A 2,2-dimethyl-5-(4-chlorobenzyl) cyclopentanone derivative and its preparation method

Abstract

The present invention belongs to the technical field of pesticide preparation, and specifically relates to 2,2-dimethyl-5-(4-chlorobenzyl) cyclopentanone derivatives and their preparation methods, and also relates to their applications in the synthesis of the fungicide metconazole intermediates. The present invention discloses a 2,2-dimethyl-5-(4-chlorobenzyl) cyclopentanone derivative, which has the structural general formula shown in Formula IV: IV: The present invention also simultaneously provides a synthesis method of the above-mentioned 2,2-dimethyl-5-(4-chlorobenzyl) cyclopentanone derivative IV. The synthesis method of the present invention can reduce production costs, simplify the reaction route, improve the preparation efficiency, avoid the production, environmental and management risks brought by the use of sodium cyanide, reduce the wastewater treatment risks and steps, and make the industrial production and operation more convenient.

Description

Technical Field

[0001] The present invention belongs to the technical field of pesticide preparation, and specifically relates to 2,2-dimethyl-5-(4-chlorobenzyl) cyclopentanone derivatives and their preparation methods, and also relates to their application in the synthesis of the fungicide metconazole intermediate. Background Art

[0002]

[0003] Metconazole, also known as triticonazole, has the chemical name: 5-(4-chlorophenyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl) cyclopentanol, and the common name: metconazole. This product is a triazole fungicide developed by the Japanese company Kureha Chemical Industry Co., Ltd. in the 1990s and is an ergosterol synthesis inhibitor. Metconazole has the characteristics of novel structure, broad fungicidal spectrum, high systemic absorption, low toxicity to non-target organisms, high fungicidal activity, etc., and has both protective and therapeutic effects. It is mainly used for controlling wheat scab, leaf rust, corn rust, soybean rust, rapeseed sclerotinia rot, etc., and has broad market application prospects.

[0004]

[0005] As an important intermediate for the synthesis of metconazole, 2,2-dimethyl-5-(4-chlorobenzyl) cyclopentanone uses cyclopentanone (Res.Chem.Intermed.2017,43,6293–6298) or diethyl adipate (Pesticides, 2017,56,478-479; Pesticides, 2012,51,413-415; Pesticides, 2019,58(11):792-795) as the starting material, with a long synthesis step, requiring multiple methylations, and the synthesis process cost is relatively high; US 6344580B1 uses isobutyronitrile as the starting material, reacts with metal lithium reagent and bromochloropropane, and is replaced by sodium cyanide to obtain the key intermediate 2,2-dimethyl dinitrile. However, the use conditions of the lithium reagent in this reaction process are harsh, and the use of sodium cyanide has certain safety, environmental, and management hazards. The reaction formula is as follows:

[0006]

[0007] Patents CN 107365262 B and CN 112592275 A use isobutyrate as the raw material, and sodium cyanide is still used in the second reaction, which has production safety and management risks, and the disposal of the wastewater containing sodium cyanide generated by the production is also relatively troublesome. The reaction formula is as follows:

[0008] Summary of the Invention

[0009] The technical problem to be solved by the present invention is to provide a 2,2-dimethyl-5-(4-chlorobenzyl) cyclopentanone derivative and a preparation method thereof.

[0010] To solve the above problems, the present invention provides a 2,2-dimethyl-5-(4-chlorobenzyl) cyclopentanone derivative, which has the general structural formula shown in Formula IV:

[0011] IV:

[0012] R is a C1-C6 alkyl substituent or hydrogen;

[0013] X is oxygen (when R is a C1-C6 alkyl substituent) or nitrogen (when R is hydrogen);

[0014] The alkyl is a straight-chain or branched-chain alkyl; the alkyl itself or as part of other substituents is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl and their isomers, and the isomers are preferably selected from isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl or tert-pentyl, etc.

[0015] 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.

[0016] The present invention also simultaneously provides a synthesis method of the above 2,2-dimethyl-5-(4-chlorobenzyl) cyclopentanone derivative IV, and the specific route is:

[0017]

[0018] 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.

[0019] It includes the following steps:

[0020] A. Preparation of intermediate II:

[0021] Under low-temperature conditions, the raw material isobutyrate derivative I is dissolved in an anhydrous aprotic organic solvent to obtain a raw material solution; an organolithium reagent is added dropwise to the solution of I, and the mixture is stirred while maintaining the temperature; then a halide (VI) is added dropwise, and a substitution reaction is carried out under the condition of maintaining the temperature; the reaction product is post-treated to obtain the intermediate valerate II;

[0022] The reaction temperature of the substitution reaction is -40 to 0 °C; the reaction time is 1 to 5 hours;

[0023] The aprotic organic solvent is selected from petroleum ether, n-hexane, cyclohexane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or 2-methyltetrahydrofuran;

[0024] The organolithium reagent is selected from butyllithium, isopropyllithium, methyllithium, lithium diisopropylamide or lithium bis(trimethylsilyl)amide, etc.;

[0025] R 1 is a C1-C6 alkyl substituent; preferably: methyl, isopropyl, isobutyl, tert-butyl;

[0026] L is a halogen chlorine, bromine, iodine; preferably: bromine;

[0027] X, R are defined as above, preferably the substituents are defined as above;

[0028] The molar ratio of the amount of the isobutyrate derivative I to the organolithium reagent is 1:1.1 to 2.2; the molar ratio of the amount of the isobutyrate derivative I to the halide is 1:0.9 to 2.1;

[0029] B. Preparation of intermediate III:

[0030] Dissolve intermediate II in an aprotic organic solvent, add an alkali metal alkoxide, and heat under reflux (the heating reaction temperature is preferably 60-130 °C), and low-boiling substances are removed during the reflux reaction; after the reflux reaction is completed, through post-treatment, compound III is obtained;

[0031] The reaction time is 0.5-10 hours; the molar ratio of the amount of intermediate II to the alkali metal alkoxide is 1:1.1 to 2.2;

[0032] The aprotic organic solvent is selected from acetone, toluene, ethylbenzene, xylene, mesitylene, ethylene glycol dimethyl ether, dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, etc., preferably toluene, xylene, mesitylene, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran or 2-methyltetrahydrofuran, etc.; the alkali metal alkoxide is selected from potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium isobutoxide or sodium tert-butoxide, etc.;

[0033] X, R are defined as above, preferably the substituents are defined as above;

[0034] C. Preparation of intermediate IV:

[0035] Dissolve Intermediate III in an aprotic organic solvent, first add an alkali metal salt and react at 100 - 130 °C for 1 ± 0.2 hours; then dropwise add 4-chlorobenzyl chloride and heat under reflux (the reaction temperature is preferably 50 - 120 °C), and remove low-boiling substances during the reflux reaction. After the reflux reaction is completed, perform post-treatment to obtain Intermediate IV;

[0036] The heating reflux reaction time is 0.5 - 15 hours; the molar ratio of the amount of Intermediate III to the alkali metal salt is 1:1.05 - 2.3; the molar ratio of the amount of Intermediate III to 4-chlorobenzyl chloride is 1:0.9 - 1.3;

[0037] The aprotic organic solvent is selected from acetone, toluene, ethylbenzene, xylene, mesitylene, ethylene glycol dimethyl ether, dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, etc., and preferably toluene, xylene, mesitylene, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran or 2-methyltetrahydrofuran, etc.; 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 isobutoxide, sodium tert-butoxide, sodium hydride, potassium hydride or lithium hydride, etc.

[0038] As an improvement to the synthesis method of the 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone derivative IV of the present invention:

[0039] In step A: Monitor the reaction process using gas chromatography (GC);

[0040] The post-treatment of step A is: After the reaction is completed, add water to quench the reaction, adjust the pH to neutral with dilute hydrochloric acid, separate the layers, and recover the aprotic organic solvent from the organic layer by vacuum distillation to obtain Product II;

[0041] The post-treatment of step B is: After the reaction is completed, cool to room temperature, add water to quench the reaction, adjust the pH to neutral with dilute hydrochloric acid, separate the layers, and recover the solvent from the organic layer by vacuum distillation to obtain Compound III;

[0042] The post-treatment of step C is: After the reaction is completed, cool to room temperature, add water to quench the reaction, separate the layers, and recover the solvent from the organic layer by vacuum distillation to obtain Intermediate IV.

[0043] The present invention also simultaneously provides a synthesis method of 2,2-dimethyl-5-(4-chloro)cyclopentanone (V), using the 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone derivative IV as described above,

[0044] Reaction route:

[0045]

[0046] Preparation of Intermediate V:

[0047] Dissolve Intermediate IV in a mixed acid, heat under reflux (the reaction temperature is preferably 40 - 120 °C), and after the reaction is completed, carry out post-treatment to obtain the target product V;

[0048] 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, p-toluenesulfonic acid (one or several mixed acids, and the concentration of the mixed acid can be selected from 10% - 100%). The amount of the mixed acid used is 0.5 - 20 times the molar amount of Intermediate IV.

[0049] Based on previous research and route exploration, through a large number of experiments and optimization of the scheme, the present invention has developed a synthetic route for a 2,2-dimethyl-5-(4-chlorobenzyl) cyclopentanone derivative, namely 2,2-dimethyl-5-(4-chlorobenzyl) cyclopentanone intermediate.

[0050] The synthetic method of the present invention can reduce production costs, simplify the reaction route, improve the preparation efficiency, avoid the production, environmental and management risks brought by the use of sodium cyanide, reduce the risk and steps of wastewater treatment, and make industrial production and operation more convenient.

[0051] Specifically, the synthetic method of the 2,2-dimethyl-5-(4-chlorobenzyl) cyclopentanone derivative (IV) described in the present invention is divided into the following steps:

[0052] A. Preparation of Compound II:

[0053] Under the protection of N2 gas, cool to a low temperature, dissolve isobutyrate (I) in an anhydrous aprotic solvent, and gradually add an organolithium reagent dropwise to the solution of I, keep warm and stir; then gradually add halide (VI), and keep warm for the reaction. Monitor the reaction process by gas chromatography (GC). After the raw materials are reacted completely, add water to quench the reaction, adjust the pH to neutral with dilute hydrochloric acid, separate the layers, recover the aprotic solvent by vacuum distillation of the organic layer, and obtain the product II by vacuum distillation;

[0054] The reaction temperature of the substitution reaction is -78 - 0 °C, preferably -40 - 0 °C; the reaction time is 1 - 20 hours, preferably 1 - 5 hours; the aprotic organic solvent is preferably selected from petroleum ether, n-hexane, cyclohexane, ether, 1,2-dimethoxyethane, tetrahydrofuran, 2-methyltetrahydrofuran, etc.; the organolithium reagent is preferably selected from butyllithium, isopropyllithium, methyllithium, lithium diisopropylamide, or bis(trimethylsilyl)amide, etc.; R 1R is a C1-C6 alkyl substituent, preferably methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl; X is oxygen or nitrogen, preferably oxygen; L is selected from halogen chlorine, bromine, iodine, preferably bromine; the molar ratio of the amount of the isobutyrate (I) to the organolithium reagent is 1:1.1 to 2.2; the molar ratio of the amount of I to the halide is 1:0.9 to 2.1.

[0055] B. Preparation of Compound III:

[0056] Dissolve II in an aprotic organic solvent, add an alkali metal alkoxide, heat under reflux, and remove low-boiling substances during the process. After the reaction is completed, cool down, quench the reaction with water, adjust the pH to neutral with dilute hydrochloric acid, separate the layers, and recover the solvent by vacuum distillation of the organic layer to obtain Compound III;

[0057] The reaction temperature of the ring-closure reaction is 20-220 °C, preferably 60-130 °C; the reaction time is 0.5-10 hours, preferably 2-8 hours; the aprotic organic solvent is selected from acetone, toluene, ethylbenzene, xylene, mesitylene, ethylene glycol dimethyl ether, dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, etc., preferably toluene, xylene, mesitylene, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran or 2-methyltetrahydrofuran, etc.; the alkali metal alkoxide is selected from potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium isobutoxide or sodium tert-butoxide, etc.; further, the molar ratio of the amount of II to the alkali metal alkoxide is 1:1.1 to 2.2.

[0058] C. Preparation of Compound IV:

[0059] Dissolve III in an aprotic organic solvent, add an alkali metal salt, dropwise add 4-chlorobenzyl chloride, heat under reflux, and remove low-boiling substances during the process. After the reaction is completed, cool down, quench the reaction with water, separate the layers, and recover the solvent by vacuum distillation of the organic layer to obtain the target compound IV;

[0060] The reaction temperature of the said reaction is 20 to 150 °C, preferably 50 to 120 °C; 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, mesitylene, ethylene glycol dimethyl ether, dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 2-methyltetrahydrofuran, etc., preferably toluene, xylene, mesitylene, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran or 2-methyltetrahydrofuran, etc.; 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 isobutoxide, sodium tert-butoxide, sodium hydride, potassium hydride or lithium hydride, etc.; further, the molar ratio of the dosage of III to the alkali metal salt is 1:1.05 to 2.3; the molar ratio of the dosage of III to 4-chlorobenzyl chloride is 1:0.9 to 1.3.

[0061] Application of the compound of formula (IV) in the synthesis of 2,2-dimethyl-5-(4-chlorophenyl)cyclopentanone (V)

[0062]

[0063] Dissolve IV in the mixed acid, heat under reflux, after the reaction is completed, cool down, quench the reaction with water, separate the layers, and recover the solvent by vacuum distillation of the organic layer to obtain compound V;

[0064] The reaction temperature of the said reaction is 50 to 200 °C, preferably 60 to 140 °C; 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, etc. or a mixture of one or several of them; the concentration of the mixed acid can be selected from 10% to 100%, preferably 20 to 80%, and the amount of acid used is generally 0.5 to 20 times the molar ratio of IV, preferably 1 to 10 times.

[0065] The present invention has the following beneficial effects:

[0066] First, compared with the background technology, the content of the obtained 2,2-dimethyl-5-(4-chlorophenyl)cyclopentanone derivative (IV) is ≥95%, which can be directly used in the synthesis of the fungicide metconazole intermediate (V), providing an alternative for the safe preparation of 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone (V). Second, the preparation method of the present invention obtains the key intermediate 2,2-dimethyl-cyclopentanone derivative in two steps, shortening the reaction steps and improving the preparation efficiency. Third, during the reaction process, the use of cyanide with safety hazards is avoided, improving the safety of production, environment and management. Fourth, the preparation method provided by the present invention is suitable for industrial-scale production and has good economic benefits. Detailed implementation mode

[0067] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0068] Example 1 Preparation of intermediate valerate II:

[0069] Scheme 1.1 Preparation of 6-(tert-butyl)-1-isobutyl 2,2-dimethyladipate

[0070]

[0071] Under the protection of N2 gas, 14.4 g (100 mmol) of isobutyl isobutyrate was dissolved in a 250 mL three-necked round-bottom flask containing 80 mL of anhydrous tetrahydrofuran, cooled to -20 °C and stirred evenly. 55 mL (110 mmol) of a n-hexane solution of lithium diisopropylamide was added dropwise to the above system over 30 - 60 minutes, and the reaction was carried out at -20 °C for 0.5 hour; then 23 g (105 mmol) of tert-butyl 4-bromobutyrate was added dropwise over 15 - 30 minutes. After the addition was completed, the reaction was carried out at -20 °C for 2 hours.

[0072] At this time, GC monitoring showed that the raw materials had completely reacted. 50 g of water was added dropwise, and the pH was adjusted to neutral with 2M hydrochloric acid. After liquid separation, the upper organic layer was distilled under normal pressure to recover the solvents (tetrahydrofuran and n-hexane), and then distilled under reduced pressure to obtain 26 g of 6-(tert-butyl)-1-isobutyl 2,2-dimethyladipate, with a yield of 92%.

[0073] Gas phase detection method: Injection port temperature: 250 °C; FID detector temperature: 250 °C; Capillary column SE-54; Program temperature rise: Hold at 50 °C for 1 minute, then rise to 240 °C at a rate of 15 °C per minute, and hold at 240 °C for 6 minutes.

[0074] Scheme 1.2 Preparation of 6-(tert-butyl)-1-methyl 2,2-dimethyladipate

[0075]

[0076] Under the protection of N2 gas, 14 g (137 mmol) of methyl isobutyrate was dissolved in a 250 mL three-necked round-bottom flask containing 80 mL of anhydrous tetrahydrofuran, cooled to -20 °C and stirred evenly. 75 mL (150 mmol) of a n-hexane solution of lithium diisopropylamide was added dropwise over 15 - 30 minutes, and the reaction was carried out at -20 °C for 0.5 hour; 28 g (130 mmol) of tert-butyl 4-bromobutyrate was added dropwise over 15 - 30 minutes. After the addition was completed, the reaction was carried out at -20 °C for 2 hours.

[0077] At this time, GC monitored the reaction process and found that the raw materials had completely reacted. 50 g of water was added dropwise, and the pH was adjusted to neutral with 2M hydrochloric acid. After liquid separation, the organic layer was distilled under normal pressure to recover the solvent, and then distilled under reduced pressure to obtain 30.4 g of the product 6-(tert-butyl)-1-methyl 2,2-dimethyladipate, with a yield of 91%. 1 1H NMR (400 MHz, CDCl3) δ 3.65 (s, 1H), 2.18 (m, 2H), 1.51 (m, 4H), 1.43 (s, 9H), 1.17 (d, J = 2.9 Hz, 6H).

[0078] Preparation of Intermediate III in Example 2:

[0079] Scheme 2.1 Preparation of methyl 3,3-dimethyl-2-oxocyclopentane-1-carboxylate

[0080]

[0081] 10 g (50 mmol) of dimethyl 2,2-dimethyladipate was dissolved in a 250 mL round-bottom flask containing 150 mL of toluene. 2.8 g (54 mmol) of sodium methoxide was added, and the temperature was raised to 100 - 130 °C and heated under reflux for 5 hours. During this period, low-boiling substances were removed (i.e., during reflux, the low-boiling substances were discharged from the reaction system through the water separator). When the raw materials (i.e., Intermediate (II)) detected by GC ≤ 2%, after the reaction was completed, the temperature was lowered to room temperature, 50 mL of water was added, and the pH was adjusted to neutral with 2M hydrochloric acid. After liquid separation, the organic solvent in the upper layer was distilled under reduced pressure for recovery. The residue was 7.2 g of methyl 3,3-dimethyl-2-oxocyclopentane-1-carboxylate, with a yield of 86%. 1 1H NMR (400 MHz, CDCl3) δ 3.74 (s, 3H), 3.26 (t, J = 9.1 Hz, 1H), 2.39–2.11 (m, 2H), 1.99–1.68 (m, 3H), 1.09 (s, 3H), 1.08 (s, 3H).

[0082] Example 2.2 Isobutyl 3,3-dimethyl-2-oxocyclopentane-1-carboxylate

[0083]

[0084] Dissolve 14.3 g (50 mmol) of diisobutyl 2,2-dimethyladipate in a 150 mL round-bottom flask containing 50 mL of toluene. Add 5.3 g (55 mmol) of sodium isobutoxide, heat up to 100 - 130 °C, and reflux for 6 hours, during which low-boiling substances are removed. When the raw materials detected by GC are ≤2%, cool to room temperature after the reaction is completed, add 50 mL of water, adjust the pH to neutral with 2M hydrochloric acid, separate the layers, and recover the organic solvent in the upper layer by vacuum distillation. The residue is 8.8 g of isobutyl 3,3-dimethyl-2-oxocyclopentane-1-carboxylate, with a yield of 83%. 1 1H NMR (400 MHz, CDCl3) δ 3.96–3.81 (m, 2H), 3.22 (t, J = 9.0 Hz, 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 = 6.8 Hz, 6H).

[0085] Preparation of Intermediate IV in Example 3:

[0086] Scheme 3.1 Preparation of isobutyl 1-(4-chlorobenzyl)-3,3-dimethyl-2-oxocyclopentane-1-carboxylate

[0087]

[0088] Dissolve 21 g (100 mmol) of isobutyl 3,3-dimethyl-2-oxocyclopentane-1-carboxylate in a 250 mL round-bottom flask containing 150 mL of toluene. Add 6.5 g (120 mmol) of sodium methoxide, heat up to 100 - 130 °C, react for 1 hour, and gradually add 16 g (100 mmol) of 4-chlorobenzyl chloride dropwise over 15 - 30 minutes, then reflux for 4 hours. When the raw materials (Intermediate (III)) detected by GC are ≤2%, cool to room temperature after the reaction is completed, add 50 mL of water, separate the layers, and recover the organic solvent in the upper layer by vacuum distillation. The residue is 29 g of isobutyl 1-(4-chlorobenzyl)-3,3-dimethyl-2-oxocyclopentane-1-carboxylate, with a yield of 88%.

[0089] Scheme 3.2 Preparation of isobutyl 1-(4-chlorobenzyl)-3,3-dimethyl-2-oxocyclopentane-1-carboxylate

[0090]

[0091] Dissolve 21 g (100 mmol) of isobutyl 3,3-dimethyl-2-oxocyclopentane-1-carboxylate in a 250 mL round-bottom flask equipped with 75 mL of tetrahydrofuran. Under the condition of 0 °C, add 5 g (130 mmol) of sodium hydride in portions, and after returning to room temperature, react for 0.5 h. Dropwise add 19 g (120 mmol) of 4-chlorobenzyl chloride over 15 - 30 minutes, then raise the temperature to 40 - 70 °C and reflux for 10 h. When the raw material (intermediate (III)) detected by GC ≤ 5%, after the reaction is completed, cool to room temperature, add 80 mL of water, separate the layers, recover the organic solvent in the upper layer by distillation under reduced pressure, and the residue is 33 g of isobutyl 1-(4-chlorobenzyl)-3,3-dimethyl-2-oxocyclopentane-1-carboxylate, with a yield of 91% (area normalization). 1 H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 7.4 Hz, 2H), 7.06 (d, J = 7.7 Hz, 2H), 3.89 (d, J = 6.4 Hz, 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 = 6.7 Hz, 6H), 0.68 (s, 3H).

[0092] Preparation of intermediate V in Example 4:

[0093]

[0094] Dissolve 34 g (100 mmol) of isobutyl 1-(4-chlorobenzyl)-3,3-dimethyl-2-oxocyclopentane-1-carboxylate in a mixed acid solution of 120 mL of glacial acetic acid and 50 mL of 12.5% concentrated sulfuric acid, raise the temperature to 90 - 120 °C, and reflux for 10 h. When the raw material (intermediate (IV)) detected by GC ≤ 5%, after the reaction is completed, cool to room temperature, pour it into 150 mL of ice water, add 150 mL of ethyl acetate, separate the layers, recover the organic solvent in the upper layer by distillation under reduced pressure, and the residue is 22 g of 2,2-dimethyl-5-(4-chlorobenzyl)cyclopentanone, with a yield of 93%. 1 H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 3.06 (dd, J = 13.8, 4.4 Hz, 1H), 2.62 (dd, J = 13.9, 8.7 Hz, 1H), 2.47–2.39 (m, 1H), 1.99–1.49 (m, 4H), 1.08 (s, 3H), 0.86 (s, 3H).

[0095] Example 5

[0096] At room temperature, 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 γ-butyrolactone. The temperature was raised to 40 °C and the mixture was stirred for 1 hour. Then 9.8 g (0.21 mol) of absolute ethanol was added and the reaction was continued with stirring for 4 hours. GC detection showed that the raw materials were ≤2%. After the reaction was completed, the temperature was lowered to room temperature, 50 ml of water was added, and the mixture was shaken well and allowed to stand for phase separation. The lower organic phase was washed with saturated sodium bicarbonate solution, allowed to stand for phase separation, and the lower organic phase was taken for solvent recovery by vacuum distillation. The residue was 35 g of ethyl 4-bromobutyrate, and the yield was 93.5%.

[0097] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent substitution methods and are all included in the protection scope of the present invention.

Claims

1. A method for synthesizing 2,2-dimethyl-5-(4-chlorobenzyl) cyclopentanone derivatives, characterized in that: The route is as follows: R is a C1-C6 alkyl substituent or hydrogen; X is oxygen or nitrogen; The alkyl group is a straight-chain or branched-chain alkyl group; the alkyl group itself or as part of other substituents is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl and their isomers, and the isomers are selected from isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl or tert-pentyl; It includes the following steps: A. Preparation of intermediate II: Under low-temperature conditions, dissolve the raw material isobutyrate derivative I in an anhydrous aprotic organic solvent to obtain a raw material solution; slowly dropwise add an organolithium reagent to the solution of I, keep warm and stir; then slowly dropwise add the halide (VI), and carry out a substitution reaction under the condition of keeping warm; the reaction product is post-treated to obtain the intermediate valerate II; The reaction temperature of the substitution reaction is -40 to 0 °C; the reaction time is 1 to 5 hours; The aprotic organic solvent is selected from petroleum ether, n-hexane, cyclohexane, ether, 1,2-dimethoxyethane, tetrahydrofuran or 2-methyltetrahydrofuran; The organolithium reagent is selected from butyllithium, isopropyllithium, methyllithium, lithium diisopropylamide or bis(trimethylsilyl)amide; R 1 is a C1-C6 alkyl substituent; L is halogen chlorine, bromine or iodine; The molar ratio of the amount of the isobutyrate derivative I to the organolithium reagent is 1:1.1 to 2.2; the molar ratio of the amount of the isobutyrate derivative I to the halide is 1:0.9 to 2.1; B. Preparation of intermediate III: Dissolve intermediate II in an aprotic organic solvent, add an alkali metal alkoxide, and heat under reflux for reaction, and remove low-boiling substances during the reflux reaction; after the reflux reaction is completed, it is post-treated to obtain compound III; the reflux reaction temperature is 60 to 130 °C; The reaction time is 0.5 to 10 hours; the molar ratio of the amount of intermediate II to the alkali metal alkoxide is 1:1.1 to 2.2; The aprotic organic solvent is selected from acetone, toluene, ethylbenzene, xylene, mesitylene, ethylene glycol dimethyl ether, dioxane, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, 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 isobutoxide or sodium tert-butoxide; C. Preparation of intermediate IV: Dissolve intermediate III in an aprotic organic solvent, first add an alkali metal salt and react at 100 to 130 °C for 1 ± 0.2 hours; then slowly dropwise add 4-chlorobenzyl chloride, heat under reflux, and remove low-boiling substances during the reflux reaction. After the reflux reaction is completed, it is post-treated to obtain intermediate IV, and the intermediate IV is 2,2-dimethyl-5-(4-chlorobenzyl) cyclopentanone derivative; the reflux reaction temperature is 50 to 120 °C; The reaction time is 0.5 to 15 hours; the molar ratio of the amount of intermediate III to the alkali metal salt is 1:1.05 to 2.3; the molar ratio of the amount of intermediate III to 4-chlorobenzyl chloride is 1:0.9 to 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 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 isobutoxide, sodium tert-butoxide, sodium hydride, potassium hydride or lithium hydride.

2. The method for synthesizing the 2,2-dimethyl-5-(4-chlorobenzyl) cyclopentanone derivative according to claim 1, characterized in that: R is methyl, isopropyl, isobutyl, tert-butyl; X is oxygen; In step A: R 1 is: methyl, isopropyl, isobutyl, tert-butyl; L is: bromine; In step B: the aprotic organic solvent is toluene, xylene, trimethylbenzene, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran or 2-methyltetrahydrofuran; In step C: the aprotic organic solvent is toluene, xylene, trimethylbenzene, ethylene glycol dimethyl ether, dioxane, tetrahydrofuran or 2-methyltetrahydrofuran.

3. The method for synthesizing the 2,2-dimethyl-5-(4-chlorobenzyl) cyclopentanone derivative according to claim 1 or 2, characterized in that: In step A: the reaction process is monitored by gas chromatography (GC); The post-treatment of step A is: after the reaction is completed, water is added to quench the reaction, and the pH is adjusted to neutral with dilute hydrochloric acid, and then layered. The organic layer is distilled under reduced pressure to recover the aprotic organic solvent to obtain product II; The post-treatment of step B is: after the reaction is completed, the temperature is lowered to room temperature, water is added to quench the reaction, and the pH is adjusted to neutral with dilute hydrochloric acid, and then layered. The organic layer is distilled under reduced pressure to recover the solvent to obtain compound III; The post-treatment of step C is: after the reaction is completed, the temperature is lowered to room temperature, water is added to quench the reaction, and then layered. The organic layer is distilled under reduced pressure to recover the solvent to obtain intermediate IV. 4.2,2-Dimethyl-5-(4-chloro) cyclopentanone synthesis method, characterized in that: First, intermediate IV is synthesized by using any one of the methods according to claims 1 to 3, and then 2,2-dimethyl-5-(4-chloro) cyclopentanone is synthesized by using intermediate IV; Reaction route: Preparation of the target product V: Intermediate IV is dissolved in a mixed acid, heated under reflux. After the reaction is completed, through post-treatment, the target product V is obtained; the target product V is 2,2-dimethyl-5-(4-chloro) cyclopentanone; the reflux temperature is 40-120 °C; 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, p-toluenesulfonic acid; the amount of the mixed acid used is 0.5-20 times the molar amount of intermediate IV.

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