0, 1:1.1, 1:1.2, 1:1.3, etc.
Further preferably, the feeding mass ratio of the compound II to the alkali to the magnesium chloride is 1.0: (0.9-1.7): (0.5 to 1.2), and further 1: (0.9-1.2): (0.5-0.7), for example 1:0.9:0.5, 1:1.0:0.5, 1:1.1:0.5, 1:1.2:0.5, 1:0.9:0.6, 1:1.0:0.6, 1:1.1:0.6, 1:0.9:0.7, 1:1.0:0.7, 1:1.1:0.7, etc.
Preferably, the step of cyclopropanation of said compound iii to compound iv comprises: reacting the compound III, dihaloethane including one or more of dichloroethane, difluoroethane, dibromoethane, and an inorganic base including potassium carbonate and/or sodium carbonate in the presence of an organic solvent.
Further preferably, in the step (4), the feeding mass ratio of the compound iii to the dihaloethane is 1: (0.5-1.5), e.g., 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:1, etc.
Further preferably, in the step (4), the feeding mass ratio of the compound iii to the inorganic base is 1: (0.4 to 1.1), for example, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, etc.
Preferably, the cyclopropanation reaction is carried out at a temperature of 65-75 ℃ for a time of 6-7 hours.
Preferably, the organic solvent used in the cyclopropanation reaction comprises one or more of acetonitrile, DMF, methanol.
Preferably, the specific steps of the hydrolytic decarboxylation reaction include: after the cyclopropanation reaction is finished, removing the organic solvent, then adding methanol, water and sodium hydroxide, reacting for 2-3 hours at 35-45 ℃, and after the reaction is finished, adding hydrochloric acid, heating to 40-50 ℃ and reacting for 1.5-2.5 hours.
Further preferably, the mass ratio of the compound III to the sodium hydroxide is 1: (0.2 to 0.5), for example, 1:0.2, 1:0.3, 1:0.4, 1:0.5, etc.
Preferably, the specific step of subjecting the o-chloroacetic acid to an acyl chlorination reaction to produce the compound I comprises: adding the o-chloroacetic acid and the phosphorus trichloride into a reactor, stirring, preserving the temperature at 25-35 ℃, and introducing a halogenating reagent to react for 3-4 hours; wherein the halogenating reagent is chlorine, and the feeding mass ratio of the o-chloroacetic acid to the phosphorus trichloride is 1: (0.5-1.2), e.g., 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, etc.
Preferably, the specific step of reacting said dimethyl malonate with said inorganic base to form said compound ii comprises: and respectively adding dimethyl malonate and an alcohol solvent into a reactor, preserving heat at 15-25 ℃, dropwise adding a mixed solution of the alcohol solvent and inorganic base, heating to 70-80 ℃ after the addition, carrying out reflux reaction, filtering while the mixture is hot, cooling the filtrate to 0-10 ℃, and separating out the compound II.
Further preferably, the alcohol solvent is one or more of methanol, ethanol, propanol.
Further preferably, in the step, the inorganic base is potassium hydroxide and/or sodium hydroxide, and the feeding mass ratio of the dimethyl malonate to the inorganic base is 1: (0.2 to 1.1), for example, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, etc.
Preferably, the specific step of subjecting said compound v to a chlorination reaction to produce said prothioconazole intermediate comprises: respectively adding the compound V and a chlorinating reagent into a reactor, and reacting for 6-7 h at 65-75 ℃ in a heat preservation way; wherein the chlorinating reagent is dichloroethane and/or chlorine gas, and the feeding mass ratio of the compound V to the chlorinating reagent is 1: (0.5 to 1.5), for example, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, etc.
Preferably, the prothioconazole intermediate is prepared under the protection of nitrogen.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
The preparation method avoids the use of Grignard reagent, does not need to be carried out under the harsh anhydrous and anaerobic condition, and reduces the potential safety hazard of production;
The preparation method provided by the invention has the advantages that the raw materials used are low in price, the preparation cost of the prothioconazole intermediate is reduced, and the preparation method is suitable for industrial production.
Detailed Description
According to the application, o-chloroacetic acid and dimethyl malonate are used as starting materials, and the prothioconazole intermediate is prepared through the reactions of acyl chlorination, condensation, decarboxylation, cyclopropanation, chlorination and the like. The scheme of the application is further discussed below.
