A method for preparing milopalline intermediate (2E)-4-ethylheptyl-2,6-dienoic acid

Abstract

The invention belongs to the technical field of drug synthesis, and in particular to a method for preparing a milobalin intermediate (2E)-4-ethylheptyl-2,6-dienoic acid. Compound SM-1, i.e., (E)-2-hexenoic acid ester compounds, is reacted with allyl bromide as a raw material, and a target compound is obtained by post-processing. The reaction conditions of the present invention are mild, and the operating process is simple. The complex operation problems such as high temperature or long-term reaction and preparation of iminium salts in the prior art are solved, and the product has high purity and yield.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a method for preparing a milobalin intermediate (2E)-4-ethylhept-2,6-dienoic acid. Background Art

[0002] Mirogabalin (DS-5565) is a gabapentinoid drug developed by Daiichi Sankyo Co., Ltd. Similar to drugs such as gabapentin and pregabalin, it acts on the voltage-gated calcium channel subunit α2δ, and inhibits the release of neurotransmitters mediated by calcium ions in the dorsal horn by binding to α2δ-1, thereby blocking neuronal excitation and sensory signal transmission. On January 8, 2019, Mirogabalin besilate developed by Daiichi Sankyo Co., Ltd. was approved for marketing by the Japanese Medical Device Evaluation and Approval Agency (PMDA). The trade name is Tarlige (oral tablets, each containing 2.5 mg, 5 mg, 10 mg, 15 mg of Mirogabalin), which is used to treat peripheral neuropathic pain, including diabetic peripheral neuropathy and postherpetic neuralgia. The structural formula of Mirogabalin besilate is as follows:

[0003]

[0004] The original patents (EP2192109, US2010249229, WO20010110361) reported the synthesis of 3-ethylbicyclo[3.2.0]hept-3-en-6-one, a key intermediate of milobarlin. This process uses ethyl acetoacetate as a starting material, uses n-butyl lithium reagent, and also requires the reduction of the 2-carbonyl group. The steps are long and the yield is not high, so there is room for further improvement.

[0005]

[0006] Chinese patent CN103582622A and literature (Improved synthesis process of milobalin benzenesulfonate, Zheng Linri et al., Shandong Chemical Industry, 2021, 50, 56) both reported the use of n-butyraldehyde and diisobutylamine as starting materials, dehydration to form an enamine intermediate, and then addition reaction with 3-bromopropylene to form a quaternary ammonium salt, Knoevenagel condensation reaction to obtain (2E)-4-ethylhept-2,6-dienoic acid, and then intramolecular [2+2] reaction to form the key intermediate 3-ethylbicyclo[3.2.0]hept-3-ene-6-one. Then Horner-Wadsworth-Emmons reaction with tert-butyl dimethoxyphosphonoacetate, and then addition, D-mandelic acid chiral resolution, hydrolysis and other steps to obtain milobalin, and then salified with benzenesulfonic acid to obtain milobalin benzenesulfonate. This route improves the first two steps of the CN103562170B route and avoids the acetal reaction and the Claisen rearrangement reaction; however, the diisobutylamine in this route is relatively expensive, has many reaction sites, contains many impurities, and is difficult to control quality, which is not conducive to industrial production.

[0007]

[0008] CN103562170B reports that n-butyraldehyde and propenol are used as starting materials, and (2E)-4-ethylhept-2,6-dienoic acid is obtained through acetal protection, Claisen rearrangement, and Knoevenagel condensation reaction, and then a [2+2] reaction within the molecule is performed to form a key intermediate. This route can also obtain the key intermediate 3-ethylbicyclo[3.2.0]hept-3-ene-6-one, but there are the following problems: (1) the condensation reaction process of n-butyraldehyde and propenol is complicated, and distillation operation is required for post-treatment; (2) in the Claisen rearrangement reaction step, high temperature and many impurities are required, purification is difficult, and it is not conducive to impurity control; (3) during the [2+2] cycloaddition reaction, high temperature reaction and other operations are also required, resulting in low yield, many impurities, and difficult purification. In general, this route has a low yield, many impurities, and difficult purification, which is a challenge for impurity control in the drug production process.

