CN118146096A - 2, 2-Dimethyl-5- (4-chlorobenzyl) cyclopentanone derivative and preparation method thereof - Google Patents

2, 2-Dimethyl-5- (4-chlorobenzyl) cyclopentanone derivative and preparation method thereof Download PDF

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CN118146096A
CN118146096A CN202311539955.XA CN202311539955A CN118146096A CN 118146096 A CN118146096 A CN 118146096A CN 202311539955 A CN202311539955 A CN 202311539955A CN 118146096 A CN118146096 A CN 118146096A
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chlorobenzyl
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赵金浩
于斌
章浩楠
张东来
杨梓枫
程敬丽
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Zhejiang University ZJU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • 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
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

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Abstract

The invention belongs to the technical field of pesticide preparation, and particularly relates to a 2, 2-dimethyl-5- (4-chlorobenzyl) cyclopentanone derivative and a preparation method thereof, and application of the derivative and the derivative in synthesis of a bactericidal metconazole intermediate. The invention discloses a 2, 2-dimethyl-5- (4-chlorobenzyl) cyclopentanone derivative, which has a structural general formula shown in a formula IV: IV:

Description

2, 2-Dimethyl-5- (4-chlorobenzyl) cyclopentanone derivative and preparation method thereof
Technical Field
The invention belongs to the technical field of pesticide preparation, and particularly relates to a2, 2-dimethyl-5- (4-chlorobenzyl) cyclopentanone derivative and a preparation method thereof, and application of the derivative and the derivative in synthesis of a bactericidal metconazole intermediate.
Background
Metconazole, also known as metconazole, chemical name: 5- (4-chlorophenyl) -2, 2-dimethyl-1- (1H-1, 2, 4-triazol-1-ylmethyl) cyclopentanol, common name: metazole. The product is triazole bactericide developed by the chemical company of Wuluping in Japan in the 90 th century, and is an ergosterol synthesis inhibitor. The metconazole has the characteristics of novel structure, wide sterilization spectrum, high systemic property, low toxicity to non-target organisms, high sterilization activity and the like, and has the protection and treatment effects. Is mainly used for preventing and treating wheat scab, leaf rust, corn rust, soybean rust, rapeseed sclerotium disease and the like, and has wide market application prospect.
2, 2-Dimethyl-5- (4-chlorobenzyl) cyclopentanone is taken as an important intermediate for synthesizing metconazole, cyclopentanone (Res. Chem. Intermediate. 2017,43, 6293-6298) or diethyl adipate (pesticide, 2017,56,478-479; pesticide, 2012,51,413-415; pesticide, 2019,58 (11): 792-795) is taken as a starting material, the synthesis steps are long, multiple methylation is needed, and the synthesis process cost is high; US 6344580B1 uses isobutyronitrile as a starting material, a metallic lithium reagent is used for reacting with bromochloropropane, and sodium cyanide is substituted to obtain a key intermediate 2, 2-dimethyl dinitrile, but the use condition of the lithium reagent in the reaction process is severe, and certain safety, environmental and management hidden hazards exist in the use of sodium cyanide, and the reaction formula is as follows:
The patent CN 107365262B and the patent CN 112592275A take isobutyrate as raw materials, sodium cyanide is still required to be used in the second reaction, production safety and management risks exist, and the disposal of sodium cyanide-containing wastewater brought by production is troublesome, and the reaction formula is as follows:
Disclosure of Invention
The invention aims to provide a2, 2-dimethyl-5- (4-chlorobenzyl) cyclopentanone derivative and a preparation method thereof.
In order to solve the problems, the invention provides a 2, 2-dimethyl-5- (4-chlorobenzyl) cyclopentanone derivative, which has a structural general formula shown in a formula IV:
IV：
R is a C1-C6 alkyl substituent or hydrogen;
x is oxygen (R is C1-C6 alkyl substituent), nitrogen (R is hydrogen);
The alkyl is a linear or branched alkyl; the alkyl group itself or as part of another substituent is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl and isomers thereof, the isomers thereof preferably being selected from isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl or tert-pentyl and the like.
