Preparation method of octadecanedioic acid mono-tert-butyl ester

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of octadecanedioic acid mono-tert-butyl ester. The method specifically comprises the following steps: reacting dodecanedioic acid, dichloromethane and DMF (Dimethyl Formamide), controlling the temperature, dropwise adding an acylation reagent, and performing reduced pressure concentration after reaction to obtain a compound 1; reacting the compound 1, dimethylbenzene, palladium-carbon and organic alkali, carrying out nitrogen displacement, introducing hydrogen at a controlled temperature, carrying out nitrogen displacement after the reaction, and filtering and concentrating to obtain a compound 2; adding tert-butyl acrylate into an acetic acid aqueous solution, dropwise adding the compound 2, reacting, adjusting the pH value, extracting, filtering and concentrating to obtain a compound 3; adding the compound 3 into dichloromethane, controlling the temperature, adding aluminum trichloride, dropwise adding a reducing agent, reacting, filtering, adjusting the pH value, separating liquid, concentrating and recrystallizing to obtain di-tert-butyl octadecanedioate; and reacting the di-tert-butyl octadecanedioate, lithium hydroxide and tert-butyl alcohol, filtering, adjusting the pH value, extracting, concentrating and recrystallizing to obtain the mono-tert-butyl octadecanedioate. The method is low in production cost and high in safety.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of monoterbutyl octadecanedioate. Background Art

[0002] Semaglutide, a long-acting glucagon-like peptide-1 (GLP-1) analogue developed by Novo Nordisk A / S in Denmark, can exert hypoglycemic and weight loss effects through multiple mechanisms. At the same time, it has been confirmed by clinical trials that it also has good performance in many other disease fields such as cardiovascular diseases.

[0003] At present, one of the important intermediates of the side chain of Semaglutide is monoterbutyl octadecanedioate, and the disclosed process routes mainly include the following categories: The first category mainly uses octadecanedioic acid as the starting material, generates di-tert-butyl ester through an esterification reaction, and then selectively hydrolyzes it to monoterbutyl octadecanedioate. The main problem of this method is that the starting material octadecanedioic acid is expensive, resulting in a relatively high overall cost.

[0004] The second category mainly uses short-chain alkane compounds as starting materials, synthesizes octadecanedioic acid or its derivatives through multiple chemical reactions, and then prepares monoterbutyl octadecanedioate through an esterification or hydrolysis reaction. The main problems of this type of reaction are high starting material costs (such as the patent application with publication number CN112939762A), complex synthesis steps, poor reaction selectivity (such as the patent application with publication number CN118005509A), and the possible involvement of dangerous reagents such as sodium borohydride during the reaction process (such as the patent with publication number CN115368234A), which is not conducive to large-scale production.

[0005] Therefore, there is an urgent need for a synthesis method of monoterbutyl octadecanedioate with low production cost and high safety. Summary of the Invention

[0006] In view of the deficiencies of the prior art, the present invention provides a preparation method of monoterbutyl octadecanedioate.

[0007] The technical solution of the present invention is as follows: A preparation method of monoterbutyl octadecanedioate, the synthesis route includes: .

[0008] The preparation method includes the following steps: Dodecanedioic acid reacts with dichloromethane and N,N-dimethylformamide (DMF), cools down, and acylating reagent is added dropwise while controlling the temperature. After the reaction ends, it is concentrated under reduced pressure to obtain compound 1; Compound 1 reacts with xylene, palladium on carbon, and an organic base. After purging with nitrogen, the temperature is controlled, hydrogen is introduced for reaction. After the reaction is complete, it is purged with nitrogen again, filtered, the filtrate is washed with water, dried, filtered again, and concentrated under reduced pressure to obtain Compound 2; tert-Butyl acrylate is added to an aqueous acetic acid solution. While controlling the temperature, Compound 2 is added dropwise. After the addition is complete, the reaction continues until the reaction ends. The pH is adjusted, and extraction is carried out. The organic phase is dried, filtered, and the filtrate is concentrated under reduced pressure to obtain Compound 3; Compound 3 is added to dichloromethane. While controlling the temperature, aluminum trichloride is added, and then a reducing agent is added dropwise. After the addition is complete, the temperature is controlled for reaction. After the reaction ends, it is filtered, the pH of the filtrate is adjusted, allowed to stand for liquid separation, and the organic phase is concentrated under reduced pressure to obtain a crude product of di-tert-butyl octadecanedioate. The crude product is recrystallized to obtain di-tert-butyl octadecanedioate; Di-tert-butyl octadecanedioate reacts with lithium hydroxide and tert-butanol. After the reaction ends, it is filtered, the pH of the filtrate is adjusted, extraction is carried out. The organic phase is dried and concentrated under reduced pressure. The concentrate is recrystallized to obtain mono-tert-butyl octadecanedioate.