[0009]

[0010] According to the literature, there are different reports on the synthesis route of milobarline, but all of them use the key intermediate 3-ethylbicyclo[3.2.0]hept-3-ene-6-one or its single chiral substance as the starting material. However, in the prior art, the (2E)-4-ethylhept-2,6-dienoic acid intermediate plays a key role in the synthesis of the 3-ethylbicyclo[3.2.0]hept-3-ene-6-one racemate, but the prior art preparation method of (2E)-4-ethylhept-2,6-dienoic acid requires high temperature or long-term reaction and complex operations such as the preparation of iminium salts, which also causes the prior art yield and purity to be low. Although it is directly used in the next step of the reaction without purification, it brings losses and difficulties to the purification of downstream products, resulting in waste of materials.

[0011] Therefore, how to prepare (2E)-4-ethylheptyl-2,6-dienoic acid in a green, efficient, safe, environmentally friendly and low-cost manner has become the main technical challenge in the synthesis process of milobarlin. The structure of (2E)-4-ethylheptyl-2,6-dienoic acid is as follows:

[0012] Summary of the invention

[0013] In order to overcome the deficiencies in the prior art, the present invention provides a method for preparing a milobarlin intermediate (2E)-4-ethylhept-2,6-dienoic acid. The preparation method of the present invention has mild reaction conditions, simple operation, few reaction steps, high product yield, low cost, and is suitable for industrialized scale-up production.

[0014] In order to achieve the above object, the present invention is implemented by the following scheme:

[0015] Add compound SM-1, i.e., (E)-2-hexenoic acid ester compound and reaction solvent to the reaction vessel, stir and cool, and maintain the temperature at T 1 When the base catalyst is slowly added, SM-2, i.e., allyl bromide, is slowly added. After the addition is complete, the temperature is raised to T 2 , continue the reaction, after the reaction is completed, slowly add the alkaline solution to the reaction system, at T 3 The reaction was stirred at a temperature of 400 °C. After detection, the reaction was completed and the target product I was obtained by post-treatment.

[0016]

[0017] In a preferred embodiment, the substituent R of the compound SM-1 is Me, Et, Pr, i Pr,Bu, t One of the Bu groups; preferably Me.

[0018] In a preferred embodiment, the molar ratio of the compounds SM-1, SM-2 and the base catalyst is 1:1.1-1.5:1.1-1.5; preferably 1:1.3:1.3.

[0019] In a preferred embodiment, the reaction solvent is an inert solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, n-hexane, n-heptane, cyclohexane, etc., preferably tetrahydrofuran and ethylene glycol dimethyl ether.

[0020] In a preferred embodiment, the base catalyst is one of n-butyl lithium, sodium hydride, potassium tert-butoxide, and sodium methoxide, preferably sodium hydride.

[0021] Preferably, the temperature T 1 -30~10℃, preferably -10~0℃; temperature T 2 10~50℃, preferably 20~30℃; temperature T 3 The temperature is 20 to 80°C, preferably 30 to 50°C.

[0022] In a preferred embodiment, the alkaline solution is an aqueous solution of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium carbonate, or potassium carbonate, preferably an aqueous solution of sodium hydroxide, preferably a 2-3 mol / L aqueous solution of sodium hydroxide.

[0023] In a preferred embodiment, the molar ratio of the alkali to SM-1 in the alkali solution is 2 to 8:1, preferably 2 to 4:1.

[0024] The preferred embodiment is the post-treatment: after the reaction is completed, ethyl acetate is added to extract and separate the liquid, and the aqueous phase is collected; then, in the aqueous phase, a hydrochloric acid aqueous solution is used to adjust the pH value of the aqueous phase to 1-4, and then ethyl acetate is added to extract and separate the liquid, and the organic phase is collected, and then washed with water and saturated brine, and the organic phase is dried with anhydrous sodium sulfate and dried under reduced pressure to obtain the title compound as a colorless oil.

[0025] In a preferred embodiment, the pH value of the aqueous phase is adjusted to 1-2 using aqueous hydrochloric acid solution in the post-treatment.

[0026] Compared with the prior art, the technical effects achieved by the present invention are:

[0027] The present invention provides a method for preparing (2E)-4-ethylheptyl-2,6-dienoic acid, a key intermediate of milobalin, in an efficient synthesis. Through the preparation technology of the present invention, a large amount of inexpensive synthesis of the key intermediate (2E)-4-ethylheptyl-2,6-dienoic acid can be well achieved. The method has easy-to-obtain raw materials, mild reaction conditions, simple post-treatment, high yield and purity, and avoids the complex operation problems of high temperature or long-term reaction and preparation of iminium salts in the prior art. It provides basic raw materials for the subsequent synthesis of milobalin, which is conducive to the industrial production of milobalin. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Attached Figure 1 This is the liquid phase spectrum of (2E)-4-ethylhept-2,6-dienoic acid obtained in Example 1.

[0029] Attached Figure 2 This is the liquid phase spectrum of (2E)-4-ethylhept-2,6-dienoic acid obtained in Comparative Example 1. DETAILED DESCRIPTION

[0030] The present invention is further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention based on the method of the present invention are all within the scope of protection claimed by the present invention.

[0031] In the following embodiments, various processes and methods not described in detail are conventional methods known in the art.

[0032] Example 1

[0033] Add 128.2g of compound (E)-2-hexenoic acid methyl ester (1.0mol) and 500mL of tetrahydrofuran to the reaction container, stir and cool to 0°C, maintain the temperature, slowly add 31.2g of NaH (1.3mol), after the addition is complete, keep the temperature for 1 hour, then slowly drop 157.3g of allyl bromide (1.3mol), after the addition is complete, keep the temperature for 1 hour, then heat to 25°C, continue to stir the reaction, and the reaction is complete after detection. Then slowly add 3mol / L sodium hydroxide aqueous solution (1000mL) to the reaction system, stir the reaction at 35°C, and the reaction is complete after detection. Use 500 mL of ethyl acetate to extract and separate the liquid, and collect the aqueous phase; then use 6 mol / L hydrochloric acid aqueous solution to adjust the pH value of the aqueous phase to 1-2, and then add 500 mL of ethyl acetate to extract and separate the liquid, collect the organic phase, and then wash it with water and saturated brine, separate the organic phase, and then dry it with anhydrous sodium sulfate, and dry it under reduced pressure to obtain the target product I, namely (2E)-4-ethylhept-2,6-dienoic acid (colorless oil), with a yield of 93.5% and an HPLC value of 98.409%.

[0034] Example 2

[0035] Add 128.2g of compound (E)-2-hexenoic acid methyl ester (1.0mol) and 500mL of tetrahydrofuran to the reaction container, stir and cool to 0°C, maintain the temperature, slowly add 26.4g of NaH (1.1mol), after the addition is complete, keep warm for 1 hour, then slowly drop 133.1g of allyl bromide (1.1mol), after the addition is complete, keep warm for 1 hour, then heat to 25°C, continue to stir and react, and the reaction is complete after detection. Then slowly add 3mol / L sodium hydroxide aqueous solution (1000mL) to the reaction system, stir and react at 35°C, and the reaction is complete after detection. The extraction was performed with 500 mL of ethyl acetate, and the aqueous phase was collected; then, a 6 mol / L hydrochloric acid aqueous solution was used to adjust the pH value of the aqueous phase to 1-2, and then 500 mL of ethyl acetate was added to extract the liquid, and the organic phase was collected, and then washed with water and saturated brine, the organic phase was separated, and then dried with anhydrous sodium sulfate, and the target product I, i.e., (2E)-4-ethylhept-2,6-dienoic acid (colorless oil) was obtained by rotary drying under reduced pressure, with a yield of 90.6% and an HPLC value of 98.319%.

[0036] Example 3

[0037] Add 128.2g of compound (E)-2-hexenoic acid methyl ester (1.0mol) and 500mL of tetrahydrofuran to the reaction container, stir and cool to 0°C, maintain the temperature, slowly add 36.0g of NaH (1.5mol), after the addition is complete, keep warm for 1 hour, then slowly drop 181.5g of allyl bromide (1.5mol), after the addition is complete, keep warm for 1 hour, then heat to 25°C, continue to stir and react, and the reaction is complete after detection. Then slowly add 3mol / L sodium hydroxide aqueous solution (1000mL) to the reaction system, stir and react at 35°C, and the reaction is complete after detection. The extraction was performed with 500 mL of ethyl acetate, and the aqueous phase was collected; then, a 6 mol / L hydrochloric acid aqueous solution was used to adjust the pH value of the aqueous phase to 1-2, and then 500 mL of ethyl acetate was added to extract the liquid, and the organic phase was collected, and then washed with water and saturated brine, the organic phase was separated, and then dried with anhydrous sodium sulfate, and the target product I, i.e., (2E)-4-ethylhept-2,6-dienoic acid (colorless oil) was obtained by rotary drying under reduced pressure, with a yield of 92.7% and an HPLC value of 98.247%.

[0038] Example 4

[0039] Add 128.2g of compound (E)-2-hexenoic acid methyl ester (1.0mol) and 500mL of tetrahydrofuran to the reaction container, stir and cool to 0°C, maintain the temperature, slowly add 31.2g of NaH (1.3mol), after the addition is complete, keep the temperature for 1 hour, then slowly drop 157.3g of allyl bromide (1.3mol), after the addition is complete, keep the temperature for 1 hour, then heat to 10°C, continue to stir the reaction, and the reaction is complete after detection. Then slowly add 3mol / L sodium hydroxide aqueous solution (1000mL) to the reaction system, stir the reaction at 35°C, and the reaction is complete after detection. The extraction was performed with 500 mL of ethyl acetate, and the aqueous phase was collected; then, a 6 mol / L hydrochloric acid aqueous solution was used to adjust the pH value of the aqueous phase to 1-2, and then 500 mL of ethyl acetate was added to extract the liquid, and the organic phase was collected, and then washed with water and saturated brine, the organic phase was separated, and then dried with anhydrous sodium sulfate, and the target product I, i.e., (2E)-4-ethylhept-2,6-dienoic acid (colorless oil) was obtained by rotary drying under reduced pressure, with a yield of 90.5% and an HPLC value of 98.376%.

[0040] Example 5

[0041] Add 128.2g of compound (E)-2-hexenoic acid methyl ester (1.0mol) and 500mL of tetrahydrofuran to the reaction container, stir and cool to 0°C, maintain the temperature, slowly add 31.2g of NaH (1.3mol), after the addition is complete, keep the temperature for 1 hour, then slowly drop 157.3g of allyl bromide (1.3mol), after the addition is complete, keep the temperature for 1 hour, then heat to 50°C, continue to stir the reaction, and the reaction is complete after detection. Then slowly add 3mol / L sodium hydroxide aqueous solution (1000mL) to the reaction system, stir the reaction at 35°C, and the reaction is complete after detection. The extraction was performed with 500 mL of ethyl acetate, and the aqueous phase was collected; then, a 6 mol / L hydrochloric acid aqueous solution was used to adjust the pH value of the aqueous phase to 1-2, and then 500 mL of ethyl acetate was added to extract the liquid, and the organic phase was collected, and then washed with water and saturated brine, the organic phase was separated, and then dried with anhydrous sodium sulfate, and the target product I, i.e., (2E)-4-ethylhept-2,6-dienoic acid (colorless oil) was obtained by rotary drying under reduced pressure, with a yield of 91.6% and an HPLC value of 98.278%.