As an improvement of the 2, 2-dimethyl-5- (4-chlorobenzyl) cyclopentanone derivative IV of the present invention, R is preferably: methyl, isopropyl, isobutyl, tert-butyl; x is preferably: oxygen.
The invention also provides a synthetic method of the 2, 2-dimethyl-5- (4-chlorobenzyl) cyclopentanone derivative IV, which comprises the following specific routes:
Wherein R 1 and R represent saturated or unsaturated alkyl substituents; r 1 is a C1-C6 alkyl substituent, preferably methyl, isopropyl, isobutyl, tert-butyl; r is a C1-C6 alkyl substituent or hydrogen, preferably: methyl, isopropyl, isobutyl, tert-butyl; x is oxygen, nitrogen, preferably oxygen; l is chlorine, bromine, iodine, preferably bromine.
The method comprises the following steps:
A. preparation of intermediate II:
under the low temperature condition, dissolving a raw material isobutyric acid ester derivative I in an anhydrous aprotic organic solvent to obtain a raw material solution; dropwise adding an organic lithium reagent into the solution I, and stirring at a constant temperature; dropwise adding a halogenated compound (VI) and carrying out substitution reaction under the heat preservation condition; post-treating the reaction product to obtain intermediate valerate II;
the reaction temperature of the substitution reaction is-40-0 ℃; the reaction time is 1-5 hours;
the aprotic organic solvent is selected from petroleum ether, n-hexane, cyclohexane, diethyl ether, 1, 2-dimethoxyethane, tetrahydrofuran or 2-methyltetrahydrofuran;
the organic lithium reagent is selected from butyl lithium, isopropyl lithium, methyl lithium, diisopropyl lithium amide or di (trimethylsilyl) lithium amide and the like;
R 1 is a C1-C6 alkyl substituent; preferably, it is: methyl, isopropyl, isobutyl, tert-butyl;
l is halogen chlorine, bromine or iodine; preferably, it is: bromine;
x, R are defined above, preferably substituents are defined above;
The molar ratio of the dosage of the isobutyric acid ester derivative I to the organic lithium reagent is 1:1.1-2.2; the molar ratio of the dosage of the isobutyric acid ester derivative I to the halide is 1:0.9-2.1;
B. preparation of intermediate III:
Dissolving the intermediate II in an aprotic organic solvent, adding alkali metal alkoxide, and heating and refluxing for reaction (the temperature of the heating reaction is preferably 60-130 ℃), wherein low-boiling-point substances are removed during the refluxing reaction; after the reflux reaction is finished, carrying out post-treatment to obtain a compound III;
the reaction time is 0.5-10 hours; the molar ratio of the using amount of the intermediate II to the alkali metal alkoxide is 1:1.1-2.2;
The aprotic organic solvent is selected from acetone, toluene, ethylbenzene, xylene, trimethylbenzene, ethylene glycol dimethyl ether, dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran and the like, and preferably toluene, xylene, trimethylbenzene, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran or 2-methyltetrahydrofuran and the like; the alkali metal alkoxide is selected from potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium isobutanol, sodium tert-butoxide and the like;
x, R are defined as above, preferably substituents are defined as above;
C. Preparation of intermediate IV:
dissolving the intermediate III in an aprotic organic solvent, and adding alkali metal salt to react for 1+/-0.2 hours at the temperature of 100-130 ℃; then dropwise adding 4-chlorobenzyl chloride, heating and refluxing (the reaction temperature is preferably 50-120 ℃), removing low-boiling-point substances during the refluxing reaction, and carrying out aftertreatment after the refluxing reaction is finished to obtain an intermediate IV;
the heating reflux reaction time is 0.5-15 hours; the molar ratio of the using amount of the intermediate III to the alkali metal salt is 1:1.05-2.3; the mol ratio of the using amount of the intermediate III to the 4-chlorobenzyl chloride is 1:0.9-1.3;
The aprotic organic solvent is selected from acetone, toluene, ethylbenzene, xylene, trimethylbenzene, ethylene glycol dimethyl ether, dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran and the like, and preferably toluene, xylene, trimethylbenzene, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran or 2-methyltetrahydrofuran and the like; the alkali metal salt is selected from sodium carbonate, potassium carbonate, sodium hydride, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium isobutanol, sodium tert-butoxide, sodium hydride, potassium hydride or lithium hydride, etc.
