Preparation method of 6, 8-dichloro ethyl caprylate

Abstract

The invention provides a preparation method of 6, 8-dichloro ethyl caprylate, which comprises the following steps: carrying out oxidation reaction on cyclohexene to obtain 6-oxo ethyl caproate, carrying out Grignard reaction on the 6-oxo ethyl caproate to obtain 6-hydroxy-8-chloro ethyl caprylate, and carrying out chlorination reaction on the 6-hydroxy-8-chloro ethyl caprylate to obtain the 6, 8-dichloro ethyl caprylate. The method disclosed by the invention is relatively low in cost, mild in reaction condition, environment-friendly, high in product yield and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis and relates to a method for preparing ethyl 6,8-dichlorooctanoate. Background Art

[0002] The molecular formula of 6,8-dichlorooctanoic acid ethyl ester is C 10 H 18 Cl 2 O 2 , molecular weight is 241.15, and its chemical structure is as follows:

[0003] Ethyl 6,8-dichlorooctanoate is an important intermediate for the synthesis of lipoic acid. Lipoic acid is a coenzyme existing in mitochondria, similar to vitamins, which can eliminate free radicals that accelerate aging and cause disease. Lipoic acid enters cells after being absorbed through the intestines in the body, and has both fat-soluble and water-soluble properties.

[0004] At present, the method for preparing 6,8-dichlorooctanoic acid ethyl ester mainly adopts the method in the document LESTER J. REEDAND CHIXG-INIU. Syntheses of DL-a-Lipoic Acid. Journal of the American Chemical Society, 1955, vol. 77, p. 416-418, and the synthesis route is as follows:

[0005]

[0006] The method firstly reacts monoethyl adipate with thionyl chloride to obtain monoethyl adipate chloride, and then reacts with ethylene to obtain 6-carbonyl-8-chlorooctanoic acid ethyl ester intermediate by Friedel-Crafts alkylation reaction, and then the 6-carbonyl-8-chlorooctanoic acid ethyl ester intermediate is reduced with sodium borohydride to obtain 6-hydroxy-8-chlorooctanoic acid ethyl ester intermediate, and finally the 6-hydroxy-8-chlorooctanoic acid ethyl ester intermediate is subjected to thionyl chloride to obtain the target product 6,8-dichlorooctanoic acid ethyl ester. In general, the price of monoethyl adipate raw material in this method is very high, and the use of aluminum chloride produces more three wastes, and ethylene with a very low boiling point and a large amount of aluminum chloride are used at the same time. In addition, two steps of chlorination are required, which is highly polluting, and it is not an ideal synthesis route.

[0007] Therefore, developing a method for preparing 6,8-dichlorooctanoic acid ethyl ester with low cost, mild reaction conditions and environmental friendliness remains a research focus in this field. Summary of the invention

[0008] In view of the shortcomings of the prior art, the object of the present invention is to provide a method for preparing ethyl 6,8-dichlorooctanoate. The method of the present invention has low cost, mild reaction conditions, is environmentally friendly, and has a high product yield.

[0009] To achieve this object, the present invention adopts the following technical solutions:

[0010] The present invention provides a method for preparing ethyl 6,8-dichlorooctanoate, which comprises the following steps:

[0011] (1) The cyclohexene represented by formula I is subjected to oxidation reaction and reacted with acetic anhydride to obtain 6-oxohexanoic acid ethyl ester represented by formula II, wherein the reaction formula is as follows:

[0012]

[0013] (2) reacting ethyl 6-oxohexanoate represented by formula II in the presence of a Grignard reagent in a solvent to obtain ethyl 6-hydroxy-8-chlorooctanoate represented by formula III, wherein the reaction formula is as follows:

[0014]

[0015] (3) 6-hydroxy-8-chlorooctanoic acid ethyl ester represented by formula III is subjected to chlorination reaction to obtain 6,8-dichlorooctanoic acid ethyl ester represented by formula IV, and the reaction formula is as follows:

[0016]

[0017] Preferably, the oxidant in the oxidation reaction in step (1) is selected from ozone.

[0018] Preferably, the oxidation reaction in step (1) is carried out in the presence of an alkaline substance.

[0019] Preferably, the alkaline substance in step (1) is selected from at least one of sodium carbonate, potassium carbonate and cesium carbonate; more preferably sodium carbonate.

[0020] Preferably, the oxidation reaction in step (1) is carried out in a first solvent, and the first solvent is selected from at least one of methanol, ethanol, and dichloromethane; more preferably, the first solvent is selected from at least one of ethanol and dichloromethane; more preferably, the first solvent is a mixture of ethanol and dichloromethane.

[0021] Preferably, the reaction with acetic anhydride in step (1) is carried out in a second solvent, and the second solvent is selected from at least one of dichloromethane and toluene; more preferably dichloromethane.

[0022] Preferably, the reaction with acetic anhydride in step (1) is carried out in the presence of an acid binding agent.

[0023] Preferably, the acid binding agent is selected from at least one of triethylamine and diisopropylethylamine; more preferably triethylamine.

[0024] Preferably, the molar ratio of cyclohexene to the alkaline substance in step (1) is 1:0.5-0.9, for example 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.85 or 1:0.9.

[0025] Preferably, the temperature of the oxidation reaction in step (1) is -78 to -60°C (e.g., -78°C, -70°C, -65°C or -60°C), preferably -78 to -65°C, more preferably -78°C; and the reaction time is more than 0.5 hours.

[0026] Preferably, the molar ratio of cyclohexene to acetic anhydride in step (1) is 1:1.5-2.5;

[0027] Preferably, the temperature for reacting with acetic anhydride in step (1) is 0-5°C (e.g., 0°C, 1°C, 2°C, 3°C, 4°C or 5°C), and the reaction time is more than 0.5h (e.g., 0.5h, 1h, 2h, 3h, 5h, 6h, 8h, etc.).

[0028] In the present invention, the specific operation of step (1) is as follows: cyclohexene (1.0 eq.), alkaline substance (0.5-0.9 eq.) and the first solvent are mixed, the temperature is reduced to -78--60°C, ozone is introduced, after 5-8 hours, the temperature is returned to 20-30°C, and nitrogen is introduced for 10-30 minutes; filtering, concentrating the reaction solution, adding the second solvent and acetic anhydride to the residual solution, cooling to 0-5°C, adding an acid binding agent dropwise, and then adding ethanol, stirring for more than 0.5 hours, and post-treating to obtain the product 6-oxohexanoic acid ethyl ester.

[0029] Preferably, the Grignard reagent used in the Grignard reaction in step (2) is prepared from halogenated alkane and magnesium.

[0030] Preferably, the halogenated alkane is selected from any one or a combination of at least two of 1-bromo-3-chloropropane, 1,3-dichloropropane, 1-chloro-3-iodopropane or 1-bromo-3-iodopropane.

[0031] Preferably, the molar ratio of magnesium to halogenated alkane is 1-1.2:1, for example 1:1, 1.05:1, 1.08:1, 1:1, 1.15:1, 1.18:1 or 1.2:1.

[0032] Preferably, the specific method for preparing the Grignard reagent in step (2) is: mix tetrahydrofuran and halogenated alkane (1.0 eq.), cool to 0-5°C, add magnesium powder (1-1.2 eq.), control the temperature to 0-5°C, add a few drops of 3M methylmagnesium bromide as a catalyst under nitrogen protection, and stir at 0-5°C for more than 1 hour.

[0033] Preferably, the molar ratio of ethyl 6-oxohexanoate to halogenated alkane in step (2) is 0.83 to 1:1, for example, 0.83:1, 0.85:1, 0.9:1, 0.95:1, 0.98:1 or 1:1.

[0034] Preferably, the solvent in step (2) is selected from any one of tetrahydrofuran, dichloromethane, toluene or dioxane, or a combination of at least two thereof.

[0035] Preferably, the reaction temperature in step (2) is -78 to -60°C (e.g., -78°C, -77°C, -76°C, -75°C, -74°C, -72°C, -70°C, -68°C, -64°C, -60°C), and the reaction time is 0.5 to 6 h.

