A process for the preparation of monotertiary butyl octadecandioate

Abstract

The application belongs to the technical field of organic synthesis and particularly relates to a preparation method of monotert-butyl octadecanedioate. Specifically, dodecanedioic acid, dichloromethane and DMF are reacted, temperature is controlled, an acylation reagent is added dropwise, compound 1 is obtained after reaction and concentration under reduced pressure; compound 1, dimethylbenzene, palladium charcoal and an organic base are reacted, nitrogen is replaced, hydrogen is introduced under temperature control, nitrogen is replaced after reaction, filtration and concentration are performed, and compound 2 is obtained; tert-butyl acrylate is added into an acetic acid aqueous solution, compound 2 is added dropwise, reaction is performed, pH is adjusted, extraction is performed, filtration and concentration are performed, and compound 3 is obtained; compound 3 is added into dichloromethane, temperature is controlled, aluminum chloride is added, a reducing agent is added dropwise, reaction is performed, filtration is performed, pH is adjusted, liquid separation is performed, concentration and recrystallization are performed, and di-tert-butyl octadecanedioate is obtained; di-tert-butyl octadecanedioate, lithium hydroxide and tert-butyl alcohol are reacted, filtration is performed, pH is adjusted, extraction is performed, concentration and recrystallization are performed, and monotert-butyl octadecanedioate is obtained. The method has low production cost and high safety.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing tert-butyl octadecanoate. Background Technology

[0002] Semaglutide, developed by Novo Nordisk of Denmark, is a long-acting glucagon-like peptide-1 (GLP-1) analog that exerts its blood sugar-lowering and weight-loss effects through multiple mechanisms. Furthermore, clinical trials have demonstrated its effectiveness in treating cardiovascular and other diseases.

[0003] Currently, one of the important intermediates for the side chain of semaglutide is tert-butyl octadecanoate, and its disclosed process routes mainly fall into the following categories:

[0004] The first type primarily uses octadecanoic acid as the starting material, which undergoes esterification to produce di-tert-butyl ester, followed by selective hydrolysis to octadecanoic acid mono-tert-butyl ester. The main problem with this method is the high cost of octadecanoic acid as the starting material, resulting in a higher overall cost.

[0005] The second type mainly uses short-chain alkane compounds as starting materials to synthesize octadecanoic acid or its derivatives through multiple chemical reactions, followed by esterification or hydrolysis to prepare tert-butyl octadecanoic acid. The main problems with this type of reaction are the high cost of starting materials (such as patent application CN112939762A), complex synthesis steps, poor reaction selectivity (such as patent application CN118005509A), and the potential involvement of hazardous reagents such as sodium borohydride during the reaction (such as patent CN115368234A), which is not conducive to large-scale production.

[0006] Therefore, there is an urgent need for a method to synthesize tert-butyl octadecanoate with low production cost and high safety. Summary of the Invention

[0007] To address the shortcomings of existing technologies, this invention provides a method for preparing tert-butyl octadecanoate.

[0008] The technical solution of this invention is as follows:

[0009] A method for preparing tert-butyl octadecanoate, the synthetic route including:

[0010] .

[0011] The preparation method includes the following steps:

[0012] Dodecanoic acid, dichloromethane, and N,N-dimethylformamide (DMF) were reacted, the temperature was lowered, and an acylation reagent was added dropwise under controlled temperature. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain compound 1.

[0013] Compound 1, xylene, palladium on carbon, and an organic base were reacted. Nitrogen was used to purge the mixture, and the temperature was controlled. Hydrogen was then introduced to purge the mixture. After the reaction was complete, nitrogen was used to purge the mixture, and the mixture was filtered. The filtrate was washed with water, dried, filtered, and concentrated under reduced pressure to obtain compound 2.

[0014] tert-butyl acrylate was added to an aqueous acetic acid solution, and compound 2 was added dropwise under controlled temperature. After the addition was complete, the reaction continued until the reaction was finished. The pH was adjusted, the mixture was extracted, the organic phase was dried and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 3.

[0015] Compound 3 was added to dichloromethane, and the temperature was controlled. After adding aluminum trichloride, a reducing agent was added dropwise. After the addition was completed, the temperature was controlled and the reaction was carried out. After the reaction was completed, the mixture was filtered, the pH of the filtrate was adjusted, and the mixture was allowed to stand and separated. The organic phase was concentrated under reduced pressure to obtain crude di-tert-butyl octadecanoate. The crude product was recrystallized to obtain di-tert-butyl octadecanoate.

[0016] Di-tert-butyl octadecanoate, lithium hydroxide, and tert-butanol were reacted. After the reaction was completed, the mixture was filtered, the pH of the filtrate was adjusted, and the mixture was extracted. The organic phase was dried and concentrated under reduced pressure. The concentrate was recrystallized to obtain mono-tert-butyl octadecanoate.

[0017] In several embodiments, more specifically, the steps include the following:

[0018] Step 1: Add dodecanoic acid, dichloromethane and N,N-dimethylformamide to a reaction flask, cool to 0~20℃, add acylation reagent dropwise under controlled temperature, monitor the reaction and concentrate under reduced pressure to obtain compound 1.

[0019] Step 2: Add compound 1, xylene, palladium on carbon and organic base to the reactor, purge with nitrogen, control the temperature at 10~40℃, introduce hydrogen to react, after the reaction is complete, purge with nitrogen, filter, wash the filtrate with water several times, dry, filter, concentrate under reduced pressure to obtain compound 2.

[0020] Step 3: Add tert-butyl acrylate to an aqueous acetic acid solution, and add compound 2 dropwise while controlling the temperature at 10~40℃. After the addition is complete, continue the reaction until the reaction is finished. Adjust the pH to 7~8 with an aqueous sodium hydroxide solution, extract with dichloromethane multiple times, dry the organic phase, filter, and concentrate the filtrate under reduced pressure to obtain compound 3.

[0021] Step 4: Add compound 3 to dichloromethane (DCM), control the temperature at -20~15℃, add aluminum trichloride first, then add reducing agent dropwise. After the addition is complete, control the temperature at 10~25℃ for reaction. After the reaction is completed, filter, adjust the pH of the filtrate to 7~8 with saturated sodium bicarbonate aqueous solution, let stand and separate the liquid, concentrate the organic phase under reduced pressure to obtain crude di-tert-butyl octadecanoate, and recrystallize the crude product from acetonitrile to obtain di-tert-butyl octadecanoate.

[0022] Step 5: Add di-tert-butyl octadecanoate, lithium hydroxide (LiOH) and tert-butanol to the reactor. After the reaction is completed at room temperature, filter the solution. Adjust the pH of the filtrate to weakly acidic with dilute hydrochloric acid, then extract with dichloromethane. After drying the organic phase, concentrate under reduced pressure. Recrystallize the concentrate from toluene to obtain mono-tert-butyl octadecanoate.

[0023] Furthermore, in step 1, the acylation agent includes at least one of thionyl chloride and oxalyl chloride.

[0024] More specifically, the molar ratio of dodecanoic acid to thionyl chloride is 1:2.2 to 5.0; preferably 1:2.5.

[0025] More specifically, the molar ratio of dodecanoic acid to oxaloyl chloride is 1:4.0 to 7.0; preferably 1:5.0.

[0026] Furthermore, in step 2, the organic base includes at least one of N,N-dimethylacetamide (DMAC), sodium acetate, and N,N-diisopropylethylamine (DIPEA).

[0027] More specifically, the molar ratio of compound 1 to organic base is 1:2.5 to 5.0, preferably 1:3.0.

[0028] Furthermore, in step 3, the water content of the acetic acid aqueous solution is 5% to 20%, preferably 10%.

[0029] Furthermore, in step 4, the reducing agent is selected from tetramethyldisiloxane (TMDSO), triethylsilane, and hexamethyldisiloxane (HMDSO), with tetramethyldisiloxane being preferred.

[0030] More specifically, the molar ratio of compound 3 to the reducing agent is 1:1.5~6.0.

[0031] Compared with the prior art, the beneficial effects of the present invention are:

[0032] This invention provides a novel method for preparing tert-butyl octadecanoate, an important intermediate in the side chain of smegglutinin.

[0033] This method uses inexpensive dodecanoic acid as a starting material, avoiding the use of high-risk reducing agents such as sodium borohydride. The reaction process is safer and more efficient, significantly reducing production costs and improving production safety, which is conducive to industrial production.

[0034] The synthetic route is simplified and efficient, and the target product can be synthesized in just five steps, reducing the number of functional group transformations or complex protection / deprotection steps in traditional methods. Attached Figure Description

[0035] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0036] Figure 1 This is the HPLC blank chromatogram of the present invention;

[0037] Figure 2 This is the HPLC chromatogram of tert-butyl octadecanoate of the present invention;

[0038] Figure 3 The image shows the 1H NMR spectrum of octadecanoic acid monotert-butyl ester of this invention. Detailed Implementation

[0039] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments and accompanying drawings. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0040] Unless otherwise specified, the experimental methods used below are all conventional methods. Unless otherwise specified, the equipment, materials, reagents, etc. used can all be obtained commercially. The principles or mechanisms of equipment that can be purchased commercially are well known, so they will not be elaborated further.

[0041] Unless otherwise specified, the raw materials involved in this invention are of analytical grade with a purity ≥ 97%.

[0042] It should be noted that 5% wet palladium on carbon refers to a 5% loading, i.e., 5% palladium on carbon.

[0043] The detection method in the following embodiments is as follows: the compound is detected and identified by HPLC chromatography and / or 1H NMR spectroscopy.

[0044] The blank chromatogram for HPLC can be found by referring to... Figure 1 .

[0045] This invention provides a method for preparing tert-butyl octadecanoate, the synthetic route of which is as follows:

[0046] .

[0047] Example 1

[0048] The specific steps for preparing compound 1 are as follows:

[0049] Dodecanoic acid (10.0 g, 43.42 mmol), 50 mL dichloromethane, and 5 mL DMF were added to a reaction flask. The mixture was cooled to 5 °C, and thionyl chloride (12.9 g, 108.4 mmol) was added dropwise at a controlled temperature of 0–15 °C. After the addition was complete, the reaction was allowed to continue for 1.5 h. The reaction was then monitored by TLC until it was complete. The mixture was concentrated under reduced pressure at 35 °C to obtain the intermediate, compound 1 (11.5 g, 43.04 mmol), with a yield of 99.1%.

[0050] Example 2

[0051] The specific steps for preparing compound 1 are as follows:

[0052] Dodecanoic acid (10.0 g, 43.42 mmol), 50 mL dichloromethane, and 5 mL DMF were added to a reaction flask. The mixture was cooled to 2 °C, and oxaloyl chloride (27.6 g, 217.4 mmol) was added dropwise at a controlled temperature of 5–20 °C. After the addition was complete, the reaction was continued for 2 h. The reaction was then monitored by TLC until it ended. The mixture was concentrated under reduced pressure at 40 °C to obtain the intermediate, compound 1 (11.44 g, 42.81 mmol), with a yield of 98.6%.

[0053] Unlike Example 1, this example uses oxalyl chloride instead of thionyl chloride.

[0054] Example 3

[0055] The specific steps for preparing compound 2 are as follows:

[0056] At room temperature, compound 1 (11.5 g, 43.04 mmol) prepared in Example 1, 60 ml xylene, 0.13 g of 5% wet palladium on carbon, and DMAC (11.25 g, 129.13 mmol) were added to a reactor. The reactor was purged with nitrogen three times, heated to 30-40 °C, and hydrogen was introduced to react. After 3 h of reaction, the reaction was monitored by TLC to ensure complete reaction. The reactor was purged with nitrogen three times, filtered, and the filtrate was washed with water three times. 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 (7.57 g, 38.17 mmol), with a yield of 88.7%.

[0057] Example 4

[0058] The specific steps for preparing compound 2 are as follows:

[0059] At room temperature, compound 1 (11.5 g, 43.04 mmol) prepared in Example 1, 60 ml xylene, 0.13 g of 5% wet palladium on carbon, and sodium acetate (10.6 g, 129.22 mmol) were added to a reactor. The reactor was purged with nitrogen three times, heated to 25-35 °C, and hydrogen was introduced to react. After 5 h of reaction, the reaction was monitored by TLC to be complete. The reactor was purged with nitrogen three times, filtered, and the filtrate was washed with water three times. 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 (6.70 g, 33.79 mmol), with a yield of 78.5%.

[0060] Unlike Example 3, sodium acetate is used instead of DMAC in this example.

[0061] Example 5

[0062] The specific steps for preparing compound 2 are as follows:

[0063] At room temperature, compound 1 (11.5 g, 43.04 mmol) prepared in Example 1, 60 ml xylene, 0.13 g of 5% wet palladium on carbon, and DIPEA (16.69 g, 129.13 mmol) were added to a reactor. The reactor was purged with nitrogen three times, heated to 30-40 °C, and hydrogen was introduced to react. After 2 h of reaction, the reaction was monitored by TLC to ensure it was complete. The reactor was purged with nitrogen three times, filtered, and the filtrate was washed with water three times. 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%.

[0064] Unlike Example 3, this example uses DIPEA instead of DMAC.

[0065] Example 6

[0066] The specific steps for preparing compound 3 are as follows:

[0067] 12.23 g (95.4 mmol) of tert-butyl acrylate was added to 100 ml of 90% acetic acid aqueous solution. Compound 2 (7.57 g (38.17 mmol) prepared in Example 3 was added dropwise at a controlled temperature of 15-30 °C. After the addition was complete, the reaction was continued for 4 h. The reaction was monitored by TLC until it ended. The pH of the system was adjusted to 8 with sodium hydroxide aqueous solution. The mixture was extracted three times with dichloromethane, 100 ml each time. The organic phases were combined, dried with 10 g of anhydrous sodium sulfate, and 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%.

[0068] Example 7

[0069] The specific steps for preparing di-tert-butyl octadecanoate are as follows:

[0070] Compound 3 (15.49 g, 31.57 mmol) prepared in Example 6 was added to 150 ml of DCM, cooled to -20 to -15 °C, and aluminum trichloride (8.42 g, 63.15 mmol) was added. The mixture was stirred for 0.5 h, and the temperature was controlled not to exceed 15 °C. TMDSO (15.26 g, 113.60 mmol) was added dropwise. After the addition was complete, the temperature was raised to 10 to 25 °C, and the reaction was carried out for 1.5 h. The reaction was monitored by TLC until it ended. The mixture was filtered, and the pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The mixture was allowed to stand and separated. The organic phase was concentrated under reduced pressure at 40 °C to obtain crude di-tert-butyl octadecanoate.

[0071] Add 93 ml of acetonitrile to the crude product, heat to 70 °C and stir to dissolve, cool to 5-15 °C to crystallize for more than 2 hours, filter and dry to obtain di-tert-butyl octadecanoate (9.61 g, 22.52 mmol), yield 71.3%.

[0072] Example 8

[0073] The specific steps for preparing di-tert-butyl octadecanoate are as follows:

[0074] Compound 3 (15.49 g, 31.57 mmol) prepared in Example 6 was added to 150 ml of DCM, cooled to -20 to -15 °C, and aluminum trichloride (8.42 g, 63.15 mmol) was added. The mixture was stirred for 0.5 h, and the temperature was controlled not to exceed 20 °C. Triethylsilane (21.83 g, 189.38 mmol) was added dropwise. After the addition was complete, the temperature was raised to 20 to 25 °C. The reaction was carried out for 3 h, and the reaction was monitored by TLC until it ended. The mixture was filtered, and the pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The mixture was allowed to stand and separated. The organic phase was concentrated under reduced pressure at 40 °C to obtain crude di-tert-butyl octadecanoate.

[0075] Add 93 ml of acetonitrile to the crude product, heat to 70 °C and stir to dissolve, cool to 5-15 °C to crystallize for more than 2 hours, filter and dry to obtain di-tert-butyl octadecanoate (8.48 g, 19.87 mmol), yield 62.9%.

[0076] Unlike Example 7, this example uses triethylsilane instead of TMDSO.

[0077] Example 9

[0078] The specific steps for preparing di-tert-butyl octadecanoate are as follows:

[0079] Compound 3 (15.49 g, 31.57 mmol) prepared in Example 6 was added to 150 ml of DCM and cooled to -20 to -15 °C. Aluminum trichloride (8.42 g, 63.15 mmol) was added and stirred for 0.5 h. HMDSO (14.35 g, 88.36 mmol) was added dropwise while controlling the temperature not to exceed 20 °C. After the addition was complete, the temperature was raised to 15 to 25 °C and the reaction was carried out for 2 h. The reaction was monitored by TLC and the mixture was filtered. The pH of the filtrate was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The mixture was allowed to stand and separated. The organic phase was concentrated under reduced pressure at 35 °C to obtain crude di-tert-butyl octadecanoate.

[0080] Add 93 ml of acetonitrile to the crude product, heat to 70 °C and stir to dissolve, cool to 5-15 °C to crystallize for more than 2 hours, filter and dry to obtain di-tert-butyl octadecanoate (9.31 g, 21.82 mmol), yield 69.1%.

[0081] Unlike Example 7, this example uses HMDSO instead of TMDSO.

[0082] Example 10

[0083] The specific steps for preparing tert-butyl octadecanoate are as follows:

[0084] Di-tert-butyl octadecanoate (9.61 g, 22.52 mmol), LiOH (2.70 g, 112.73 mmol), and 150 ml of tert-butanol prepared in Example 7 were added to a reactor and reacted at room temperature for 3 h. After the reaction was completed, the mixture was filtered, and the pH of the filtrate was adjusted to 6 with dilute hydrochloric acid. 150 ml of dichloromethane was added for extraction, and the mixture was allowed to stand and separated. The organic phase was dried with anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure at 35 °C to obtain crude tert-butyl octadecanoate.

[0085] Add 80 ml of toluene to the crude product, heat to 80 °C until the solid is completely dissolved, then cool to 10–25 °C to allow crystals to precipitate for at least 1 hour. Filter and dry the solid to obtain 6.38 g (17.22 mmol) of tert-butyl octadecanoate, a white solid with a yield of 76.5% and a purity of 99.37%. See the results below. Figure 2 and Figure 3 .

[0086] It should be noted that, as can be seen from the yields of Examples 7-9, the reducing agent is selected from tetramethyldisiloxane (TMDSO), triethylsilane, and hexamethyldisiloxane (HMDSO), with tetramethyldisiloxane being preferred.

[0087] In summary, this invention provides a novel method for preparing tert-butyl octadecanoate, an important intermediate in the side chain of smegglutide, using dodecanoic acid as a starting material. The method is highly safe, yields good results at each step, and produces a high-purity final product.

[0088] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing tert-butyl octadecanoate, characterized in that, Includes the following steps: Dodecanoic acid, dichloromethane, and N,N-dimethylformamide were reacted, the temperature was lowered, and an acylation reagent was added dropwise under controlled temperature. After the reaction, the mixture was concentrated under reduced pressure to obtain compound 1. Compound 1, xylene, palladium on carbon, and an organic base were reacted. Nitrogen was used for purging, the temperature was controlled, and hydrogen was introduced for further reaction. After the reaction, nitrogen was used for purging, the mixture was filtered, the filtrate was washed with water, dried, filtered, and concentrated under reduced pressure to obtain compound 2. tert-butyl acrylate was added to an aqueous acetic acid solution, and compound 2 was added dropwise while maintaining the temperature at 10-40℃. After the addition was complete, the reaction continued until the reaction was finished. The pH was adjusted to 7-8 with an aqueous sodium hydroxide solution, and the mixture was extracted multiple times with dichloromethane. The organic phase was dried and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 3. The aqueous acetic acid solution contained 5%-20% water. Compound 3 was added to dichloromethane and the temperature was controlled at -20 to 15°C. Aluminum trichloride was added first, followed by the reducing agent. After the addition was complete, the temperature was controlled at 10 to 25°C for the reaction. After the reaction was completed, the mixture was filtered, and the pH of the filtrate was adjusted to 7 to 8 with a saturated sodium bicarbonate aqueous solution. The mixture was allowed to stand and separated. The organic phase was concentrated under reduced pressure to obtain crude di-tert-butyl octadecanoate. The crude product was recrystallized from acetonitrile to obtain di-tert-butyl octadecanoate. The reducing agent was at least one of tetramethyldisiloxane, triethylsilane, and hexamethyldisiloxane. The molar ratio of compound 3 to the reducing agent was 1:1.5 to 6.

0. Di-tert-butyl octadecanoate, lithium hydroxide and tert-butanol were reacted, filtered after reaction, pH was adjusted, extracted, the organic phase was dried and concentrated under reduced pressure, and the concentrate was recrystallized to obtain mono-tert-butyl octadecanoate. The synthetic route includes: 。 2. The method for preparing tert-butyl octadecanoate according to claim 1, characterized in that, The acylation reagent includes at least one of thionyl chloride and oxalyl chloride; the molar ratio of dodecanoic acid to thionyl chloride is 1:2.2~5.0; the molar ratio of dodecanoic acid to oxalyl chloride is 1:4.0~7.

0.

3. The method for preparing tert-butyl octadecanoate 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 tert-butyl octadecanoate according to claim 1, characterized in that, Dodecanoic acid, dichloromethane, and N,N-dimethylformamide were added to a reaction flask, the temperature was lowered to 0-20°C, and the acylation reagent was added dropwise under controlled temperature. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain compound 1.

5. The method for preparing tert-butyl octadecanoate according to claim 1, characterized in that, Compound 1, xylene, palladium on carbon, and an organic base were added to a reactor, purged with nitrogen, and the temperature was controlled at 10-40°C. Hydrogen was introduced to react, and after the reaction was complete, nitrogen was purged again. The mixture was filtered, and the filtrate was washed with water, dried, filtered, and concentrated under reduced pressure to obtain compound 2.

6. The method for preparing tert-butyl octadecanoate according to claim 1, characterized in that, Di-tert-butyl octadecanoate, lithium hydroxide, and tert-butanol were added to a reactor. After the reaction was completed at room temperature, the mixture was filtered. The pH of the filtrate was adjusted to weakly acidic with dilute hydrochloric acid, and then extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure. The concentrate was recrystallized from toluene to obtain mono-tert-butyl octadecanoate.

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