As an improvement of the synthetic method of the 2, 2-dimethyl-5- (4-chlorobenzyl) cyclopentanone derivative IV of the present invention:
In the step A: monitoring the progress of the reaction by Gas Chromatography (GC);
the post-treatment of the step A is as follows: after the reaction is finished, adding water to quench the reaction, regulating the pH to be neutral by dilute hydrochloric acid, layering, and recovering the aprotic organic solvent from the organic layer by reduced pressure distillation to obtain a product II;
The post-treatment of the step B is as follows: cooling to room temperature after the reaction is completed, adding water to quench the reaction, regulating the pH to be neutral by dilute hydrochloric acid, layering, and distilling an organic layer under reduced pressure to recover a solvent to obtain a compound III;
The post-treatment of the step C is as follows: cooling to room temperature after the reaction is completed, adding water to quench the reaction, layering, and distilling the organic layer under reduced pressure to recover the solvent to obtain an intermediate IV.
The invention also provides a synthesis method of the 2, 2-dimethyl-5- (4-chlor-yl) cyclopentanone (V), which utilizes the 2, 2-dimethyl-5- (4-chlorbenzyl) cyclopentanone derivative IV,
The reaction route is as follows:
preparation of intermediate V:
Dissolving the intermediate IV in mixed acid, heating and refluxing (the reaction temperature is preferably 40-120 ℃), and carrying out post-treatment after the reaction is finished to obtain a target product V;
The heating reflux reaction time is 0.5-10 hours; the mixed acid is at least one of glacial acetic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, nitric acid, hydrobromic acid, phosphoric acid, methanesulfonic acid and p-toluenesulfonic acid (one or more mixed acids with the concentration of 10-100 percent can be selected), and the dosage of the mixed acid is 0.5-20 times of the mole of the intermediate IV.
The invention develops a synthetic route of 2, 2-dimethyl-5- (4-chlorobenzyl) cyclopentanone derivative, namely 2, 2-dimethyl-5- (4-chlorobenzyl) cyclopentanone intermediate through a large number of experiments and scheme optimization based on earlier stage research and route exploration.
The synthesis method of the invention can reduce the production cost, simplify the reaction route, improve the preparation efficiency, avoid the production, environment and management risks brought by the use of sodium cyanide, reduce the wastewater treatment risks and steps, and lead the industrialized production and the operation to be simpler and more convenient.
Specifically, the synthesis method of the 2, 2-dimethyl-5- (4-chlorobenzyl) cyclopentanone derivative (IV) comprises the following steps:
A. preparation of Compound II:
Under the protection of N 2 gas, cooling to low temperature, dissolving isobutyrate (I) in anhydrous aprotic solvent, dropwise adding an organic lithium reagent into the solution of I, and stirring under heat preservation; then adding the halogenated compound (VI) dropwise, and reacting at a constant temperature. Monitoring the reaction progress by utilizing Gas Chromatography (GC), adding water to quench after the raw materials are reacted, regulating the pH to be neutral by dilute hydrochloric acid, layering, recovering an aprotic solvent by reduced pressure distillation of an organic layer, and obtaining a product II by reduced pressure distillation;
The reaction temperature of the substitution reaction is-78-0 ℃, preferably-40-0 ℃; the reaction time is 1 to 20 hours, preferably 1 to 5 hours; the aprotic organic solvent is preferably selected from petroleum ether, n-hexane, cyclohexane, diethyl ether, 1, 2-dimethoxyethane, tetrahydrofuran or 2-methyltetrahydrofuran, etc.; the organolithium reagent is preferably selected from butyllithium, isopropyllithium, methyllithium, diisopropyllithium amide, lithium bis (trimethylsilyl) amide, and the like; r 1 and R are C1-C6 alkyl substituents, preferably methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl; x is oxygen, nitrogen, preferably oxygen; l is selected from halogen chlorine, bromine, iodine, preferably bromine; the molar ratio of the dosage of the isobutyrate (I) to the organic lithium reagent is 1:1.1-2.2; the molar ratio of the amount of the I to the halide is 1:0.9-2.1.