According to some preferred embodiments, a method for preparing a prothioconazole intermediate, the method comprising the steps of:
(1) Under the protection of N 2, o-chloroacetic acid and phosphorus trichloride are added into a reactor, stirred, kept at 25-35 ℃ and introduced with a halogenating reagent for reaction for 3-4 hours, and a compound I is generated, wherein the structural formula of the compound I is X is selected from fluorine, chlorine, bromine or iodine;
(2) Under the protection of N 2, dimethyl malonate and an alcohol solvent are respectively added into a reactor, the temperature is kept at 15-25 ℃, a mixed solution of the alcohol solvent and inorganic alkali is dripped, after the addition is finished, the temperature is raised to 70-80 ℃, the reflux reaction is carried out while the mixture is hot, the filtrate is cooled to 0-10 ℃, a compound II is separated out, and the structural formula of the compound II is that Wherein A is selected from sodium or potassium;
(3) Under the protection of N 2, respectively adding a compound II, an organic solvent, alkali and magnesium chloride into a reactor, carrying out heat preservation reaction for 2-3 h at 15-25 ℃, then cooling to 0-10 ℃, adding a compound I in a dropwise manner, heating to 20-25 ℃ after the dropwise addition is finished, carrying out heat preservation reaction for 16-17 h, then adding hydrochloric acid, heating to 40-50 ℃ and carrying out reaction for 1.5-2.5 h, thereby generating a compound III, wherein the structural formula of the compound III is that
(4) Under the protection of N 2, the compound III, dihaloethane and inorganic base are reacted in the presence of organic solvent, the temperature is kept between 65 ℃ and 75 ℃, stirring reaction is carried out for 6 to 7 hours, after the reaction is finished, the organic solvent is removed, methanol, water and sodium hydroxide are added, stirring reaction is carried out for 2 to 3 hours at 35 ℃ to 45 ℃, hydrochloric acid is added after the reaction is finished, the temperature is increased to 40 ℃ to 50 ℃ for reaction for 1.5 to 2.5 hours, and the compound V is produced, wherein the structural formula of the compound V is
(5) Under the protection of N 2, respectively adding a compound V and a chlorinating reagent into a reactor, and carrying out heat preservation reaction for 6-7 h at 65-75 ℃ to obtain a prothioconazole intermediate, wherein the structural formula of the prothioconazole intermediate is
According to some specific and preferred embodiments, a reaction equation for a prothioconazole intermediate is as follows:
the scheme of the invention has at least the following specific advantages:
(1) The invention avoids the use of Grignard reagent (organic metal reagent), the reaction is not required to be carried out under the harsh conditions of no water and no oxygen, and the reaction condition is milder; compared with the high requirements of Grignard reagent on the reactor, the method has low requirements on the reactor; compared with the Grignard reagent which is easy to explode, the preparation method has high safety coefficient.
(2) The invention has low price and is easy to obtain, and the production cost of the prothioconazole intermediate is reduced.
(3) The preparation method of the prothioconazole intermediate has fewer steps and improves the yield compared with the prior art.
(4) The preparation method of the invention also has the advantages of less three wastes, short time and the like, and is especially suitable for industrial production.
The invention is further described below with reference to examples. The present invention is not limited to the following examples. The implementation conditions adopted in the embodiments can be further adjusted according to different requirements of specific use, and the implementation conditions which are not noted are conventional conditions in the industry. The technical features of the various embodiments of the present invention may be combined with each other as long as they do not collide with each other.
Unless otherwise specified, the yields in the examples below refer to molar yields.
Example 1
Under the protection of N 2, 17.0g of o-chloroacetic acid and 13.7g of phosphorus trichloride are sequentially added into a reaction bottle, stirred, kept at 25-35 ℃, slowly introduced with chlorine, after 3-4 hours, after the introduction reaction is finished, the solvent (phosphorus trichloride) is removed after the reaction is detected to be complete by GC (gas chromatography), and the reaction is directly carried out without purification.
HPLC (high performance liquid chromatography) showed compound I to be 95% pure with 97.3% yield.
