CN116874358A - Clean synthesis method of prothioconazole intermediate 2-chlorobenzyl- (1-chlorocyclopropyl) ketone - Google Patents
Clean synthesis method of prothioconazole intermediate 2-chlorobenzyl- (1-chlorocyclopropyl) ketone Download PDFInfo
- Publication number
- CN116874358A CN116874358A CN202310374722.2A CN202310374722A CN116874358A CN 116874358 A CN116874358 A CN 116874358A CN 202310374722 A CN202310374722 A CN 202310374722A CN 116874358 A CN116874358 A CN 116874358A
- Authority
- CN
- China
- Prior art keywords
- chlorobenzyl
- chlorocyclopropyl
- ketone
- synthesis method
- catalyst
- 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.)
- Granted
Links
- 238000001308 synthesis method Methods 0.000 title claims abstract description 25
- FDLYBVBKEKAILV-UHFFFAOYSA-N bis[1-chloro-2-[(2-chlorophenyl)methyl]cyclopropyl]methanone Chemical compound ClC1=CC=CC=C1CC1C(C(=O)C2(Cl)C(C2)CC=2C(=CC=CC=2)Cl)(Cl)C1 FDLYBVBKEKAILV-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 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 14
- 239000005825 Prothioconazole Substances 0.000 title claims abstract description 14
- -1 o-chloro benzyl halide Chemical class 0.000 claims abstract description 20
- 239000002994 raw material Substances 0.000 claims abstract description 20
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- 238000007259 addition reaction Methods 0.000 claims abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 7
- 229910052751 metal Inorganic materials 0.000 claims abstract description 6
- 239000002184 metal Substances 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 15
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- 229910052740 iodine Inorganic materials 0.000 claims description 8
- 229910052749 magnesium Inorganic materials 0.000 claims description 8
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 7
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 7
- 229940045803 cuprous chloride Drugs 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 229910052725 zinc Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- GFPIZDSAQDWLJE-UHFFFAOYSA-N methyl 1-chlorocyclopropane-1-carboxylate Chemical compound COC(=O)C1(Cl)CC1 GFPIZDSAQDWLJE-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- BASMANVIUSSIIM-UHFFFAOYSA-N 1-chloro-2-(chloromethyl)benzene Chemical compound ClCC1=CC=CC=C1Cl BASMANVIUSSIIM-UHFFFAOYSA-N 0.000 description 11
- 239000007818 Grignard reagent Substances 0.000 description 8
- 150000004795 grignard reagents Chemical class 0.000 description 8
- 239000003513 alkali Substances 0.000 description 7
- 239000011777 magnesium Substances 0.000 description 7
- 239000002253 acid Substances 0.000 description 6
- NHWQMJMIYICNBP-UHFFFAOYSA-N 2-chlorobenzonitrile Chemical compound ClC1=CC=CC=C1C#N NHWQMJMIYICNBP-UHFFFAOYSA-N 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 230000000977 initiatory effect Effects 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000005191 phase separation Methods 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 238000006114 decarboxylation reaction Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 125000002560 nitrile group Chemical group 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- CDLNYRRFZAUVIP-UHFFFAOYSA-N 1-chlorocyclopropane-1-carbonyl chloride Chemical compound ClC(=O)C1(Cl)CC1 CDLNYRRFZAUVIP-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000003899 bactericide agent Substances 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 229940106681 chloroacetic acid Drugs 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- KHBWTRFWQROKJZ-UHFFFAOYSA-N methyl 2-(2-chlorophenyl)acetate Chemical compound COC(=O)CC1=CC=CC=C1Cl KHBWTRFWQROKJZ-UHFFFAOYSA-N 0.000 description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- MPLGPKQCMGHDRP-UHFFFAOYSA-N 1-chlorocyclopropane-1-carboxamide Chemical compound NC(=O)C1(Cl)CC1 MPLGPKQCMGHDRP-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000031320 Teratogenesis Diseases 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 1
- 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000001965 increasing effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 231100000299 mutagenicity Toxicity 0.000 description 1
- 230000007886 mutagenicity Effects 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- QPDUQKTYZRXRBC-UHFFFAOYSA-N triazole-4-thione Chemical compound S=C1C=NN=N1 QPDUQKTYZRXRBC-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a clean synthesis method of prothioconazole intermediate 2-chlorobenzyl- (1-chlorocyclopropyl) ketone. The synthesis method takes o-chloro benzyl halide metal reagent and 1-chlorocyclopropane-1-methyl formate as main raw materials, and obtains the prothioconazole intermediate 2-chlorobenzyl- (1-chlorocyclopropyl) ketone through direct addition reaction in the presence of a catalyst. The synthesis method has the advantages of cheap and easily obtained raw materials, cleanness, high efficiency, higher atom economy and high industrial production value.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a clean synthesis method of a prothioconazole intermediate 2-chlorobenzyl- (1-chlorocyclopropyl) ketone.