[0042] Example 6

[0043] Add 128.2g of compound (E)-2-hexenoic acid methyl ester (1.0mol) and 500mL of n-hexane to the reaction container, stir and cool to -30°C, maintain the temperature, slowly add 83.3g of n-butyl lithium (1.3mol), after the addition is complete, keep warm for 1 hour, then slowly drop 157.3g of allyl bromide (1.3mol), after the addition is complete, keep warm for 1 hour, then heat to 10°C, continue to stir and react, and the reaction is complete after detection. Then slowly add 3mol / L sodium hydroxide aqueous solution (1000mL) to the reaction system, stir and react at 35°C, and the reaction is complete after detection. The extraction was performed with 500 mL of ethyl acetate, and the aqueous phase was collected; then, a 6 mol / L hydrochloric acid aqueous solution was used to adjust the pH value of the aqueous phase to 1-2, and then 500 mL of ethyl acetate was added to extract the liquid, and the organic phase was collected, and then washed with water and saturated brine, the organic phase was separated, and then dried with anhydrous sodium sulfate, and the target product I, i.e., (2E)-4-ethylhept-2,6-dienoic acid (colorless oil) was obtained by rotary drying under reduced pressure, with a yield of 90.8% and an HPLC value of 98.304%.

[0044] Example 7

[0045] Add 142.2g of compound (E)-2-hexenoic acid ethyl ester (1.0mol) and 500mL of tetrahydrofuran to the reaction container, stir and cool to -10°C, maintain the temperature, slowly add 145.9g of potassium tert-butoxide (1.3mol), after the addition is complete, keep the temperature for 1 hour, then slowly drop 157.3g of allyl bromide (1.3mol), after the addition is complete, keep the temperature for 1 hour, then raise the temperature to 10°C, continue to stir the reaction, and the reaction is complete after detection. Then slowly add 3mol / L sodium hydroxide aqueous solution (1000mL) to the reaction system, stir the reaction at 20°C, and the reaction is complete after detection. The extraction was performed with 500 mL of ethyl acetate, and the aqueous phase was collected; then, a 6 mol / L hydrochloric acid aqueous solution was used to adjust the pH value of the aqueous phase to 1-2, and then 500 mL of ethyl acetate was added to extract the liquid, and the organic phase was collected, and then washed with water and saturated brine, the organic phase was separated, and then dried with anhydrous sodium sulfate, and the target product I, i.e., (2E)-4-ethylhept-2,6-dienoic acid (colorless oil) was obtained by rotary drying under reduced pressure, with a yield of 91.2% and an HPLC value of 98.314%.

[0046] Example 8

[0047] Add 156.2g of compound (E)-2-hexenoic acid propyl ester (1.0mol) and 500mL of tetrahydrofuran to the reaction container, stir and cool to 0°C, maintain the temperature, slowly add 70.2g of sodium methoxide (1.3mol), after the addition is complete, keep warm for 1 hour, then slowly drop 157.3g of allyl bromide (1.3mol), after the addition is complete, keep warm for 1 hour, then heat to 20°C, continue to stir and react, and the reaction is complete after detection. Then slowly add 3mol / L sodium hydroxide aqueous solution (1000mL) to the reaction system, stir and react at 50°C, and the reaction is complete after detection. The extraction was performed with 500 mL of ethyl acetate, and the aqueous phase was collected; then, a 6 mol / L hydrochloric acid aqueous solution was used to adjust the pH value of the aqueous phase to 1-2, and then 500 mL of ethyl acetate was added to extract the liquid, and the organic phase was collected, and then washed with water and saturated brine, the organic phase was separated, and then dried with anhydrous sodium sulfate, and the target product I, i.e., (2E)-4-ethylhept-2,6-dienoic acid (colorless oil) was obtained by rotary drying under reduced pressure, with a yield of 90.7% and an HPLC value of 98.378%.

[0048] Example 9

[0049] Add 156.2g of compound (E)-2-hexenoic acid isopropyl ester (1.0mol) and 500mL of ethylene glycol dimethyl ether to the reaction container, stir and cool to 0°C, maintain the temperature, slowly add 31.2g of NaH (1.3mol), after the addition is complete, keep the temperature for 1 hour, then slowly drop 157.3g of allyl bromide (1.3mol), after the addition is complete, keep the temperature for 1 hour, then heat to 30°C, continue to stir the reaction, and the reaction is complete after detection. Then slowly add 3mol / L sodium hydroxide aqueous solution (1000mL) to the reaction system, stir the reaction at 30°C, and the reaction is complete after detection. The extraction was performed with 500 mL of ethyl acetate, and the aqueous phase was collected; then, a 6 mol / L hydrochloric acid aqueous solution was used to adjust the pH value of the aqueous phase to 1-2, and then 500 mL of ethyl acetate was added to extract the liquid, and the organic phase was collected, and then washed with water and saturated brine, the organic phase was separated, and then dried with anhydrous sodium sulfate, and the target product I, i.e., (2E)-4-ethylhept-2,6-dienoic acid (colorless oil) was obtained by rotary drying under reduced pressure, with a yield of 91.4% and an HPLC value of 98.375%.