Example 2
Under the protection of N 2, 13.2g of dimethyl malonate and 20g of methanol are sequentially added into a reaction bottle, the mixture solution of 20g of methanol and 5.6g of potassium hydroxide is slowly dripped at 15-25 ℃ under the heat preservation, the temperature is raised to 70-80 ℃ after the addition is completed for about 1.5-2 hours, the reflux reaction is carried out, the reaction byproduct dipotassium salt (filter residue) is filtered and removed while the reaction product is hot, the filtrate is cooled to 0-10 ℃, and the solid (compound II) is separated out, wherein the yield is 87.3%.
Example 3
Under the protection of N 2, 15.6g of potassium methyl malonate (compound II), 20g of acetonitrile, 16.2g of triethylamine and 9.5g of magnesium chloride are sequentially added into a reaction bottle, the temperature is kept at 15-25 ℃, stirring is carried out for 2-3 h, the temperature is reduced to 0-10 ℃, 18.8g of o-chlorobenzoyl acetyl chloride (compound I) is slowly added dropwise, the charging is completed after about 0.5-1 h, the temperature is raised to 20-25 ℃, the temperature is kept for 16-17 h, hydrochloric acid is added, the temperature is raised to 40-50 ℃ for 2h, water and ethyl acetate are added for extraction, the solvent is removed, and the direct reaction is carried out without purification.
HPLC showed 92% purity of compound iii with a total yield of 82.3%.
MS-EI(m/z,％):227(M++H+);265(M++K+)。
Example 4
Under the protection of N 2, 22.6g of 4- (2-chlorophenyl) -3-oxo-methyl butyrate (compound III), 14.5g of potassium carbonate, 20g of dichloroethane and 10g of acetonitrile are sequentially added into a reaction bottle, the temperature is kept at 65-75 ℃, stirring is carried out for 6-7 h, after the reaction is finished, the solvent is removed, 10g of methanol, 15g of water and 8.4g of sodium hydroxide are added, stirring is carried out for 2-3 h at 35-45 ℃, after the reaction is finished, 18g of concentrated hydrochloric acid is added, the temperature is raised to 40-50 ℃ for 2h, finally ethyl acetate is added for extraction, the solvent is removed, and the direct casting reaction is carried out without purification.
HPLC showed 93% purity of compound v with 85.1% yield.
MS-EI(m/z,％):195(M++H+);233(M++K+)。
Example 5
Under the protection of N 2, 19.4g of 2-chlorophenyl-1-cyclopropyl ethanone (compound V) and 20g of dichloroethane are sequentially added into a reaction bottle, chlorine is introduced, the reaction is carried out at 65-75 ℃ under stirring for 6-7 h, and after the reaction is finished, the solvent (dichloroethane) is removed, so that the target product (compound VI) is obtained.
HPLC showed compound VI to be 93% pure with a yield of 81.2%.
MS-EI(m/z,％):229(M++H+);227(M+-H+)。
The present invention has been described in detail with the purpose of enabling those skilled in the art to understand the contents of the present invention and to implement the same, but not to limit the scope of the present invention, and all equivalent changes or modifications made according to the spirit of the present invention should be included in the scope of the present invention.
Claims (8)
1. A method for preparing a prothioconazole intermediate, which is characterized by comprising the following steps:
(1) The O-chloroacetic acid is subjected to acyl chlorination reaction to generate a compound I, wherein the structural formula of the compound I is The X is selected from chlorine;
(2) Reacting dimethyl malonate with an inorganic base to form a compound II of the formula Wherein A is selected from sodium or potassium;
(3) Reacting the compound II, alkali and magnesium chloride in the presence of an organic solvent at 15-25 ℃ for 2-3 hours, then cooling to 0-10 ℃, adding the compound I into a reaction system, heating to 20-25 ℃, reacting for 16-17 hours at a temperature of 16-17 hours, then adding hydrochloric acid, and reacting for 1.5-2.5 hours at a temperature of 40-50 ℃ to obtain a compound III, wherein the structural formula of the compound III is that ；
(4) Reacting the compound III, dihaloethane and inorganic base for 6-7 h at 65-75 ℃ in the presence of an organic solvent to generate a compound IV, removing the organic solvent after the reaction is finished, adding methanol, water and sodium hydroxide, reacting for 2-3 h at 35-45 ℃, adding hydrochloric acid after the reaction is finished, heating to 40-50 ℃ and reacting for 1.5-2.5 h to generate a compound V, wherein the structural formula of the compound IV is thatThe structural formula of the compound V is/>；
(5) Respectively adding the compound V and a chlorinating reagent into a reactor, and carrying out heat preservation reaction for 6-7 hours at 65-75 ℃ to generate the prothioconazole intermediate, wherein the structural formula of the prothioconazole intermediate is as followsThe chlorinating agent is dichloroethane and/or chlorine gas.