Background
2-chlorobenzyl- (1-chlorocyclopropyl) ketone is an important intermediate of the bactericide prothioconazole, and the molecular structure is shown as follows:
the prothioconazole belongs to a triazolethione bactericide, has broad sterilization spectrum, has excellent protection, treatment and eradication characteristics, and has obvious yield increasing effect. The prothioconazole has low toxicity, no teratogenesis and mutagenicity, is safe to people and environment, and has good market prospect. 2-chlorobenzyl- (1-chlorocyclopropyl) ketone is an important intermediate of prothioconazole, and various synthesis methods are reported in the related art.
The synthesis method reported in Chinese patent CN109369549 is to take 1-chlorocyclopropane-1-methyl formate and o-chlorophenyl acetic acid methyl ester as raw materials, condense the raw materials under the conditions of strong alkali sodium hydride, sodium alkoxide or sodium hydroxide as alkali, and the like, then heat up and reflux the raw materials in a large amount of acid, and hydrolyze and deacidify the raw materials to obtain 2-chlorobenzyl- (1-chlorocyclopropyl) ketone, as shown in the following figure. The synthesis method has low atom economy, and the ester group in the o-chlorophenylacetic acid methyl ester is removed by hydrolysis and decarboxylation; and a large amount of waste salt is generated by using strong alkali and a large amount of strong acid, and the synthetic method has no green cleaning.
The synthesis method reported in Chinese patent CN106928041 is to take 2-chlorobenzonitrile and 1-chlorocyclopropyl formate as raw materials, condense the raw materials under the conditions of strong alkali sodium alkoxide, sodium amide and the like to obtain nitrile metal salt, acidify the nitrile metal salt to obtain a ketonitrile intermediate, hydrolyze and deacidify the nitrile group in a large amount of strong acid to obtain 2-chlorobenzyl- (1-chlorocyclopropyl) ketone, and the chart is shown below. The synthesis method has no atomic economy, the nitrile group in the raw material 2-chlorobenzonitrile is removed by a large amount of acid hydrolysis decarboxylation, a large amount of waste salt is also generated, and the synthesis method has no atomic economy and is not environment-friendly.
The synthesis method reported in U.S. patent No. 5146001 uses o-chlorobenzyl chloride and 1-chlorocyclopropyl formyl chloride as raw materials, the o-chlorobenzyl chloride and zinc powder are prepared into an organic zinc reagent, and the organic zinc reagent and the 1-chlorocyclopropyl formyl chloride are coupled under the condition of a noble metal palladium catalyst to obtain a target product 2-chlorobenzyl- (1-chlorocyclopropyl) ketone.