[0050] Example 10

[0051] Add 170.3g of compound (E)-2-hexenoic acid n-butyl ester (1.0mol) and 500mL of 1,4-dioxane to the reaction container, stir and cool to 0°C, maintain the temperature, slowly add 31.2g of NaH (1.3mol), after the addition is complete, keep warm for 1 hour, then slowly drop 157.3g of allyl bromide (1.3mol), after the addition is complete, keep warm for 1 hour, then heat to 25°C, continue to stir and react, and the reaction is complete after detection. Then slowly add 3mol / L sodium hydroxide aqueous solution (1000mL) to the reaction system, stir and react at 80°C, and the reaction is complete after detection. The extraction was performed with 500 mL of ethyl acetate, and the aqueous phase was collected; then, a 6 mol / L hydrochloric acid aqueous solution was used to adjust the pH value of the aqueous phase to 1-2, and then 500 mL of ethyl acetate was added to extract the liquid, and the organic phase was collected, and then washed with water and saturated brine, the organic phase was separated, and then dried with anhydrous sodium sulfate, and the target product I, i.e., (2E)-4-ethylhept-2,6-dienoic acid (colorless oil) was obtained by rotary drying under reduced pressure, with a yield of 91.0% and an HPLC value of 98.298%.

[0052] Embodiment 11

[0053] Add 170.3g of compound (E)-2-tert-butyl hexenoate (1.0mol) and 500mL of 1,4-dioxane to the reaction container, stir and cool to 0°C, maintain the temperature, slowly add 31.2g of NaH (1.3mol), after the addition is complete, keep warm for 1 hour, then slowly drop 157.3g of allyl bromide (1.3mol), after the addition is complete, keep warm for 1 hour, then heat to 25°C, continue to stir and react, and the reaction is complete after detection. Then slowly add 3mol / L sodium hydroxide aqueous solution (1000mL) to the reaction system, stir and react at 50°C, and the reaction is complete after detection. The extraction was performed with 500 mL of ethyl acetate, and the aqueous phase was collected; then, a 6 mol / L hydrochloric acid aqueous solution was used to adjust the pH value of the aqueous phase to 1-2, and then 500 mL of ethyl acetate was added to extract the liquid, and the organic phase was collected, and then washed with water and saturated brine, the organic phase was separated, and then dried with anhydrous sodium sulfate, and the target product I, i.e., (2E)-4-ethylhept-2,6-dienoic acid (colorless oil) was obtained by rotary drying under reduced pressure, with a yield of 91.3% and an HPLC value of 98.376%.

[0054] Comparative Example 1

[0055] To a mixture of (E)-but-1-enyldiisobutylamine (122 g, 0.665 mol) and acetonitrile (370 mL) was added allyl bromide (75 mL, 0.865 mol) dropwise at room temperature under a nitrogen atmosphere, and the mixture was then stirred for 20 minutes. The mixture was heated and stirred at an external temperature of 70°C for 17 hours, and then a Dean-Stark tube was connected. The external temperature was set to 115°C, and about 120 mL of a fraction was extracted. Acetonitrile (360 mL) was then added thereto. About 120 mL of a fraction was extracted again and then cooled to room temperature. Pyridine (108 mL, 1.33 mol), piperidine (10 mL, 0.1 mol) and malonic acid (104 g, 0.998 mol) were added in sequence to the resulting reaction mixture, and the mixture was then stirred at an external temperature of 100°C. After cooling to room temperature, 430 mL of the solvent was distilled off under reduced pressure. The pH of the reaction mixture was adjusted to 1 by adding 6M hydrochloric acid (200mL), followed by extraction with toluene (250mL×2 and 120mL×1). After extraction into the aqueous layer with 3M sodium hydroxide aqueous solution (200mL×2 and 100mL×1), the pH of the extract was adjusted to 1 with concentrated hydrochloric acid (100mL). After extraction with toluene (200ml×2), the organic layer was concentrated under reduced pressure. Toluene (200mL) was added to the residue, and the insoluble matter was filtered out. The filtrate was concentrated under reduced pressure to obtain 97.5g of the target compound I, i.e., (2E)-4-ethylhept-2,6-dienoic acid (colorless oil), with an HPLC value of 72.253%.

Claims

1. A method for preparing a milobalin intermediate (2E)-4-ethylheptyl-2,6-dienoic acid, characterized in that: Add compound SM-1, i.e., (E)-2-hexenoic acid ester compound, and reaction solvent to the reaction container, stir and cool, and when the temperature is maintained at T1, slowly add the base catalyst, and after the addition is complete, slowly add SM-2, i.e., allyl bromide, and after the addition is complete, raise the temperature to T2 and continue the reaction. After the reaction is completed, slowly add the base solution to the reaction system, stir and react at T3 temperature, and after the reaction is completed, perform post-treatment to obtain the target product I; ； The compound SM-1 substituent group R is Me, Et, Pr, i Pr, Bu, t One of the Bu groups; The temperature T1 is -30 to 10°C, the temperature T2 is 10 to 50°C, and the temperature T3 is 20 to 80°C.

2. The preparation method according to claim 1, characterized in that: The substituent group R in the compound SM-1 is Me.

3. The preparation method according to claim 1, characterized in that: The molar ratio of the compounds SM-1, SM-2 and the base catalyst is 1:1.1-1.5:1.1-1.

5.

4. The preparation method according to claim 1, characterized in that: The molar ratio of the compounds SM-1, SM-2 and the base catalyst is 1:1.3:1.

3.

5. The preparation method according to claim 1, characterized in that: The reaction solvent is one of diethyl ether, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, n-hexane, n-heptane and cyclohexane.

6. The preparation method according to claim 1, characterized in that: The reaction solvent is tetrahydrofuran and ethylene glycol dimethyl ether.

7. The preparation method according to claim 1, characterized in that: The alkaline catalyst is one of n-butyl lithium, sodium hydride, potassium tert-butoxide and sodium methoxide.

8. The preparation method according to claim 1, characterized in that: The base catalyst is sodium hydride.

9. The preparation method according to claim 1, characterized in that: The temperature T1 is -10 to 0°C; the temperature T2 is 20 to 30°C; and the temperature T3 is 30 to 50°C.

10. The preparation method according to claim 1, characterized in that: The alkaline solution is an aqueous solution of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium carbonate and potassium carbonate.

11. The preparation method according to claim 1, characterized in that: The alkaline solution is a sodium hydroxide aqueous solution.

12. The preparation method according to claim 10, characterized in that: The molar ratio of alkali to SM-1 in the alkali solution is 2 to 8:

1.

13. The preparation method according to claim 10, characterized in that: The molar ratio of alkali to SM-1 in the alkali solution is 2-4:

1.

14. The preparation method according to claim 1, characterized in that: The post-treatment is as follows: after the reaction is completed, ethyl acetate is added for extraction, the liquids are separated, and the aqueous phase is collected; then, in the aqueous phase, a hydrochloric acid aqueous solution is used to adjust the pH value of the aqueous phase to 1-4, and then ethyl acetate is added for extraction, the liquids are separated, and the organic phase is collected, and then washed with water and saturated brine, and the organic phase is dried with anhydrous sodium sulfate and dried under reduced pressure to obtain the title compound as a colorless oil.

15. The preparation method according to claim 14, characterized in that: The pH value of the aqueous phase is adjusted to 1-2 using aqueous hydrochloric acid solution as described in the post-treatment.

Images