[0036] In the present invention, the specific operation of step (2) is as follows: prepare a Grignard reagent from a halogenated alkane and magnesium, cool to -78 to -60°C, dissolve 6-oxohexanoic acid ethyl ester (0.83 to 1.0 eq.) in a solvent, add dropwise to the above reaction solution, continue stirring at -78°C for 0.5 to 6 hours, slowly return to room temperature, and post-treat to obtain the product.

[0037] Preferably, the chlorination agent used in the chlorination reaction in step (3) is any one of thionyl chloride, oxalyl chloride or phosphorus trichloride, or a combination of at least two thereof.

[0038] Preferably, the molar ratio of 6-hydroxy-8-chlorooctanoic acid ethyl ester to the chlorination agent in step (3) is 1:1.05-2, for example, 1:1.05, 1:1.08, 1:1.1, 1:1.3, 1:1.5, 1:1.7, 1:1.9 or 1:2.

[0039] Preferably, the solvent for the chlorination reaction in step (3) is 1,2-dichloroethane or toluene.

[0040] Preferably, the reaction in step (3) is carried out in the presence of a catalyst.

[0041] Preferably, the catalyst is DMF (N,N-dimethylformamide).

[0042] Preferably, the weight ratio of 6-hydroxy-8-chlorooctanoic acid ethyl ester to DMF in step (3) is 1:0.003-0.008, for example, 1:0.003, 1:0.005, 1:0.006, 1:0.008, etc.

[0043] Preferably, the chlorination reaction in step (3) is carried out under reflux, and the chlorination reaction time is 3-10 hours, for example, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours or 10 hours.

[0044] In the present invention, as a preferred technical solution, the preparation method of 6,8-dichlorooctanoic acid ethyl ester comprises the following steps:

[0045] (1) In the presence of an alkaline substance, cyclohexene is first subjected to an oxidation reaction with ozone at -78 to -60°C for more than 0.5 h, and then subjected to an esterification reaction with acetic anhydride at 0 to 5°C for more than 0.5 h to obtain ethyl 6-oxohexanoate, wherein the molar ratio of cyclohexene to acetic anhydride is 1:1.5 to 2.5;

[0046] (2) preparing a Grignard reagent from a halogenated alkane and magnesium, reacting ethyl 6-oxohexanoate with the Grignard reagent in a solvent at -78 to -60°C for 0.5 to 6 hours to obtain ethyl 6-hydroxy-8-chlorooctanoate, wherein the molar ratio of magnesium to the halogenated alkane is 1 to 1.2:1, and the molar ratio of ethyl 6-oxohexanoate to the halogenated alkane is 0.83 to 1:1;

[0047] (3) 6-hydroxy-8-chlorooctanoic acid ethyl ester and a chlorination agent are reacted in a molar ratio of 1:1.05-2 in the presence of a catalyst under reflux for 3-10 hours, wherein the weight ratio of 6-hydroxy-8-chlorooctanoic acid ethyl ester to the catalyst is 1:0.003-0.008 to obtain 6,8-dichlorooctanoic acid ethyl ester.

[0048] Compared with the prior art, the present invention has the following beneficial effects:

[0049] The preparation method of the invention does not use aluminum trichloride and ethylene with a low boiling point, has mild reaction conditions, uses cheap cyclohexene as a basic raw material, and the reagents and raw materials used are easily available, thereby reducing production costs; only the last step is a chlorination reaction, which is more environmentally friendly, has high product purity (GC content reaches 97.5-98.5%), has a short reaction route, and has a high yield, wherein the yield of each step is above 70%, and is suitable for industrial production. DETAILED DESCRIPTION

[0050] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0051] Example 1-1 Preparation of 6-oxohexanoic acid ethyl ester (Formula II)

[0052] The reaction equation is:

[0053]

[0054] Cyclohexene (33 g, 400 mmol, 1.0 eq.), sodium carbonate (23.3 g, 0.55 eq.), ethanol (50 mL, 1.5 vol) and dichloromethane (165 mL, 15 vol) were added to the reaction flask, stirred, cooled to -78 ° C, and ozone was introduced. After 7 hours, the temperature was returned to 25 ° C, and nitrogen was introduced for 20 minutes; filtered, the reaction solution was concentrated, and dichloromethane (165 mL, 15 vol) and acetic anhydride (80 mL, 2.4 vol, 846 mmol, 2.1eq.), dissolved, cooled to 0-5°C, triethylamine (132mL, 4vol) was added dropwise, and the addition was completed in 1 hour, and ethanol (66mL, 2vol) was added, and stirring was continued for 1 hour, and concentrated. MTBE (methyl tert-butyl ether) and 3M aqueous hydrochloric acid solution were added to the concentrate, and the layers were separated. The organic phase was washed with saturated potassium bicarbonate solution and brine, and then the organic phase was dried over anhydrous magnesium sulfate, concentrated, and distilled to obtain 47.5g of ethyl 6-oxohexanoate, with a yield of 75%; 1 H-NMR (400 MHz, CDCl 3 ), δ9.768(q,J 1.6Hz,1H),4.151-4.098(q,1H),2.482-2.447(m,2H),2.342-2.306(m,2H),1.673-1.654(m,4H),1.270-1.234(t,J 7.2Hz,3H).

[0055] Example 1-2 Preparation of 6-oxohexanoic acid ethyl ester (Formula II)

[0056] Cyclohexene (33 g, 400 mmol, 1.0 eq.), sodium carbonate (30.1 g, 0.9 eq.), ethanol (50 mL, 1.5 vol) and dichloromethane (165 mL, 15 vol) were added to the reaction flask, stirred, cooled to -78 ° C, and ozone was introduced. After 7 hours, the temperature was returned to 20 ° C, and nitrogen was introduced for 20 minutes; filtered, the reaction solution was concentrated, and dichloromethane (165 mL, 15 vol) and acetic anhydride (80 mL, 2.4 vol) were added to the residual solution. , 846mmol, 2.1eq.), dissolved, cooled to 0-5°C, triethylamine (132mL, 4vol) was added dropwise, and the addition was completed in 1 hour. Ethanol (66mL, 2vol) was added, and stirring was continued for 1 hour. Concentrated, MTBE (methyl tert-butyl ether) and 3M aqueous hydrochloric acid solution were added to the concentrate, the layers were separated, the organic phase was washed with saturated potassium bicarbonate solution and brine, and then the organic phase was dried over anhydrous magnesium sulfate, concentrated, and distilled to obtain 46.3g of the product with a yield of 73%.

[0057] Example 2-1 Preparation of 6-hydroxy-8-chlorooctanoic acid ethyl ester (Formula III)

[0058] The reaction equation is:

[0059]

[0060] Add tetrahydrofuran (100mL, 10vol.), 1-bromo-3-chloropropane (10g, 63.3mmol, 1.0eq.) to the reaction bottle, cool to 0-5℃, add magnesium powder (1.6g, 66.5mmol, 1.05eq.), control the temperature to 0-5℃, add 3 drops of 3M methylmagnesium bromide catalyst under nitrogen protection, stir at 0-5℃ for 1h, cool to -78℃, dissolve 6-oxohexanoic acid ethyl ester compound (9.8g, 62.0mmol, 0.98eq.) in dry tetrahydrofuran (20mL, 2vol), add dropwise to the above reaction solution, continue stirring at -78℃ for 0.5h, and slowly return to room temperature. Pour the reaction solution into 0-5℃ ammonium chloride aqueous solution (400mL), add MTBE (methyl tert-butyl ether) (200mL×2) and extract twice. The organic phases were combined, washed with brine, separated, dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to dryness to obtain 11.7 g of an oily substance (yield: 85%). 1 H-NMR (400 MHz, CDCl 3), δ4.104(q,J 7Hz,2H),3.823(br,1H),3.716~3.618(m,2H),2.294(t,J7.5Hz,2H),2.047(br, 1H),1.876~1.819(m,2H),1.647~1.607(m,2H),1.478~1.368(m,4H),1.232(t,J 7.5Hz,3H).

[0061] Example 2-2 Preparation of 6-hydroxy-8-chlorooctanoic acid ethyl ester (Formula III)

[0062] Add tetrahydrofuran (100mL, 10vol.), 1-bromo-3-chloropropane (10g, 63.3mmol, 1.0eq.) to the reaction bottle, cool to 0-5℃, add magnesium powder (1.83g, 1.2eq.), control the temperature to 0-5℃, add 3 drops of 3M methylmagnesium bromide catalyst under nitrogen protection, stir at 0-5℃ for 1h, and cool to -78℃. Dissolve 6-oxohexanoic acid ethyl ester compound (9.8g, 62.0mmol, 0.98eq.) in dry tetrahydrofuran (20mL, 2vol), add dropwise to the above reaction solution, continue stirring at -78℃ for 0.5h, and slowly return to room temperature. Pour the reaction solution into 0-5℃ ammonium chloride aqueous solution (400mL), add toluene (200mL×2) and extract twice. Combine the organic phases, wash with brine, and separate. The organic phase was dried over anhydrous sodium sulfate and filtered, and the mother liquor was concentrated to dryness to obtain 11.3 g of an oily product (yield: 82%).

[0063] Example 2-3 Preparation of 6-hydroxy-8-chlorooctanoic acid ethyl ester (Formula III)

[0064] Add tetrahydrofuran (100mL, 10vol.), 1,3-dichloropropane (7.2g, 63.3mmol, 1.0eq.) to the reaction bottle, cool to 0-5℃, add magnesium powder (1.6g, 66.5mmol, 1.05eq.), control the temperature to 0-5℃, add 3 drops of 3M methylmagnesium bromide catalyst under nitrogen protection, stir at 0-5℃ for 1h, and cool to -78℃. Dissolve 6-oxohexanoic acid ethyl ester compound (9.8g, 62.0mmol, 0.98eq.) in dry tetrahydrofuran (20mL, 2vol), add dropwise to the above reaction solution, continue stirring at -78℃ for 0.5h, and slowly return to room temperature. Pour the reaction solution into tartaric acid aqueous solution (400mL) at 0-5℃, add MTBE (methyl tert-butyl ether) (200mL×2) and extract twice. The organic phases were combined, washed with brine, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to dryness to obtain 11.4 g of an oily substance (yield: 83%).

[0065] Example 2-4 Preparation of 6-hydroxy-8-chlorooctanoic acid ethyl ester (Formula III)

[0066] Add tetrahydrofuran (100mL, 10vol.), 1-chloro-3-iodopropane (12.9g, 63.3mmol, 1.0eq.) to the reaction bottle, cool to 0-5℃, add magnesium powder (1.6g, 66.5mmol, 1.05eq.), control the temperature to 0-5℃, add 3M methylmagnesium bromide catalyst dropwise under nitrogen protection, stir at 0-5℃ for 1h, cool to -78℃, dissolve 6-oxohexanoic acid ethyl ester compound (9.8g, 62.0mmol, 0.98eq.) in dry tetrahydrofuran (20mL, 2vol), add dropwise to the above reaction solution, continue stirring at -78℃ for 0.5h, and slowly return to room temperature. Pour the reaction solution into tartaric acid aqueous solution (400mL) at 0-5℃, add ethyl acetate (200mL×2) and extract twice. Combine the organic phases, wash with brine, and separate. The organic phase was dried over anhydrous sodium sulfate and filtered, and the mother liquor was concentrated to dryness to obtain 11.9 g of an oily product (yield: 86.5%).

[0067] Example 3-1 Preparation of 6,8-dichlorooctanoic acid ethyl ester (Formula IV)

[0068] The reaction equation is:

[0069]

[0070] Add 6-hydroxy-8-chlorooctanoic acid ethyl ester (30g, 134.7mmol, 1.0eq.), thionyl chloride (16.8g, 141.4mmol, 1.05eq.), DMF (N,N-dimethylformamide) (0.1g), 1,2-dichloroethane (150mL, 5vol.) to the reaction bottle; heat to reflux and stir under reflux for 5 hours to end the reaction. Cool down and concentrate to dryness under reduced pressure to obtain the residue for rectification, distill and collect 29.9g of light yellow transparent liquid product, with a yield of 92% and a GC purity of 98.5%. 1 H-NMR (400 MHz, CDCl 3 ), δ4.133~4.091(m,3H),3.726~3.670(m,2H),2.303(t,J 7Hz,2H),2.129~2.073(m,2H),1.774~1.728(m,2H),1.692~1.461(m,4H),1.239(t,J 7.5Hz,3H).

[0071] Example 3-2 Preparation of 6,8-dichlorooctanoic acid ethyl ester (Formula IV)

[0072] Add 6-hydroxy-8-chlorooctanoic acid ethyl ester (30 g, 134.7 mmol, 1.0 eq.), thionyl chloride (19.2 g, 161.4 mmol, 1.2 eq.), DMF (N,N-dimethylformamide) (0.1 g), 1,2-dichloroethane (150 mL, 5 vol.) to the reaction bottle; heat to reflux and stir under reflux for 5 hours to end the reaction. Cool down and concentrate to dryness under reduced pressure to obtain the residue for distillation, evaporate and collect 30.5 g of light yellow transparent liquid product, with a yield of 93.8%.

[0073] Example 3-3 Preparation of 6,8-dichlorooctanoic acid ethyl ester (Formula IV)

[0074] Add 6-hydroxy-8-chlorooctanoic acid ethyl ester (30g, 134.7mmol, 1.0eq.), oxalyl chloride (17.9g, 141.0mmol, 1.05eq.), DMF (N,N-dimethylformamide) (0.1g), 1,2-dichloroethane (150mL, 5vol.) to the reaction bottle; heat to reflux and stir under reflux for 5 hours to end the reaction. Cool down and concentrate to dryness under reduced pressure to obtain the residue for distillation, evaporate and collect 29.5g of light yellow transparent liquid product, with a yield of 90.8%.

[0075] Example 3-4 Preparation of 6,8-dichlorooctanoic acid ethyl ester (Formula IV)

[0076] Add 6-hydroxy-8-chlorooctanoic acid ethyl ester (30 g, 134.7 mmol, 1.0 eq.), phosphorus trichloride (21.7 g, 158 mmol, 1.05 eq.), DMF (N,N-dimethylformamide) (0.1 g), 1,2-dichloroethane (150 mL, 5 vol.) to the reaction bottle; heat to reflux and stir under reflux for 5 hours to end the reaction. Cool down and concentrate to dryness under reduced pressure to obtain the residue for distillation, evaporate and collect 28.3 g of light yellow transparent liquid product, with a yield of 87.1%.

[0077] The applicant declares that the present invention illustrates the preparation method of 6,8-dichlorooctanoic acid ethyl ester of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing ethyl 6,8-dichlorooctanoate, characterized in that: The preparation method comprises the following steps: (1) The cyclohexene represented by formula I is subjected to oxidation reaction and reacted with acetic anhydride to obtain ethyl 6-oxohexanoate represented by formula II, wherein the reaction formula is as follows: (2) reacting ethyl 6-oxohexanoate represented by formula II in the presence of a Grignard reagent in a solvent to obtain ethyl 6-hydroxy-8-chlorooctanoate represented by formula III, wherein the reaction formula is as follows: (3) 6-hydroxy-8-chlorooctanoic acid ethyl ester represented by formula III is subjected to chlorination reaction to obtain 6,8-dichlorooctanoic acid ethyl ester represented by formula IV, and the reaction formula is as follows:

2. The preparation method according to claim 1, characterized in that: The oxidant for the oxidation reaction in step (1) is selected from ozone.

3. The preparation method according to claim 1 or 2, characterized in that: The oxidation reaction in step (1) is carried out in the presence of an alkaline substance; Preferably, the alkaline substance is selected from any one or a combination of at least two of sodium carbonate, potassium carbonate or cesium carbonate; Preferably, the molar ratio of cyclohexene to alkaline substance in step (1) is 1:0.5-0.

9.

4. The preparation method according to any one of claims 1 to 3, characterized in that The solvent for the oxidation reaction in step (1) is any one of methanol, ethanol or dichloromethane, or a combination of at least two of them.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The temperature of the oxidation reaction in step (1) is -78 to -60°C, and the reaction time is more than 0.5h, preferably 5-8h; Preferably, the molar ratio of cyclohexene to acetic anhydride in step (1) is 1:1.5-2.5; Preferably, the solvent for reacting with acetic anhydride in step (1) is selected from at least one of dichloromethane and toluene; more preferably dichloromethane; Preferably, the reaction with acetic anhydride in step (1) is carried out in the presence of an acid binding agent; Preferably, the acid binding agent is selected from at least one of triethylamine and diisopropylethylamine; more preferably triethylamine; Preferably, the temperature for reacting with acetic anhydride in step (1) is 0-5°C, and the reaction time is more than 0.5h.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The Grignard reagent in step (2) is prepared from halogenated alkane and magnesium; Preferably, the halogenated alkane is selected from any one or a combination of at least two of 1-bromo-3-chloropropane, 1,3-dichloropropane, 1-chloro-3-iodopropane or 1-bromo-3-iodopropane; Preferably, the molar ratio of magnesium to halogenated alkane is 1:1-1.

2.

7. The preparation method according to any one of claims 1 to 6, characterized in that The molar ratio of ethyl 6-oxohexanoate to halogenated alkane in step (2) is 0.83 to 1:1; Preferably, the solvent in step (2) is selected from any one of tetrahydrofuran, dichloromethane, toluene or dioxane, or a combination of at least two thereof. Preferably, the reaction temperature in step (2) is -78 to -60°C, and the reaction time is 0.5 to 6 hours.

8. The preparation method according to any one of claims 1 to 7, characterized in that: The chlorination agent used in the chlorination reaction of step (3) is any one of thionyl chloride, oxalyl chloride or phosphorus trichloride, or a combination of at least two thereof; Preferably, the molar ratio of 6-hydroxy-8-chlorooctanoic acid ethyl ester to the chlorination agent in step (3) is 1:1.05-2. Preferably, the solvent for the chlorination reaction in step (3) is 1,2-dichloroethane or toluene.

9. The preparation method according to any one of claims 1 to 8, characterized in that: The reaction in step (3) is carried out in the presence of a catalyst; Preferably, the catalyst is selected from N,N-dimethylformamide; Preferably, the weight ratio of 6-hydroxy-8-chlorooctanoic acid ethyl ester to the catalyst in step (3) is 1:0.003-0.008; Preferably, the chlorination reaction in step (3) is carried out under reflux, and the chlorination reaction time is 3-10 hours.

10. The preparation method according to any one of claims 1 to 9, characterized in that: The preparation method of 6,8-dichlorooctanoic acid ethyl ester comprises the following steps: (1) In the presence of an alkaline substance, cyclohexene is first subjected to an oxidation reaction with ozone at -78 to -60°C for more than 0.5 h, and then subjected to an esterification reaction with acetic anhydride at 0 to 5°C for more than 0.5 h to obtain ethyl 6-oxohexanoate, wherein the molar ratio of cyclohexene to acetic anhydride is 1:1.5 to 2.5; (2) preparing a Grignard reagent from a halogenated alkane and magnesium, reacting ethyl 6-oxohexanoate with the Grignard reagent in a solvent at -78 to -60°C for 0.5 to 6 hours to obtain ethyl 6-hydroxy-8-chlorooctanoate, wherein the molar ratio of magnesium to the halogenated alkane is 1:1 to 1.2, and the molar ratio of ethyl 6-oxohexanoate to the halogenated alkane is 0.83 to 1:1; (3) 6-hydroxy-8-chlorooctanoic acid ethyl ester and a chlorination agent are reacted in a molar ratio of 1:1.05-2 in the presence of a catalyst under reflux for 3-10 hours, wherein the weight ratio of 6-hydroxy-8-chlorooctanoic acid ethyl ester to the catalyst is 1:0.003-0.008 to obtain 6,8-dichlorooctanoic acid ethyl ester.

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