Cao Yanlei (modern pesticide, 2016,15 (6), 31-32) on the basis of the above-mentioned U.S. patent, the raw material 1-chlorocyclopropylcarboxamide is first condensed with dimethylamine to obtain 1-chloro-N, N-dimethylcyclopropylcarboxamide, and then added with the formative reagent of o-chlorobenzyl chloride to obtain 2-chlorobenzyl- (1-chlorocyclopropyl) ketone. The synthesis method has the advantages of complicated preparation of the raw material 1-chloro-N, N-dimethylcyclopropylcarboxamide, low synthesis yield and unsuitability for industrial production.
The synthesis method reported in Chinese patent CN109651298 is to take o-chlorobenzonitrile and cyclopropylcarboxylate as raw materials, add the raw materials under the actions of strong alkali sodium alkoxide, sodium amide, sodium hydride and the like to obtain a nitrile intermediate, and then hydrolyze and decarboxylate the nitrile intermediate under the condition of strong acid to obtain the target molecule 2-chlorobenzyl- (1-chlorocyclopropyl) ketone. The nitrile group in the raw material o-chlorobenzonitrile is also hydrolyzed and decarboxylated in strong alkali and strong acid to be removed, so that the method has no atom economy, poor chlorination selectivity and no industrial value.
The synthesis method reported in Chinese patent CN115124440 is that o-chloroacetic acid is taken as a raw material, after acyl chlorination, the o-chloroacetic acid is condensed with dimethyl malonate to obtain an ester intermediate, then the ester intermediate reacts with dihaloethane to obtain a cyclopropyl ester intermediate, then hydrolysis and decarboxylation are carried out under strong alkali and strong acid conditions to obtain a cyclopropyl carbonyl intermediate, and then chlorine is chlorinated to obtain 2-chlorobenzyl- (1-chlorocyclopropyl) ketone.
Therefore, the method for synthesizing the 2-chlorobenzyl- (1-chlorocyclopropyl) ketone, which has the advantages of simple and smooth process, low cost, high atom economy, cleanness and environmental protection and is suitable for industrialized mass production, is always the focus of research in the field.
Disclosure of Invention
The invention aims to overcome the defects, and provides a clean synthesis method of 2-chlorobenzyl- (1-chlorocyclopropyl) ketone based on the prior art.
The invention provides a clean synthesis method of a prothioconazole intermediate 2-chlorobenzyl- (1-chlorocyclopropyl) ketone, which is characterized in that an o-chlorobenzyl halide metal reagent and 1-chlorocyclopropane-1-methyl formate are used as main raw materials, and the direct addition reaction is carried out in the presence of a catalyst to obtain the prothioconazole intermediate 2-chlorobenzyl- (1-chlorocyclopropyl) ketone. The synthetic process route is as follows:
wherein M is Mg or Zn; x is Cl, br, I.
According to the synthesis method, M is Mg, zn, preferably Mg; x is Cl, br, I, preferably Cl.
According to the synthesis method, the catalyst is selected from cuprous chloride, cuprous bromide and cuprous iodide in the presence of the catalyst; cuprous chloride is preferred.
According to the above synthesis method, the mass ratio of the catalyst to the methyl 1-chlorocyclopropane-1-carboxylate is 0.01-0.1:1, preferably 0.01-0.05:1.
According to the above synthesis method, the solvent for the addition reaction is selected from one or more of toluene, tetrahydrofuran, and 2-methyltetrahydrofuran, preferably toluene.
According to the above synthesis method, the reaction temperature of the addition reaction is 0 to 20 ℃, preferably 0 to 5 ℃; the reaction time is 1 to 5 hours, preferably 1 to 2 hours.
Compared with the synthesis process provided in the prior art, the synthesis process provided by the invention has the following advantages:
1) The method has the advantages that the p-chlorobenzyl halide metal reagent and the 1-chlorocyclopropane-1-methyl formate are adopted as raw materials, and the target product is obtained through direct addition under the condition of a catalyst, and the synthesis method has high atom economy and is environment-friendly;
2) The invention has the advantages of cheap and easily obtained synthetic raw materials, mild reaction conditions and high yield, and is suitable for industrial scale-up production.
Drawings
FIG. 1 is a clean synthetic route pattern of prothioconazole intermediate 2-chlorobenzyl- (1-chlorocyclopropyl) ketone according to the invention
Detailed Description
The production process according to the invention is further described below with reference to specific examples of implementation in order to better understand the invention.
Example 1
Fresh magnesium chips (8.2 g, 0.34 mol), a small amount of iodine and 50g of 2-methyltetrahydrofuran are added into a reaction bottle, after the temperature is raised to 35-40 ℃ for initiation, a mixed solution of 200g of 2-methyltetrahydrofuran and 50g (0.31 mol) of o-chlorobenzyl chloride is dropwise added, and the mixture is completely dropwise stirred for 1h under heat preservation, so as to obtain a Grignard reagent of o-chlorobenzyl chloride for later use.
41.5g (0.31 mol) of 1-chlorocyclopropane-1-methyl formate, 0.41g of catalyst cuprous chloride and 80g of toluene are added into another reaction bottle, the temperature is reduced to 0-5 ℃ by stirring, the Grignard reagent is slowly added dropwise, the reaction is carried out for 1h after the dropwise addition, the saturated ammonium chloride aqueous solution is added after the conventional post treatment, the phase separation is carried out, and the organic phase is decompressed and concentrated to obtain 72.3g of target product 2-chlorobenzyl- (1-chlorocyclopropyl) ketone, the content of which is 93.8%, and the yield is 95.6%.
Example 2
Fresh magnesium chips (8.2 g, 0.34 mol), a small amount of iodine and 50g of 2-methyltetrahydrofuran are added into a reaction bottle, after the temperature is raised to 35-40 ℃ for initiation, a mixed solution of 200g of 2-methyltetrahydrofuran and 50g (0.31 mol) of o-chlorobenzyl chloride is dropwise added, and the mixture is completely dropwise stirred for 1h under heat preservation, so as to obtain a Grignard reagent of o-chlorobenzyl chloride for later use.
41.5g (0.31 mol) of 1-chlorocyclopropane-1-methyl formate and 80g of 2-methyltetrahydrofuran as catalysts are added into another reaction bottle, the temperature is reduced to 0-5 ℃ by stirring, the Grignard reagent is slowly added dropwise, the reaction is carried out for 1h after the dropwise addition, the saturated ammonium chloride aqueous solution is added after the conventional post treatment, the phase separation is carried out, the organic phase is concentrated under reduced pressure to obtain 69.6g of target product 2-chlorobenzyl- (1-chlorocyclopropyl) ketone, the content is 94.3%, and the yield is 92.5%.
Example 3
Fresh magnesium chips (8.2 g, 0.34 mol), a small amount of iodine and 50g of 2-methyltetrahydrofuran are added into a reaction bottle, after the temperature is raised to 35-40 ℃ for initiation, a mixed solution of 200g of 2-methyltetrahydrofuran and 50g (0.31 mol) of o-chlorobenzyl chloride is dropwise added, and the mixture is completely dropwise stirred for 1h under heat preservation, so as to obtain a Grignard reagent of o-chlorobenzyl chloride for later use.
41.5g (0.31 mol) of 1-chlorocyclopropane-1-methyl formate, 0.41g of catalyst cuprous chloride and 80g of tetrahydrofuran are added into another reaction bottle, the temperature is reduced to 0-5 ℃ by stirring, the Grignard reagent is slowly added dropwise, the reaction is carried out for 1h after the dropwise addition, the saturated ammonium chloride aqueous solution is added for conventional post-treatment, phase separation is carried out, and the organic phase is decompressed and concentrated to obtain 68.9g of target product 2-chlorobenzyl- (1-chlorocyclopropyl) ketone with the content of 93.2 percent and the yield of 90.5 percent.