2. The method for preparing the prothioconazole intermediate according to claim 1, wherein said compound I is added dropwise; and/or the number of the groups of groups,
The base is selected from triethylamine, and the organic solvent in the step (3) comprises one or more of acetonitrile, methanol and DMF; and/or the number of the groups of groups,
The feeding mass ratio of the compound II to the compound I is 1 (1.0-1.3), and the feeding mass ratio of the compound II to the alkali to the magnesium chloride is 1.0: (0.9 to 1.7): (0.5 to 1.2).
3. The method for producing prothioconazole intermediate according to claim 1, wherein said dihaloethane comprises one or more of dichloroethane, difluoroethane and dibromoethane, and said inorganic base in step (4) comprises potassium carbonate and/or sodium carbonate.
4. The method for preparing prothioconazole intermediate according to claim 1, wherein in said step (4), the feed mass ratio of said compound iii to said dihaloethane is 1: (0.5-1.5), wherein the feeding mass ratio of the compound III to the inorganic base is 1: (0.4-1.1); and/or the number of the groups of groups,
The organic solvent used in the step (4) comprises one or more of acetonitrile, DMF and methanol.
5. The method for preparing prothioconazole intermediate according to claim 1, wherein said specific step of subjecting said o-chloroacetic acid to an acyl chlorination reaction to produce said compound I comprises: adding the o-chloroacetic acid and the phosphorus trichloride into a reactor, stirring, preserving the temperature at 25-35 ℃, and introducing a halogenating reagent to react for 3-4 hours; wherein the halogenating reagent is chlorine, and the feeding mass ratio of the o-chloroacetic acid to the phosphorus trichloride is 1: (0.5 to 1.2).
6. The method for preparing prothioconazole intermediate according to claim 1, wherein said specific step of reacting dimethyl malonate with said inorganic base to form said compound ii comprises: respectively adding dimethyl malonate and an alcohol solvent into a reactor, preserving heat at 15-25 ℃, dropwise adding a mixed solution of the alcohol solvent and inorganic base, heating to 70-80 ℃ after the addition, carrying out reflux reaction, filtering while the mixture is hot, cooling the filtrate to 0-10 ℃, and separating out the compound II;
the alcohol solvent is one or more of methanol, ethanol and propanol;
The inorganic base is potassium hydroxide and/or sodium hydroxide, and the feeding mass ratio of the dimethyl malonate to the inorganic base is 1: (0.2 to 1.1).
7. The preparation method of the prothioconazole intermediate according to claim 1, wherein the feeding mass ratio of said compound v to said chlorinating agent is 1: (0.5 to 1.5).