[0009] In multiple embodiments, more specifically, the following steps are included: Step 1: Add dodecanedioic acid, dichloromethane, and N,N-dimethylformamide to a reaction flask, cool down to 0 - 20 °C, and add the acylating reagent dropwise while controlling the temperature. After monitoring the reaction to completion, concentrate under reduced pressure to obtain Compound 1.

[0010] Step 2: Add Compound 1, xylene, palladium on carbon, and an organic base to a reactor, purge with nitrogen, control the temperature at 10 - 40 °C, introduce hydrogen for reaction. After the reaction is complete, purge with nitrogen again, filter, wash the filtrate with water multiple times, dry, filter again, and concentrate under reduced pressure to obtain Compound 2.

[0011] Step 3: Add tert-butyl acrylate to an aqueous acetic acid solution, add Compound 2 dropwise while controlling the temperature at 10 - 40 °C. After the addition is complete, continue the reaction until the reaction ends. Adjust the pH to 7 - 8 with an aqueous sodium hydroxide solution, extract with dichloromethane multiple times. The organic phase is dried, filtered, and the filtrate is concentrated under reduced pressure to obtain Compound 3.

[0012] Step 4: Add Compound 3 to dichloromethane (DCM), control the temperature at -20 - 15 °C, first add aluminum trichloride, then add the reducing agent dropwise. After the addition is complete, control the temperature at 10 - 25 °C for reaction. After monitoring the reaction to completion, filter, adjust the pH of the filtrate to 7 - 8 with a saturated aqueous sodium bicarbonate solution, allow to stand for liquid separation, and concentrate the organic phase under reduced pressure to obtain a crude product of di-tert-butyl octadecanedioate. The crude product is recrystallized with acetonitrile to obtain di-tert-butyl octadecanedioate.

[0013] Step 5: Add di-tert-butyl octadecanedioate, lithium hydroxide (LiOH), and tert-butanol into a reactor. After the reaction is completed at room temperature, filter the mixture. Adjust the pH of the filtrate to weakly acidic with dilute hydrochloric acid, then extract with dichloromethane. After drying the organic phase, concentrate it under reduced pressure. The concentrate is recrystallized from toluene to obtain mono-tert-butyl octadecanedioate.

[0014] Further, in Step 1, the acylating agent includes at least one of thionyl chloride and oxalyl chloride.

[0015] More specifically, the molar ratio of dodecanedioic acid to thionyl chloride is 1:2.2 - 5.0; preferably 1:2.5.

[0016] More specifically, the molar ratio of dodecanedioic acid to oxalyl chloride is 1:4.0 - 7.0; preferably 1:5.0.

[0017] Further, in Step 2, the organic base includes at least one of N,N-dimethylacetamide (DMAC), sodium acetate, and N,N-diisopropylethylamine (DIPEA).

[0018] More specifically, the molar ratio of Compound 1 to the organic base is 1:2.5 - 5.0, preferably 1:3.0.

[0019] Further, in Step 3, the water content of the aqueous acetic acid solution is 5% - 20%, preferably 10%.

[0020] Further, in Step 4, the reducing agent is selected from tetramethyldisiloxane (TMDSO), triethylsilane, and hexamethyldisiloxane (HMDSO), preferably tetramethyldisiloxane.

[0021] More specifically, the molar ratio of Compound 3 to the reducing agent is 1:1.5 - 6.0.

[0022] Compared with the prior art, the beneficial effects of the present invention are as follows: The present invention provides a new method for preparing mono-tert-butyl octadecanedioate, an important intermediate of the side chain of semaglutide.

[0023] This method uses inexpensive dodecanedioic acid as the starting material, avoids using high-risk reducing agents such as sodium borohydride, and the reaction process is safer and more efficient, greatly reducing the production cost and improving the production safety, which is beneficial to industrial production.

[0024] The synthetic route is simplified and efficient, and the target product can be synthesized through five-step reactions, reducing the multi-step functional group transformation or complex protection / deprotection steps in the traditional method. Description of the Drawings

[0025] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings required for describing the embodiments will be briefly introduced below. Obviously, the accompanying drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other accompanying drawings can be obtained based on these drawings.

[0026] Figure 1 This is the HPLC blank chromatogram of the present invention; Figure 2 This is the HPLC chromatogram of monoterbutyl octadecanedioate of the present invention; Figure 3 This is the 1H NMR spectrum of monoterbutyl octadecanedioate of the present invention. Detailed implementation manners

[0027] In order to make the objectives, technical solutions and advantages of the present invention more clear and understandable, the present invention will be further described in detail below in conjunction with embodiments and the accompanying drawings. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0028] Unless otherwise specified, the experimental methods used below are all conventional methods. The equipment, materials, reagents, etc. used, unless otherwise specified, can all be obtained through commercial channels. The principles or mechanisms of the equipment that can be purchased conventionally through commercial channels are well known, so they will not be elaborated here.

[0029] Unless otherwise specified, the raw materials involved in the present invention are selected as analytical pure with a purity ≥ 97%.

[0030] It should be noted that 5% wet palladium on carbon means a loading amount of 5%, that is, 5% palladium on carbon.

[0031] The detection method for the following examples is: the compound is detected and determined by HPLC chromatography or / and 1H NMR spectrum.

[0032] Among them, the blank chromatogram of HPLC can be referred to Figure 1 .

[0033] The present invention provides a preparation method for monoterbutyl octadecanedioate, and the synthesis route is as follows: .

[0034] Example 1 Prepare Compound 1, and the specific steps are as follows: Add dodecanedioic acid (10.0 g, 43.42 mmol), 50 ml of dichloromethane and 5 ml of DMF into a reaction flask, cool down to 5 °C, control the temperature at 0 - 15 °C and dropwise add thionyl chloride (12.9 g, 108.4 mmol). After the addition is completed, continue the reaction for 1.5 h. Monitor the end of the reaction by TLC. Concentrate under reduced pressure at 35 °C to obtain the intermediate, that is, compound 1 (11.5 g, 43.04 mmol), with a yield of 99.1%.

[0035] Example 2 Prepare compound 1, and the specific steps are as follows: Add dodecanedioic acid (10.0 g, 43.42 mmol), 50 ml of dichloromethane and 5 ml of DMF into a reaction flask, cool down to 2 °C, control the temperature at 5 - 20 °C and dropwise add oxalyl chloride (27.6 g, 217.4 mmol). After the addition is completed, continue the reaction for 2 h. Monitor the end of the reaction by TLC. Concentrate under reduced pressure at 40 °C to obtain the intermediate, that is, compound 1 (11.44 g, 42.81 mmol), with a yield of 98.6%.

[0036] Different from Example 1, oxalyl chloride is used to replace thionyl chloride in this example.

[0037] Example 3 Prepare compound 2, and the specific steps are as follows: Under room temperature conditions, add the compound 1 prepared in Example 1 (11.5 g, 43.04 mmol), 60 ml of xylene, 0.13 g of 5% wet palladium carbon and DMAC (11.25 g, 129.13 mmol) into a reactor. Replace with nitrogen three times, heat up to 30 - 40 °C, introduce hydrogen for reaction. After reacting for 3 h, monitor the completion of the reaction by TLC. Replace with nitrogen three times, filter. Wash the filtrate 3 times with water, dry the organic phase with 2 g of anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 2 (7.57 g, 38.17 mmol), with a yield of 88.7%.

[0038] Example 4 Prepare compound 2, and the specific steps are as follows: Under room temperature conditions, add the compound 1 prepared in Example 1 (11.5 g, 43.04 mmol), 60 ml of xylene, 0.13 g of 5% wet palladium carbon and sodium acetate (10.6 g, 129.22 mmol) into a reactor. Replace with nitrogen three times, heat up to 25 - 35 °C, introduce hydrogen for reaction. After reacting for 5 h, monitor the completion of the reaction by TLC. Replace with nitrogen three times, filter. Wash the filtrate 3 times with water, dry the organic phase with 2 g of anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 2 (6.70 g, 33.79 mmol), with a yield of 78.5%.

[0039] Different from Example 3, sodium acetate is used to replace DMAC in this example.

[0040] Example 5 To prepare Compound 2, the specific steps are as follows: At room temperature, Compound 1 (11.5 g, 43.04 mmol) prepared in Example 1, 60 ml of xylene, 0.13 g of 5% wet palladium carbon, and DIPEA (16.69 g, 129.13 mmol) were added to a reactor. After purging with nitrogen three times, the temperature was raised to 30 - 40 °C, and hydrogen was introduced for reaction. After reacting for 2 h, the reaction was monitored by TLC and found to be complete. After purging with nitrogen three times, the mixture was filtered. The filtrate was washed with water three times, and the organic phase was dried with 2 g of anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Compound 2 (6.98 g, 35.20 mmol), with a yield of 81.8%.

[0041] Different from Example 3, DIPEA is used to replace DMAC in this example.

[0042] Example 6 To prepare Compound 3, the specific steps are as follows: tert-Butyl acrylate (12.23 g, 95.4 mmol) was added to 100 ml of 90% aqueous acetic acid solution. While controlling the temperature at 15 - 30 °C, Compound 2 (7.57 g, 38.17 mmol) prepared in Example 3 was added dropwise. After the addition was complete, the reaction continued for 4 h. The reaction was monitored by TLC and found to be complete. The pH of the system was adjusted to 8 with an aqueous sodium hydroxide solution, and the mixture was extracted three times with dichloromethane (100 ml each time). The combined organic phases were dried with 10 g of anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure at 35 °C to obtain Compound 3 (15.49 g, 31.57 mmol), with a yield of 82.7%.

[0043] Example 7 To prepare di-tert-butyl octadecanedioate, the specific steps are as follows: Compound 3 (15.49 g, 31.57 mmol) prepared in Example 6 was added to 150 ml of DCM. The temperature was lowered to -20 - -15 °C, and aluminum trichloride (8.42 g, 63.15 mmol) was added. After stirring for 0.5 h and controlling the temperature not exceeding 15 °C, TMDSO (15.26 g, 113.60 mmol) was added dropwise. After the addition was complete, the temperature was raised to 10 - 25 °C, and the reaction continued for 1.5 h. The reaction was monitored by TLC and found to be complete. The mixture was filtered, and the pH of the filtrate was adjusted to 8 with a saturated aqueous sodium bicarbonate solution. After standing and separating the layers, the organic phase was concentrated under reduced pressure at 40 °C to obtain the crude product of di-tert-butyl octadecanedioate.

[0044] 93 ml of acetonitrile was added to the crude product, and the mixture was heated to 70 °C and stirred until dissolved. Then, the temperature was lowered to 5 - 15 °C for crystallization for more than 2 h. After filtration and drying, di-tert-butyl octadecanedioate (9.61 g, 22.52 mmol) was obtained with a yield of 71.3%.

[0045] Example 8 To prepare di-tert-butyl octadecanedioate, the specific steps are as follows: Compound 3 (15.49 g, 31.57 mmol) prepared in Example 6 was added to 150 ml of DCM. The temperature was lowered to -20 - -15 °C, and aluminum trichloride (8.42 g, 63.15 mmol) was added. The mixture was stirred for 0.5 h while controlling the temperature not to exceed 20 °C. Triethylsilane (21.83 g, 189.38 mmol) was added dropwise. After the addition was completed, the temperature was raised to 20 - 25 °C. After reacting for 3 h, the reaction was monitored by TLC until it ended. Then, the mixture was filtered, and the pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate aqueous solution. After standing and separating the layers, the organic phase was concentrated under reduced pressure at 40 °C to obtain the crude product of di-tert-butyl octadecanedioate.

[0046] 93 ml of acetonitrile was added to the crude product, and the mixture was heated to 70 °C and stirred until dissolved. Then, the temperature was lowered to 5 - 15 °C for crystallization for more than 2 h. After filtration and drying, di-tert-butyl octadecanedioate (8.48 g, 19.87 mmol) was obtained with a yield of 62.9%.