B. Preparation of Compound III:
dissolving II in an aprotic organic solvent, adding alkali metal alkoxide, heating and refluxing, removing low-boiling substances during the reflux, cooling after the reaction is completed, adding water for quenching reaction, regulating pH to be neutral by dilute hydrochloric acid, layering, and distilling an organic layer under reduced pressure to recover the solvent to obtain a compound III;
The reaction temperature of the ring closing reaction is 20-220 ℃, preferably 60-130 ℃; the reaction time is 0.5 to 10 hours, preferably 2 to 8 hours; the aprotic organic solvent is selected from acetone, toluene, ethylbenzene, xylene, trimethylbenzene, ethylene glycol dimethyl ether, dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran and the like, and preferably toluene, xylene, trimethylbenzene, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran or 2-methyltetrahydrofuran and the like; the alkali metal alkoxide is selected from potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium isobutanol, sodium tert-butoxide and the like; further, the molar ratio of the amount of II to the alkali metal alkoxide is 1:1.1-2.2.
C. preparation of Compound IV:
Dissolving III in an aprotic organic solvent, adding alkali metal salt, dropwise adding 4-chlorobenzyl chloride, heating and refluxing, removing low-boiling substances during the process, cooling after the reaction is completed, adding water for quenching reaction, layering, and distilling an organic layer under reduced pressure to recover the solvent to obtain a target substance IV;
The reaction temperature of the reaction is 20-150 ℃, preferably 50-120 ℃; the reaction time is 0.5 to 15 hours, preferably 2 to 8 hours; the aprotic organic solvent is selected from acetone, toluene, ethylbenzene, xylene, trimethylbenzene, ethylene glycol dimethyl ether, dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran and the like, and preferably toluene, xylene, trimethylbenzene, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran or 2-methyltetrahydrofuran and the like; the alkali metal salt is selected from sodium carbonate, potassium carbonate, sodium hydride, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium isobutanol, sodium tert-butoxide, sodium hydride, potassium hydride or lithium hydride, etc.; further, the molar ratio of the usage amount of III to alkali metal salt is 1:1.05-2.3; the mol ratio of the dosage of III to the 4-chlorobenzyl chloride is 1:0.9-1.3.
Use of compounds of formula (IV) for the synthesis of 2, 2-dimethyl-5- (4-chloro) cyclopentanone (V)
Dissolving IV in mixed acid, heating and refluxing, cooling after the reaction is completed, adding water to quench the reaction, layering, and distilling an organic layer under reduced pressure to recover a solvent to obtain a compound V;
The reaction temperature of the reaction is 50-200 ℃, preferably 60-140 ℃; the reaction time is 0.5 to 10 hours, preferably 2 to 8 hours; the mixed acid is preferably glacial acetic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, nitric acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid and the like or one or more mixed acids thereof; the concentration of the mixed acid can be 10% -100%, preferably 20% -80%, and the acid dosage is generally 0.5-20 times, preferably 1-10 times of the IV molar ratio.
The invention has the following beneficial effects:
Firstly, compared with the background technology, the content of the obtained 2, 2-dimethyl-5- (4-chlor) cyclopentanone derivative (IV) is more than or equal to 95 percent, and the method can be directly used for synthesizing a bactericide metconazole intermediate (V), and provides an alternative scheme for safely preparing the 2, 2-dimethyl-5- (4-chlorobenzyl) cyclopentanone (V). Secondly, the preparation method of the invention obtains the key intermediate 2, 2-dimethyl-cyclopentanone derivative in two steps, shortens the reaction steps and improves the preparation efficiency. Thirdly, cyanide with safety hazard is avoided in the reaction process, and the safety of production, environment and management is improved. Fourth, the preparation method provided by the invention is suitable for industrial mass production and has good economic benefit.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto.
Example 1 preparation of intermediate valerate ii:
scheme 1.1 preparation of 6- (tert-butyl) 1-isobutyl 2, 2-dimethyl adipate
Under the protection of N 2 gas, 14.4 g (100 mmol) of isobutyl isobutyrate is dissolved in a three-neck round bottom flask which is filled with 80 mL of anhydrous tetrahydrofuran and 250mL of tetrahydrofuran, the mixture is cooled to-20 ℃ and evenly stirred, 55 mL (110 mmol) of N-hexane solution of lithium diisopropylamide is dropwise added into the system in 30-60 minutes, and the mixture is subjected to heat preservation reaction for 0.5 hour at-20 ℃;23 g (105 mmol) of tert-butyl 4-bromobutyrate was then added dropwise over 15-30 minutes, and the reaction was continued at-20℃for 2 hours after completion of the dropwise addition.
At this time, the GC monitors the reaction progress to find that the raw materials are completely reacted, 50 g of water is dripped into the reaction kettle, the pH is adjusted to be neutral by 2M hydrochloric acid, the reaction kettle is layered, and after the solvent (tetrahydrofuran and n-hexane) is recovered by normal pressure distillation of an upper organic layer, 26 g of 2, 2-dimethyl adipic acid 6- (tert-butyl) 1-isobutyl ester is obtained by reduced pressure distillation, and the yield is 92%.
The gas phase detection method comprises the following steps: sample inlet temperature: 250 ℃; the FID detector temperature is 250 ℃; capillary column SE-54; programming temperature: the temperature was maintained at 50℃for 1 minute, after which the temperature was raised to 240℃at a rate of 15℃per minute, and maintained at 240℃for 6 minutes.
Scheme 1.2 preparation of 6- (tert-butyl) 1-methyl 2, 2-dimethyl adipate
Under the protection of N 2 gas, 14 g (137 mmol) of methyl isobutyrate is dissolved in a three-neck round bottom flask which is filled with 80 mL of anhydrous tetrahydrofuran and 250mL of three-neck round bottom flask, cooled to-20 ℃ and evenly stirred, 75 mL (150 mmol) of N-hexane solution of lithium diisopropylamide is added dropwise in 15-30 minutes, and the mixture is reacted for 0.5 hour at-20 ℃; 28 g (130 mmol) of tert-butyl 4-bromobutyrate was added dropwise over 15-30 min, and the reaction was continued at-20℃for 2 hours after completion of the dropwise addition.
At this time, the GC monitors the reaction progress to find that the raw materials are completely reacted, 50 g of water is dripped into the reaction kettle, the pH is regulated to be neutral by 2M hydrochloric acid, the reaction kettle is layered, the organic layer is distilled under normal pressure to recover the solvent, and then the reduced pressure distillation is carried out to obtain 30.4 g of the product 2, 2-dimethyl adipic acid 6- (tert-butyl) 1-methyl ester, the yield is obtained 91％.1H NMR(400MHz,CDCl3)δ3.65(s,1H),2.18(m,2H),1.51(m,4H),1.43(s,9H),1.17(d,J＝2.9Hz,6H).
Example 2 preparation of intermediate III:
scheme 2.1 preparation of 3, 3-dimethyl-2-oxocyclopentane-1-carboxylic acid methyl ester
10 G (50 mmol) of dimethyl 2, 2-dimethyl adipate was dissolved in a 250 ml round bottom flask containing 150ml of toluene, 2.8g (54 mmol) of sodium methoxide was added, the temperature was raised to 100 to 130℃and the reaction was heated to reflux for 5 hours, during which low boiling substances were removed (i.e., during the reflux, the low boiling substances were discharged from the reaction system from the water separator). GC detects that the raw material (namely, the intermediate (II)) is less than or equal to 2 percent, the reaction is cooled to room temperature after the completion of the reaction, 50 milliliters of water is added, the pH value is regulated to be neutral by 2M hydrochloric acid, the layers are separated, the organic solvent positioned at the upper layer is distilled and recovered under reduced pressure, and the remainder is 7.2 grams of 3, 3-dimethyl-2-oxo cyclopentane-1-methyl formate, and the yield is 86％.1H NMR(400MHz,CDCl3)δ3.74(s,3H),3.26(t,J＝9.1Hz,1H),2.39–2.11(m,2H),1.99–1.68(m,3H),1.09(s,3H),1.08(s,3H).