8. The process for the preparation of prothioconazole intermediate according to any one of claims 1 to 7, wherein said prothioconazole intermediate is prepared under the protection of nitrogen.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210735493.8A CN115124440B (en) | 2022-06-27 | 2022-06-27 | Preparation method of prothioconazole intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210735493.8A CN115124440B (en) | 2022-06-27 | 2022-06-27 | Preparation method of prothioconazole intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115124440A CN115124440A (en) | 2022-09-30 |
| CN115124440B true CN115124440B (en) | 2024-05-31 |
Family
ID=83379044
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210735493.8A Active CN115124440B (en) | 2022-06-27 | 2022-06-27 | Preparation method of prothioconazole intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115124440B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102276436A (en) * | 2010-06-10 | 2011-12-14 | 浙江九洲药业股份有限公司 | Preparation method of aromatic cyclopropyl ketone compound and purpose |
| CN111205176A (en) * | 2020-01-14 | 2020-05-29 | 大连九信精细化工有限公司 | Synthetic method of 3, 5-dihalogen-2-pentanone |
| CN112010813A (en) * | 2020-09-18 | 2020-12-01 | 安徽久易农业股份有限公司 | Synthesis method and application of prothioconazole |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2012262174B2 (en) * | 2011-06-03 | 2016-12-01 | Wisconsin Alumni Research Foundation | (22E)-2-methylene-26,27-cyclo-22-dehydro-1alpha-hydroxy-19-norvitamin D3 derivatives |
-
2022
- 2022-06-27 CN CN202210735493.8A patent/CN115124440B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102276436A (en) * | 2010-06-10 | 2011-12-14 | 浙江九洲药业股份有限公司 | Preparation method of aromatic cyclopropyl ketone compound and purpose |
| CN111205176A (en) * | 2020-01-14 | 2020-05-29 | 大连九信精细化工有限公司 | Synthetic method of 3, 5-dihalogen-2-pentanone |
| CN112010813A (en) * | 2020-09-18 | 2020-12-01 | 安徽久易农业股份有限公司 | Synthesis method and application of prothioconazole |
Non-Patent Citations (2)
| Title |
|---|
| Dylan J. Abrams等.Donor−Acceptor−Acceptor 1,3-Bisdiazo Compounds: An Exploration of Synthesis and Stepwise Reactivity.《Org. Lett.》.2020,第22卷(第5期),1791–1795. * |
| Lakshmi Muthusubramanian等.CONVENIENT SYNTHESIS OF 1-ACETYL-2,2-DIMETHYL-3-ARYLCYCLOPROPANES.《Organic Preparations and Procedures International: The New Journal for Organic Synthesis》.2008,第40卷(第3期),第311-315页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115124440A (en) | 2022-09-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108409625B (en) | Preparation method of 2-pyrrolidone compound | |
| CN111574444A (en) | Preparation method of bedaquiline | |
| CN115417793A (en) | Method for preparing (E) -2-methyl-alpha-methoxyimino methyl phenylacetate | |
| CN113185455B (en) | Preparation method of 2-hydroxy-6-trifluoromethylpyridine | |
| CN115124440B (en) | Preparation method of prothioconazole intermediate | |
| CN112898152B (en) | Preparation method of ethoxy diethyl methylene malonate | |
| CN113620867B (en) | Synthesis method of fluopyram | |
| KR101894091B1 (en) | New method for preparation of chromanone derivatives | |
| CA2409853A1 (en) | Method for the production of trifluoroethoxy-substituted benzoic acids | |
| CN110872225A (en) | Preparation method of Barosavir intermediate | |
| CN117550981B (en) | Preparation method of 2-amino-5-fluoro acetophenone | |
| CN111217709A (en) | Preparation method of (1-fluorocyclopropyl) methylamine hydrochloride | |
| CA2502360C (en) | Process for producing acetylene compound | |
| CA2479643C (en) | Process for preparing alkyl 2,2-dichloro- or dibromophenylacetates | |
| CN114920794B (en) | Preparation method of abiraterone acetate serving as prostate cancer treatment drug | |
| CN117402044B (en) | Synthesis method of 1- (4-chlorophenyl) -2-cyclopropyl-1-acetone | |
| CN114195678A (en) | Intermediate, preparation method thereof and method for preparing 3-difluoromethyl-1-methylpyrazole-4-ethyl formate by using intermediate | |
| CA2867936C (en) | Industrial method for manufacturing high-purity methiozolin | |
| JP5000031B2 (en) | Method for producing aromatic-o-dialdehyde compound | |
| CN116425671A (en) | Synthesis method of 2-chloro-4- (trifluoromethyl) pyridine | |
| EP0064021B1 (en) | Method for synthesis of long-chain carboxylic acids and alcohols | |
| CN118598912A (en) | Preparation method of N-Boc-amidine triphenylphosphine | |
| WO2023082149A1 (en) | Process and intermediates for preparation of isofetamid | |
| CN116655601A (en) | Synthesis method of octreotide | |
| NO802139L (en) | OUTPUT CONNECTIONS FOR PREPARING MORPHINE DERIVATIVES, AND PROCEDURE FOR PREPARING OUTPUT |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |