A method for synthesizing mono-tert-butyl octadecandioate

Abstract

The application provides a synthesis method of monotert-butyl octadecanedioate, and belongs to the technical field of organic synthesis. The method takes tetradecanedioic acid as a starting material, forms an active ester through a condensation reaction with N-hydroxyphthalimide, and then performs a free radical addition reaction with tert-butyl acrylate in the presence of a Hans ester to obtain di-tert-butyl octadecanedioate. Finally, one tert-butyl ester group is selectively removed through barium hydroxide to obtain the target product monotert-butyl octadecanedioate. The synthesis route provided by the application has the advantages of easy-to-obtain raw materials, mild reaction conditions in each step, simple operation, no need to use noble metal catalysts and dangerous reagents, simple post-treatment process, suitability for industrial amplification production, and the like. The application provides a new efficient, safe and economical route for the preparation of monotert-butyl octadecanedioate.

Description

Technical Field

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

[0002] tert-butyl octadecanoate is an important fine chemical intermediate with applications highly concentrated in cutting-edge pharmaceutical fields. As a core raw material for the synthesis of the semaglutide side chain, it is crucial for achieving long-term drug efficacy. Semaglutide is the world's first and only orally administered glucagon-like peptide-1 (GLP-1) receptor agonist, used to improve glycemic control in adults with type 2 diabetes, and is also a well-known hypoglycemic and weight-loss drug. Tert-butyl octadecanoate is also an important raw material for the synthesis of the tirzepatide side chain, similarly used to prepare this novel GLP-1 receptor agonist. Octadecanoate, as a key raw material for the synthesis of tert-butyl octadecanoate, is relatively expensive; therefore, developing new process routes to reduce production costs has become a research hotspot.

[0003] Currently, there are several methods for synthesizing octadecanoic acid via carbon enrichment. For example, patent 202111676791 uses oleic acid as a raw material to obtain 9-octadecenoic acid under the action of Grubbs catalyst, and then uses palladium on carbon to reduce the olefin bond to obtain octadecanoic acid; in patent 202011073267, butadiene and 2-hydroxycyclopentadienyl alcohol are first subjected to free radical coupling to obtain octadecyl-7,11-dienoic acid, and then the olefin bond is reduced by palladium on carbon to obtain octadecanoic acid; patent 202010202257 uses methyl 9-oxonanoate as a starting material to form a coupling intermediate through McMurry coupling reaction, followed by double bond reduction under palladium on carbon catalytic hydrogenation, and then hydrolysis to obtain octadecanoic acid; patent 202511837131 uses 1,12-dodecanediol as a raw material, first undergoes bromination, then adds tert-butyl acrylate, and finally removes tert-butyl acrylate to obtain octadecanoic acid. In addition, some patents synthesize tert-butyl octadecanoate directly without octadecanoic acid during carbonization. For example, patent 202410161368 condenses tetradecanoic acid with di-tert-butyl malonate, and then reduces it to remove tert-butyl ester to obtain tert-butyl octadecanoate. Patent 202211688162 uses hexadecanoic acid benzyl ester as raw material, and obtains tert-butyl octadecanoate through carbonization with tert-butyl malonate, hydroxyl elimination, and palladium-carbon reduction to remove benzyl ester.

[0004] All six synthesis schemes mentioned above have certain shortcomings. Patent 202111676791 uses a Grubbs catalyst, which is expensive and limits its industrial application. Patents 202011073267, 202010202257, and 202211688162 all use palladium on carbon catalytic reduction of alkene bonds. Although this method is commonly used, palladium is a precious metal, resulting in high costs, and high-pressure hydrogenation reduction poses certain safety risks. Patent 202410161368 uses sodium borohydride reduction, which easily releases hydrogen gas upon contact with water, posing a safety risk. Patent 202511837131 uses phosphorus tribromide, and its post-processing produces pollutants such as hydrobromic acid, causing serious pollution and making it unsuitable for industrial production. Therefore, there is an urgent need to develop a mild, low-cost, safe, environmentally friendly method for synthesizing tert-butyl octadecanoate suitable for industrial production. Summary of the Invention

[0005] The present invention addresses the problems of high catalyst / reagent costs, involvement of precious metals (palladium), use of hazardous reagents (sodium borohydride, phosphorus tribromide), and safety risks associated with high-pressure hydrogenation reactions. The purpose of this invention is to provide a method for synthesizing tert-butyl octadecanoate that is mild, low-cost, safe, environmentally friendly, and suitable for industrial production.

[0006] To achieve the above-mentioned objectives, this invention provides a synthetic route for tert-butyl octadecanoate, specifically comprising the following steps: (1) Tetradecanoic acid reacts with N-hydroxyphthalimide (NHP) in an organic solvent in the presence of a condensing agent to obtain an active ester of tetradecanoic acid; (2) Tetradecanoic acid active ester reacts with tert-butyl acrylate in an organic solvent in the presence of a reducing agent to obtain di-tert-butyl octadecanoic acid; (3) Di-tert-butyl octadecanoate dissolves in methanol and, under alkaline conditions, removes one tert-butyl group to obtain mono-tert-butyl octadecanoate.

[0007] Further, the condensing agent mentioned in step (1) is selected from any one of carbonyl diimidazole (CDI), dicyclohexyl carbodiimide (DCC), diisopropyl carbodiimide (DIC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC•HCl).

[0008] Further, the organic solvent mentioned in step (1) is any one of N,N-dimethylformamide (DMF), acetonitrile, or tetrahydrofuran (THF).

[0009] Further, the reducing agent in step (2) is hensyl ester (HEH) or tris(trimethylsilyl)silane (TMS3SiH).

[0010] Further, the alkali mentioned in step (3) is barium hydroxide or sodium hydroxide.

[0011] Further, the molar ratio of tetradecanoic acid to condensing agent in step (1) is 1:(2.0~3.0).

[0012] Further, the molar ratio of the tetradecanoic acid active ester to the reducing agent in step (2) is 1:(2.0~4.0).

[0013] Further, the molar ratio of di-tert-butyl octadecanoate to base in step (3) is 1:(2.0~10.0).

[0014] Furthermore, the organic solvent mentioned in step (2) is N,N-dimethylacetamide (DMA), and the reaction temperature is 60~65℃.

[0015] Further, the condensing agent in step (1) is carbonyl diimidazole (CDI), the organic solvent is N,N-dimethylformamide (DMF), the molar ratio of tetradecanoic acid, carbonyl diimidazole (CDI) and N-hydroxyphthalimide is 1:2.2:2.2, and the reaction temperature is 20~25 °C; And / or, the reducing agent in step (2) is hesperidin (HEH), and the molar ratio of the active tetradecanoic acid ester, hesperidin and tert-butyl acrylate is 1:3.0:3.0; And / or, the base in step (3) is barium hydroxide, the molar ratio of the di-tert-butyl octadecanoate to the barium hydroxide is 1:2.2, and the reaction temperature is 40~50 ℃.

[0016] Furthermore, steps (1) to (3) also include post-processing steps, wherein: The post-processing steps of step (1) include: adding water for filtration, washing, and drying to obtain tetradecanoic acid active ester; The post-processing steps in step (2) include: adding water for filtration, washing, and drying to obtain di-tert-butyl octadecanoate; The post-processing steps in step (3) include: filtration and concentration, adding tert-butanol for pulping, filtration, and drying to obtain tert-butyl octadecanoate.

[0017] The present invention has achieved the following beneficial effects: This invention provides a synthetic route for mono-tert-butyl octadecanoate, avoiding expensive reagents such as palladium on carbon or dangerous reagents such as sodium borohydride and phosphorus tribromide. The route is characterized by mild conditions, low cost, and high safety. Furthermore, this route exhibits good yields in each key step: In Example 1, using DMF as solvent and N-hydroxyphthalimide as the active esterifying agent, the yield of the active tetradecanoate ester (B) reached 92.4% at room temperature; using DMA as solvent and hensyl ester (HEH) as the reducing agent, a free radical addition reaction was carried out at 60–65 °C, yielding di-tert-butyl octadecanoate (C) with a yield of 89.7%; and using barium hydroxide as the selective hydrolysis agent, mono-tert-butyl octadecanoate (D) was prepared at 40–50 °C with a yield of 84.3%. The overall yield of the three steps is approximately 69.9%, and the reaction conditions in each step are mild, with simple post-processing operations (mostly using conventional separation methods such as filtration, washing, and pulping), making it suitable for industrial-scale production.

[0018] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0019] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0020] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0021] Example 1: Synthesis of tert-butyl octadecanoate (D) (a) Under nitrogen protection, 20 g of tetradecanoic acid (A), 100 mL of N,N-dimethylformamide (DMF), and 27.62 g of carbonyl diimidazole (CDI) were added to a 500 mL reaction flask. The mixture was stirred at room temperature (20~25 °C) for 1 hour. Then, 27.78 g of N-hydroxyphthalimide (NHP) was added, and the mixture was reacted at room temperature for 5 hours. 100 mL of water was added, and the mixture was filtered. The filter cake was washed with deionized water and dried to obtain 39.24 g of active tetradecanoic acid ester (B), with a yield of 92.4% and a purity of 97.6%.

[0022] (b) Under nitrogen protection, 35 g of tetradecanoic acid active ester (B), 200 mL of NN-dimethylacetamide (DMA), 48.5 g of hesperidin (HEH), and 24.5 g of tert-butyl acrylate were added to a 500 mL reaction flask. The mixture was heated to 60-65 °C and stirred for 8 hours. 200 mL of water was added, and the mixture was filtered. The filter cake was washed with deionized water and dried to obtain 24.42 g of di-tert-butyl octadecanoic acid (C), with a yield of 89.7%.

[0023] (c) Under nitrogen protection, 50 g of di-tert-butyl octadecanoate (C), 200 mL of methanol, and 44.17 g of barium hydroxide were added to a 500 mL reaction flask. The mixture was heated to 40-50 °C and stirred for 5 hours. After filtration, the filter cake was concentrated to dryness. 100 mL of tert-butanol was added and the mixture was stirred. After filtration and drying, 36.61 g of mono-tert-butyl octadecanoate (D) was obtained, with a yield of 84.3% and a purity of 99.0%.

[0024] The following is a comparative example.

[0025] Comparative Example 1: Synthesis of di-tert-butyl octadecanoate (C) The main difference between this comparative example and Example 1 is that N-hydroxyphthalimide in step (a) is replaced with N-hydroxysuccinimide to synthesize di-tert-butyl octadecanoate (C). The specific preparation steps are as follows: (a) Under nitrogen protection, 20 g of tetradecanoic acid (A), 100 mL of DMF, and 27.62 g of CDI were added to a 500 mL reaction flask. The mixture was stirred at room temperature (20-25 °C) for 1 hour. Then, 19.6 g of N-hydroxysuccinimide was added, and the mixture was reacted at room temperature for 5 hours. 100 mL of water was added, and the mixture was filtered. The filter cake was washed with deionized water and dried to obtain 31.24 g of active tetradecanoic acid ester (B1), with a yield of 89.2%.

[0026] (b) Under nitrogen protection, 33 g of active tetradecanoic acid ester (B1), 200 mL of DMA, 48.5 g of hansyl ester, and 21.0 g of tert-butyl acrylate were added to a 500 mL reaction flask. The mixture was heated to 60-65 °C and stirred for 8 hours. 200 mL of water was added, and the mixture was filtered. The filter cake was washed with deionized water and dried to obtain 5.88 g of di-tert-butyl octadecanoic acid ester (C), with a yield of 25.2%.

[0027] Comparative Example 2: Synthesis of tert-butyl octadecanoate (D) The main difference between this comparative example and Example 1 is that barium hydroxide in step (c) is replaced with sodium hydroxide to synthesize tert-butyl octadecanoate (D). The specific preparation steps are as follows: (c) Under nitrogen protection, 15 g of di-tert-butyl octadecanoate (C), 50 mL of methanol, and 3.1 g of sodium hydroxide were added to a 500 mL reaction flask. The mixture was heated to 40-50 °C and stirred for 5 hours. After filtration, the filter cake was concentrated to dryness. 40 mL of tert-butanol was added and the mixture was stirred. After filtration and drying, 3.67 g of mono-tert-butyl octadecanoate (D) was obtained, with a yield of 28.2%.

[0028] Comparative Example 3: Synthesis of Tetradecanoic Acid Active Ester (B) The main difference between this comparative example and Example 1 is that DMF in step (a) was replaced with tetrahydrofuran (THF) to synthesize the tetradecanoic acid active ester (B). The specific preparation steps are as follows: (a) Under nitrogen protection, 20 g of tetradecanoic acid (A), 100 mL of THF, and 27.62 g of CDI were added to a 500 mL reaction flask. The mixture was stirred at room temperature for 1 hour, and then 27.78 g of N-hydroxyphthalimide was added. The mixture was reacted at room temperature for 5 hours, and then 100 mL of water was added. The mixture was filtered, the filter cake was washed with deionized water, and the filter cake was dried to obtain 37.6 g of active tetradecanoic acid ester (B), with a yield of 88.6%.

[0029] Comparative Example 4: Synthesis of di-tert-butyl octadecanoate (C) The main difference between this comparative example and Example 1 is that the mass ratio of tetradecanoic acid active ester (B): hansyl ester: tert-butyl acrylate in step (b) was changed from 35:48.5:24.5 to 10:18.5:9.3 (i.e., the molar ratio was changed from 1:3.0:3.0 to approximately 1:4.0:4.0) to synthesize di-tert-butyl octadecanoic acid (C). The specific preparation steps are as follows: (b) Under nitrogen protection, 10 g of active tetradecanoic acid ester (B), 70 mL of DMA, 18.5 g of hansyl ester, and 9.3 g of tert-butyl acrylate were added to a 500 mL reaction flask. The mixture was heated to 60-65 °C and stirred for 8 hours. 100 mL of water was added, and the mixture was filtered. The filter cake was washed with deionized water and dried to obtain 6.1 g of di-tert-butyl octadecanoic acid ester (C), with a yield of 78.5%.