[0047] Different from Example 7, triethylsilane was used to replace TMDSO in this example.

[0048] Example 9 To prepare di-tert-butyl octadecanedioate, the specific steps are as follows: Compound 3 (15.49 g, 31.57 mmol) prepared in Example 6 was added to 150 ml of DCM. The temperature was lowered to -20 - -15 °C, and aluminum trichloride (8.42 g, 63.15 mmol) was added. The mixture was stirred for 0.5 h while controlling the temperature not to exceed 20 °C. HMDSO (14.35 g, 88.36 mmol) was added dropwise. After the addition was completed, the temperature was raised to 15 - 25 °C. After reacting for 2 h, the reaction was monitored by TLC until it ended. Then, the mixture was filtered, and the pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate aqueous solution. After standing and separating the layers, the organic phase was concentrated under reduced pressure at 35 °C to obtain the crude product of di-tert-butyl octadecanedioate.

[0049] 93 ml of acetonitrile was added to the crude product, and the mixture was heated to 70 °C and stirred until dissolved. Then, the temperature was lowered to 5 - 15 °C for crystallization for more than 2 h. After filtration and drying, di-tert-butyl octadecanedioate (9.31 g, 21.82 mmol) was obtained with a yield of 69.1%.

[0050] Different from Example 7, HMDSO was used to replace TMDSO in this example.

[0051] Example 10 To prepare monoterbutyl octadecanedioate, the specific steps are as follows: Put ditertbutyl octadecanedioate (9.61 g, 22.52 mmol) prepared in Example 7, LiOH (2.70 g, 112.73 mmol), and 150 ml of tert-butanol into a reactor, react at room temperature for 3 h, perform suction filtration after the reaction ends, adjust the pH of the filtrate to 6 with dilute hydrochloric acid, add 150 ml of dichloromethane for extraction, let it stand for liquid separation, dry the organic phase with anhydrous sodium sulfate and then filter, and concentrate the filtrate under reduced pressure at 35 °C to obtain the crude product of monoterbutyl octadecanedioate.

[0052] Add 80 ml of toluene to the crude product, first heat it to 80 °C, after the solid is completely dissolved, cool it to 10 - 25 °C for crystallization for more than 1 h, filter, and dry the solid to obtain monoterbutyl octadecanedioate (6.38 g, 17.22 mmol), a white solid, with a yield of 76.5% and a purity of 99.37%. The results are shown in Figure 2 and Figure 3 .

[0053] It should be noted that from the yields of Examples 7 - 9, the reducing agent is selected from tetramethyldisiloxane (TMDSO), triethylsilane, and hexamethyldisiloxane (HMDSO), and preferably tetramethyldisiloxane.

[0054] Generally speaking, starting from dodecanedioic acid, the present invention provides a preparation method of monoterbutyl octadecanedioate, an important intermediate of the side chain of semaglutide, which has high safety, better yields in each step, and a relatively high purity of the final product.

[0055] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than a limitation on the protection scope of the present invention. Any simple modification or equivalent replacement of the technical solution of the present invention by those of ordinary skill in the art shall not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing octadecane dioic acid mono-tert-butyl ester, characterized in that: The steps include: Dodecanedioic acid, dichloromethane and N,N-dimethylformamide are reacted, the temperature is lowered, and an acylating agent is added dropwise under temperature control. After the reaction, the compound 1 is obtained by concentrating under reduced pressure; Compound 1, xylene, palladium carbon and an organic base are reacted, replaced with nitrogen, the temperature is controlled, hydrogen is introduced for reaction, and after the reaction, nitrogen is replaced, filtered, the filtrate is washed with water, dried, filtered, and concentrated under reduced pressure to obtain compound 2; Tert-butyl acrylate is added to an aqueous solution of acetic acid, and compound 2 is added dropwise at a controlled temperature. After the addition, the reaction is continued until completion, the pH is adjusted, extraction is performed, the organic phase is dried and filtered, and the filtrate is concentrated under reduced pressure to obtain compound 3; Compound 3 is added to dichloromethane, the temperature is controlled, aluminum chloride is added, and a reducing agent is added dropwise, and the temperature is controlled to react after the addition, and after the reaction, the reaction is filtered, the pH is adjusted, and the liquid is separated by standing. The organic phase is concentrated under reduced pressure to obtain a crude product, and the crude product is recrystallized to obtain di-tert-butyl octadecane dioate; Octadecanedioic acid di-tert-butyl ester, lithium hydroxide and tert-butyl alcohol are reacted, filtered after the reaction, pH is adjusted, extracted, the organic phase is dried and concentrated under reduced pressure, and the concentrate is recrystallized to obtain octadecanedioic acid mono-tert-butyl ester.

2. The method for preparing octadecane dioic acid mono-tert-butyl ester according to claim 1, characterized in that: The acylating agent comprises at least one of thionyl chloride and oxalyl chloride; the molar ratio of dodecanedioic acid to thionyl chloride is 1:2.2-5.0; the molar ratio of dodecanedioic acid to oxalyl chloride is 1:4.0-7.

0.

3. The method for preparing octadecane dioic acid mono-tert-butyl ester according to claim 1, characterized in that: The organic base includes at least one of N,N-dimethylacetamide, sodium acetate, and N,N-diisopropylethylamine; the molar ratio of compound 1 to the organic base is 1:2.5-5.

0.

4. The method for preparing octadecane dioic acid mono-tert-butyl ester according to claim 1, characterized in that: The reducing agent includes at least one of tetramethyldisiloxane, triethylsilane and hexamethyldisiloxane; the molar ratio of compound 3 to the reducing agent is 1:1.5-6.

0.

5. The method for preparing octadecanedioic acid mono-tert-butyl ester according to claim 1, characterized in that: Dodecanedioic acid, dichloromethane and N,N-dimethylformamide were added to a reaction bottle, the temperature was lowered to 0-20°C, and the acylating reagent was added dropwise under temperature control. After the reaction was completed, the reaction was concentrated under reduced pressure to obtain compound 1.

6. The method for preparing octadecanedioic acid mono-tert-butyl ester according to claim 1, characterized in that: Compound 1, xylene, palladium carbon and organic base are added to a reactor, replaced with nitrogen, the temperature is controlled at 10-40°C, hydrogen is introduced for reaction, and after the reaction is complete, nitrogen is replaced, filtered, the filtrate is washed with water, dried, filtered, and concentrated under reduced pressure to obtain compound 2.

7. The method for preparing octadecanedioic acid mono-tert-butyl ester according to claim 1, characterized in that: Add tert-butyl acrylate to an acetic acid aqueous solution, control the temperature at 10-40°C, add compound 2 dropwise, continue the reaction after the addition is complete, adjust the pH to 7-8 with an aqueous sodium hydroxide solution, extract with dichloromethane for several times, dry the organic phase and filter, and concentrate the filtrate under reduced pressure to obtain compound 3; wherein the water content of the acetic acid aqueous solution is 5%-20%.

8. The method for preparing octadecanedioic acid mono-tert-butyl ester according to claim 1, characterized in that: Compound 3 was added to dichloromethane, the temperature was controlled at -20~15°C, aluminum chloride was added first, and then the reducing agent was added dropwise. After the addition was completed, the temperature was controlled at 10~25°C for reaction. After the reaction was completed, it was filtered, and the pH of the filtrate was adjusted to 7~8 with a saturated sodium bicarbonate aqueous solution. The filtrate was allowed to stand for separation, and the organic phase was concentrated under reduced pressure to obtain a crude product of di-tert-butyl octadecane dioate. The crude product was recrystallized from acetonitrile to obtain di-tert-butyl octadecane dioate.

9. The method for preparing octadecanedioic acid mono-tert-butyl ester according to claim 1, characterized in that: Di-tert-butyl octadecane dioate, lithium hydroxide and tert-butyl alcohol are added into a reactor. After the reaction is completed at room temperature, the reaction is filtered. The pH of the filtrate is adjusted to weak acidity with dilute hydrochloric acid, and then extracted with dichloromethane. The organic phase is dried and concentrated under reduced pressure. The concentrate is recrystallized from toluene to obtain mono-tert-butyl octadecane dioate.

10. The method for preparing octadecanedioic acid mono-tert-butyl ester according to claim 1, characterized in that: The synthetic routes include: 。

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