Example 4
Fresh magnesium chips (8.2 g, 0.34 mol), a small amount of iodine and 50g of 2-methyltetrahydrofuran are added into a reaction bottle, after the temperature is raised to 35-40 ℃ for initiation, a mixed solution of 200g of 2-methyltetrahydrofuran and 50g (0.31 mol) of o-chlorobenzyl chloride is dropwise added, and the mixture is completely dropwise stirred for 1h under heat preservation, so as to obtain a Grignard reagent of o-chlorobenzyl chloride for later use.
41.5g (0.31 mol) of 1-chlorocyclopropane-1-methyl formate, 2.1g of catalyst cuprous chloride and 80g of toluene are added into another reaction bottle, the temperature is reduced to 0-5 ℃ by stirring, the Grignard reagent is slowly added dropwise, the reaction is carried out for 1h after the dropwise addition, the saturated ammonium chloride aqueous solution is added after the conventional post treatment, the phase separation is carried out, and the organic phase is decompressed and concentrated to obtain 73.0g of target product 2-chlorobenzyl- (1-chlorocyclopropyl) ketone, the content of which is 93.6%, and the yield is 96.3%.
The above description of the specific embodiments of the present invention is given by way of example only, and the present invention is not limited to the above-described specific embodiments. Any equivalent modifications and substitutions for the present invention are also within the scope of the present invention.
Claims (6)
1. A clean synthesis method of a prothioconazole intermediate 2-chlorobenzyl- (1-chlorocyclopropyl) ketone is characterized in that an o-chlorobenzyl halide metal reagent and 1-chlorocyclopropane-1-methyl formate are used as main raw materials, and the direct addition reaction is carried out in the presence of a catalyst to obtain the prothioconazole intermediate 2-chlorobenzyl- (1-chlorocyclopropyl) ketone. The synthetic process route is as follows:
wherein M is Mg or Zn; x is Cl, br, I.
2. The method of claim 1, wherein M is Mg, zn, preferably Mg; x is Cl, br, I, preferably Cl.
3. The method of synthesis according to claim 1, wherein the catalyst is selected from the group consisting of cuprous chloride, cuprous bromide, and cuprous iodide in the presence of a catalyst; cuprous chloride is preferred.
4. The synthesis according to claim 1, wherein the mass ratio of catalyst to methyl 1-chlorocyclopropane-1-carboxylate is 0.01-0.1:1, preferably 0.01-0.05:1.
5. The synthetic method according to claim 1, wherein the solvent for the addition reaction is selected from one or more of toluene, tetrahydrofuran, 2-methyltetrahydrofuran, preferably toluene.
6. The synthesis according to claim 1, wherein the reaction temperature of the addition reaction is between 0 and 20 ℃, preferably between 0 and 5 ℃; the reaction time is 1 to 5 hours, preferably 1 to 2 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310374722.2A CN116874358B (en) | 2023-04-10 | 2023-04-10 | Synthesis method of prothioconazole intermediate 2-chlorobenzyl- (1-chlorocyclopropyl) ketone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310374722.2A CN116874358B (en) | 2023-04-10 | 2023-04-10 | Synthesis method of prothioconazole intermediate 2-chlorobenzyl- (1-chlorocyclopropyl) ketone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116874358A true CN116874358A (en) | 2023-10-13 |
| CN116874358B CN116874358B (en) | 2024-08-02 |
Family
ID=88255586
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310374722.2A Active CN116874358B (en) | 2023-04-10 | 2023-04-10 | Synthesis method of prothioconazole intermediate 2-chlorobenzyl- (1-chlorocyclopropyl) ketone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116874358B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2025219897A1 (en) * | 2024-04-19 | 2025-10-23 | Adama Makhteshim Ltd. | Process for the preparation of prothioconazole intermediates |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5146001A (en) * | 1990-06-13 | 1992-09-08 | Bayer Aktiengesellschaft | Preparation of benzyl ketones and an oxirane |
| CN109369549A (en) * | 2018-12-29 | 2019-02-22 | 安徽久易农业股份有限公司 | A kind of preparation method of prothioconazoles |
-
2023
- 2023-04-10 CN CN202310374722.2A patent/CN116874358B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5146001A (en) * | 1990-06-13 | 1992-09-08 | Bayer Aktiengesellschaft | Preparation of benzyl ketones and an oxirane |
| CN109369549A (en) * | 2018-12-29 | 2019-02-22 | 安徽久易农业股份有限公司 | A kind of preparation method of prothioconazoles |
Non-Patent Citations (3)
| Title |
|---|
| 刘瑛 等: "2-氰基-4-甲基联苯的合成研究", 《化工时刊》, vol. 20, no. 9, 9 September 2006 (2006-09-09), pages 48 - 49 * |
| 唐利平 等: "丙硫菌唑中间体的工艺合成", 《化工进展》, vol. 34, no. 7, 5 July 2015 (2015-07-05), pages 1989 - 1992 * |
| 陆阳 等: "新型高效杀菌剂丙硫菌唑的合成研究", 《化工技术与开发》, vol. 38, no. 10, 15 October 2009 (2009-10-15), pages 21 - 24 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2025219897A1 (en) * | 2024-04-19 | 2025-10-23 | Adama Makhteshim Ltd. | Process for the preparation of prothioconazole intermediates |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116874358B (en) | 2024-08-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Takai et al. | Nucleophilic addition of organochromium reagents to carbonyl compounds | |
| CN116874358B (en) | Synthesis method of prothioconazole intermediate 2-chlorobenzyl- (1-chlorocyclopropyl) ketone | |
| CN114635145A (en) | Electrochemical preparation method of imide derivative | |
| Tan et al. | Novel carbonyl allylation mediated by SnCl2/Cu in water | |
| US20200207693A1 (en) | Method for synthesizing 2,3,5,6-tetrafluoro-4-methoxymethyl benzyl alcohol | |
| CN110117256B (en) | Synthesis method of bixafen | |
| Kagan et al. | Ferric chloride in ether. A convenient reagent for the conversion of epoxides into chlorohydrins | |
| CN107827735B (en) | Synthetic method of 2-hydroxy-3, 6-dichlorobenzoic acid | |
| CN113651837B (en) | Preparation method of 3, 3-trifluoropropanol | |
| Zhang et al. | PbCl2/Ga bimetal redox system-mediated carbon–carbon bond formation reactions between carbonyl compounds and ethyl trichloroacetate and iodoacetonitrile | |
| CN103012131A (en) | Method for preparing 4-acetoxy-2-methyl-2-butenal | |
| CN115490589B (en) | Synthesis method of sex attractant for potato tuber moth | |
| CN110092755B (en) | Process for producing pyraclostrobin | |
| CN111170837A (en) | Synthetic method of methyl ketone compound | |
| CN101941903B (en) | Method for producing 2-methyl-4-MCPA | |
| CN111170846A (en) | A kind of method for preparing 3,3-dimethyl-2-oxo-butyric acid | |
| JPH085823B2 (en) | Method for producing hexafluoroacetone or its hydrate | |
| JPH05140137A (en) | Intermediate for synthesizing halogenated hexane ring derivative, and its preparation | |
| CN108484347B (en) | Preparation method of cyclopropanation of terminal isoprene compound | |
| CN115286500B (en) | A preparation method and composition of acetoacetic acid, 6-ethylthio-3-heptene-2-one and intermediates thereof | |
| WO1988006151A1 (en) | A process for the preparation of pyrethroid type ester compounds | |
| CN113563287A (en) | Preparation method of epoxy caprylate and preparation method of melonal | |
| CN115246772B (en) | Preparation method of isobutyryl methyl acetate | |
| US20240217912A1 (en) | Method for preparing phenoxycarboxylate | |
| US4412082A (en) | Method for preparing 4-hydroxyphenylacetic acid |
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 |