Example 2.2 3, 3-dimethyl-2-oxocyclopentane-1-carboxylic acid isobutyl ester
14.3 G (50 mmol) of diisobutyl 2, 2-dimethylbenzoate are dissolved in a 150 ml round-bottomed flask containing 50 ml of toluene, 5.3g (55 mmol) of sodium isobutanol are added, the temperature is raised to 100-130℃and the reaction is carried out under reflux for 6 hours, during which time the low boilers are removed. GC detects that the raw material is less than or equal to 2 percent, the reaction is cooled to room temperature after the completion, 50 milliliters of water is added, the pH value is regulated to be neutral by 2M hydrochloric acid, the layers are separated, the organic solvent positioned at the upper layer is distilled and recovered under reduced pressure, and the remainder is 8.8 grams of 3, 3-dimethyl-2-oxo cyclopentane-1-isobutyl formate, and the yield is 83％.1H NMR(400MHz,CDCl3)δ3.96–3.81(m,2H),3.22(t,J＝9.0Hz,1H),2.32–2.13(m,2H),2.02–1.85(m,2H),1.82–1.63(m,1H),1.06(s,3H),1.05(s,3H),0.90(d,J＝6.8Hz,6H).
Example 3 preparation of intermediate IV:
Scheme 3.1 preparation of 1- (4-chlorobenzyl) -3, 3-dimethyl-2-oxocyclopentane-1-carboxylic acid isobutyl ester
21 G (100 mmol) of 3, 3-dimethyl-2-oxocyclopentane-1-carboxylic acid isobutyl ester were dissolved in a 250 ml round bottom flask containing 150 ml of toluene, 6.5g (120 mmol) of sodium methoxide was added, the temperature was raised to 100-130℃and the reaction was carried out for 1 hour, 16g (100 mmol) of 4-chlorobenzyl chloride was added dropwise over 15-30 minutes and the reaction was heated under reflux for 4 hours. GC detects that the raw material (the intermediate (III)) is less than or equal to 2 percent, the reaction is cooled to room temperature after the completion, 50 milliliters of water is added, the layers are separated, the organic solvent positioned at the upper layer is distilled and recovered under reduced pressure, and the remainder is 29 grams of 1- (4-chlorobenzyl) -3, 3-dimethyl-2-oxo cyclopentane-1-carboxylic acid isobutyl ester, and the yield is 88 percent.
Scheme 3.2 preparation of 1- (4-chlorobenzyl) -3, 3-dimethyl-2-oxocyclopentane-1-carboxylic acid isobutyl ester
21 G (100 mmol) of isobutyl 3, 3-dimethyl-2-oxocyclopentane-1-carboxylate are dissolved in a 250 ml round bottom flask containing 75 ml of tetrahydrofuran, 5g (130 mmol) of sodium hydride are added in portions at 0℃and the reaction is carried out for 0.5 h at room temperature, 19g (120 mmol) of 4-chlorobenzyl chloride are added dropwise over 15-30 min, the temperature is raised to 40-70℃and the reflux reaction is carried out for 10 h. GC detects that the raw material (the intermediate (III)) is less than or equal to 5 percent, the reaction is cooled to room temperature after the completion, 80 milliliters of water is added, the layers are separated, the organic solvent positioned at the upper layer is distilled and recovered under reduced pressure, and the remainder is 33 grams of 1- (4-chlorobenzyl) -3, 3-dimethyl-2-oxo cyclopentane-1-carboxylic acid isobutyl ester, and the yield is 91 percent (area normalization) ).1H NMR(400MHz,CDCl3)δ7.21(d,J＝7.4Hz,2H),7.06(d,J＝7.7Hz,2H),3.89(d,J＝6.4Hz,2H),3.13(s,2H),2.35–2.26(m,1H),2.00–1.74(m,3H),1.50–1.38(m,1H),1.09(s,3H),0.91(d,J＝6.7Hz,6H),0.68(s,3H).
Example 4 preparation of intermediate V:
34 g (100 mmol) of 1- (4-chlorobenzyl) -3, 3-dimethyl-2-oxocyclopentane-1-carboxylic acid isobutyl ester was dissolved in a mixed acid solution containing 120 ml of glacial acetic acid and 50ml of 12.5% concentrated sulfuric acid, and the temperature was raised to 90-120℃and the reaction was heated under reflux for 10 hours. GC detects that the raw material (the Intermediate (IV)) is less than or equal to 5 percent, the reaction is cooled to room temperature after completion, the reaction is poured into 150 milliliters of ice water, 150 milliliters of ethyl acetate is added, the layers are separated, the organic solvent positioned on the upper layer is distilled and recovered under reduced pressure, and the remainder is 22 grams of 2, 2-dimethyl-5- (4-chlorobenzyl) cyclopentanone, and the yield is 93％.1H NMR(400MHz,CDCl3)δ7.23(d,J＝8.4Hz,2H),7.09(d,J＝8.4Hz,2H),3.06(dd,J＝13.8,4.4Hz,1H),2.62(dd,J＝13.9,8.7Hz,1H),2.47–2.39(m,1H),1.99–1.49(m,4H),1.08(s,3H),0.86(s,3H).
Example 5
19.4 G (0.24 mol) of hydrogen bromide gas was slowly introduced into a 100 ml round bottom flask containing 17.2 g (0.2 mol) of gamma-butyrolactone at room temperature, and the temperature was raised to 40℃and the reaction was stirred for 1 hour; 9.8 g (0.21 mol) of absolute ethanol was added and the reaction stirred for 4 hours. GC detects that the raw material is less than or equal to 2 percent, the reaction is cooled to room temperature after the completion, 50 milliliters of water is added, the mixture is fully oscillated, the mixture is stood for layering, the organic phase at the lower layer is washed by saturated sodium bicarbonate solution, the mixture is stood for layering, the lower organic phase is taken for reduced pressure distillation to recover the solvent, the remainder is 35 grams of ethyl 4-bromobutyrate, and the yield is 93.5 percent.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims (6)

1. A2, 2-dimethyl-5- (4-chlorobenzyl) cyclopentanone derivative characterized in that: has a structural general formula shown in a formula IV:
R is a C1-C6 alkyl substituent or hydrogen;
X is oxygen or nitrogen;
The alkyl is a linear or branched alkyl; the alkyl group itself or as part of another substituent is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl and isomers thereof selected from isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl or tert-pentyl.
2. 2, 2-Dimethyl-5- (4-chlorobenzyl) cyclopentanone derivative according to claim 1, characterized in that: r is preferably: methyl, isopropyl, isobutyl, tert-butyl; x is preferably: oxygen.
3. A process for the synthesis of 2, 2-dimethyl-5- (4-chlorobenzyl) cyclopentanone derivatives according to claim 1 or 2, characterized in that:
The route is as follows:
The method comprises the following steps:
A. preparation of intermediate II:
under the low temperature condition, dissolving a raw material isobutyric acid ester derivative I in an anhydrous aprotic organic solvent to obtain a raw material solution; dropwise adding an organic lithium reagent into the solution I, and stirring at a constant temperature; dropwise adding a halogenated compound (VI) and carrying out substitution reaction under the heat preservation condition; post-treating the reaction product to obtain intermediate valerate II;
the reaction temperature of the substitution reaction is-40-0 ℃; the reaction time is 1-5 hours;
the aprotic organic solvent is selected from petroleum ether, n-hexane, cyclohexane, diethyl ether, 1, 2-dimethoxyethane, tetrahydrofuran or 2-methyltetrahydrofuran;
The organolithium reagent is selected from butyllithium, isopropyllithium, methyllithium, diisopropyllithium amide or lithium bis (trimethylsilyl) amide;
R 1 is a C1-C6 alkyl substituent;
L is halogen chlorine, bromine or iodine;
x, R is defined in claim 1,
The molar ratio of the dosage of the isobutyric acid ester derivative I to the organic lithium reagent is 1:1.1-2.2; the molar ratio of the dosage of the isobutyric acid ester derivative I to the halide is 1:0.9-2.1;
B. preparation of intermediate III:
dissolving the intermediate II in an aprotic organic solvent, adding alkali metal alkoxide, heating and refluxing for reaction, and removing low-boiling substances during the refluxing reaction; after the reflux reaction is finished, carrying out post-treatment to obtain a compound III;
the reaction time is 0.5-10 hours; the molar ratio of the using amount of the intermediate II to the alkali metal alkoxide is 1:1.1-2.2;
The aprotic organic solvent is selected from acetone, toluene, ethylbenzene, xylene, trimethylbenzene, ethylene glycol dimethyl ether, dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and 2-methyltetrahydrofuran, and the alkali metal alkoxide is selected from potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium isobutanoxide or sodium tert-butoxide;
X, R is defined in claim 1;
C. Preparation of intermediate IV:
Dissolving the intermediate III in an aprotic organic solvent, and adding alkali metal salt to react for 1+/-0.2 hours at the temperature of 100-130 ℃; then dropwise adding 4-chlorobenzyl chloride, heating and refluxing, removing low-boiling substances during the reflux reaction, and performing post-treatment after the reflux reaction is completed to obtain an intermediate IV;
The reaction time is 0.5-15 hours; the molar ratio of the using amount of the intermediate III to the alkali metal salt is 1:1.05-2.3; the mol ratio of the using amount of the intermediate III to the 4-chlorobenzyl chloride is 1:0.9-1.3;
The aprotic organic solvent is selected from acetone, toluene, ethylbenzene, xylene, trimethylbenzene, ethylene glycol dimethyl ether, dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and 2-methyltetrahydrofuran, and the alkali metal salt is selected from sodium carbonate, potassium carbonate, sodium hydride, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium isobutanoxide, sodium tert-butoxide, sodium hydride, potassium hydride or lithium hydride.
4. A process for the synthesis of 2, 2-dimethyl-5- (4-chlorobenzyl) cyclopentanone derivative IV according to claim 3, characterized in that:
In step A: r 1 is preferably: methyl, isopropyl, isobutyl, tert-butyl; l is preferably: bromine; x, R preferred substituents are as defined in claim 2;
in step B: the aprotic organic solvent is preferably toluene, xylene, trimethylbenzene, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran or 2-methyltetrahydrofuran; x, R preferred substituents are as defined in claim 2;
In step C: the aprotic organic solvent is preferably toluene, xylene, trimethylbenzene, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran or 2-methyltetrahydrofuran.
5. The method for synthesizing 2, 2-dimethyl-5- (4-chlorobenzyl) cyclopentanone derivative IV according to claim 3 or 4, characterized in that:
In the step A: monitoring the progress of the reaction by Gas Chromatography (GC);
the post-treatment of the step A is as follows: after the reaction is finished, adding water to quench the reaction, regulating the pH to be neutral by dilute hydrochloric acid, layering, and recovering the aprotic organic solvent from the organic layer by reduced pressure distillation to obtain a product II;
The post-treatment of the step B is as follows: cooling to room temperature after the reaction is completed, adding water to quench the reaction, regulating the pH to be neutral by dilute hydrochloric acid, layering, and distilling an organic layer under reduced pressure to recover a solvent to obtain a compound III;
The post-treatment of the step C is as follows: cooling to room temperature after the reaction is completed, adding water to quench the reaction, layering, and distilling the organic layer under reduced pressure to recover the solvent to obtain an intermediate IV.
The synthetic method of 6.2,2-dimethyl-5- (4-chloro) cyclopentanone (V) is characterized in that: use of a2, 2-dimethyl-5- (4-chlorobenzyl) cyclopentanone derivative IV as described in claim 1 or 2,
The reaction route is as follows:
preparation of intermediate V:
Dissolving the intermediate IV in mixed acid, heating and refluxing, and performing post-treatment after the reaction is finished to obtain a target product V;
The reaction time is 0.5-10 hours; the mixed acid is at least one of glacial acetic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, nitric acid, hydrobromic acid, phosphoric acid, methanesulfonic acid and p-toluenesulfonic acid; the dosage of the mixed acid is 0.5 to 20 times of the mole of the intermediate IV.
CN202311539955.XA 2023-11-20 2023-11-20 2, 2-Dimethyl-5- (4-chlorobenzyl) cyclopentanone derivative and preparation method thereof Pending CN118146096A (en)

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