[0030] Comparative Example 5: Synthesis of Tetradecanoic Acid Active Ester (B) The main difference between this comparative example and Example 1 is that the solvent DMF in step (a) was replaced with acetonitrile to synthesize the tetradecanoic acid active ester (B). The specific preparation steps are as follows: (a) Under nitrogen protection, 20 g of tetradecanoic acid (A), 100 mL of acetonitrile, and 27.62 g of CDI were added to a 500 mL reaction flask. The mixture was stirred at room temperature for 1 hour, and then 27.78 g of N-hydroxyphthalimide was added. The mixture was reacted at room temperature for 5 hours, and then 100 mL of water was added. The mixture was filtered, the filter cake was washed with deionized water, and the filter cake was dried to obtain 36.8 g of active tetradecanoic acid ester (B), with a yield of 86.6%.

[0031] Comparative Example 6: Synthesis of di-tert-butyl octadecanoate (C) The main difference between this comparative example and Example 1 is that HEH in step (b) is replaced with tris(trimethylsilyl)silane (TMS3SiH) to synthesize di-tert-butyl octadecanoate (C). The specific preparation steps are as follows: (b) Under nitrogen protection, 10 g of active tetradecanoic acid ester (B), 80 mL of DMA, 13.6 g of TMS3SiH and 7.0 g of tert-butyl acrylate were added to a 500 mL reaction flask. The mixture was heated to 60-65 °C and stirred for 8 hours. 80 mL of water was added, and the mixture was filtered. The filter cake was washed with deionized water and dried to obtain 3.4 g of di-tert-butyl octadecanoic acid ester (C), with a yield of 43.5%.

[0032] A comparison of Example 1 and Comparative Examples 1-6 clearly demonstrates that the method for synthesizing mono-tert-butyl octadecanoate provided by this invention has significant advantages: In Example 1, step (a) uses DMF as a solvent and N-hydroxyphthalimide as an active esterification reagent, reacting at room temperature, and the yield of active tetradecanoate ester (B) can reach 92.4%; in step (b), using DMA as a solvent, under the conditions of an active tetradecanoate ester (B): hemisyl ester (HEH): tert-butyl acrylate mass ratio of 35:48.5:24.5 and a reaction temperature of 60-65 °C, the yield of di-tert-butyl octadecanoate (C) is 89.7%; in step (c), using barium hydroxide as a hydrolysis reagent, selective single hydrolysis is performed at 40-50 °C, and the yield of mono-tert-butyl octadecanoate (D) is 84.3%.

[0033] Comparative Example 1 shows that replacing N-hydroxyphthalimide with N-hydroxysuccinimide significantly reduced the yield of di-tert-butyl octadecanoate (C) in step (b) to 25.2%; Comparative Example 2 shows that replacing barium hydroxide with sodium hydroxide in step (c) resulted in a yield of only 28.2% of the target product, mono-tert-butyl octadecanoate (D); in Comparative Example 3, replacing DMF with THF in step (a) slightly reduced the yield of the active ester (B) to 88.6%; in Comparative Example 4, when step... When the feed ratio in step (b) was adjusted to tetradecanoic acid active ester (B): hansyl ester: tert-butyl acrylate = 10:18.5:9.3, the yield of di-tert-butyl octadecanoic acid (C) decreased to 78.5%; in Comparative Example 5, when the solvent DMF in step (a) was replaced with acetonitrile, the yield of tetradecanoic acid active ester (B) decreased to 86.6%; in Comparative Example 6, when HEH was replaced with TMS3SiH in step (b), the yield of di-tert-butyl octadecanoic acid (C) was only 43.5%.

[0034] In summary, the present invention uses DMF as a solvent, N-hydroxyphthalimide as an active esterification reagent, HEH as a reducing reagent and controls a specific feed ratio in step (b), and barium hydroxide for selective hydrolysis in step (c). These are the key process parameter combinations for obtaining a high yield, providing a feasible synthetic route for tert-butyl octadecanoate.

Claims

1. A method for synthesizing tert-butyl octadecanoate, characterized in that: The method includes the following steps: (1) Tetradecanoic acid reacts with N-hydroxyphthalimide in an organic solvent in the presence of a condensing agent to obtain an active ester of tetradecanoic acid; (2) Tetradecanoic acid active ester reacts with tert-butyl acrylate in an organic solvent in the presence of a reducing agent to obtain di-tert-butyl octadecanoic acid; (3) Di-tert-butyl octadecanoate dissolves in methanol and, under alkaline conditions, removes one tert-butyl group to obtain mono-tert-butyl octadecanoate.

2. The synthesis method according to claim 1, characterized in that: The condensing agent mentioned in step (1) is selected from any one of carbonyl diimidazole, dicyclohexyl carbodiimide, diisopropyl carbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.

3. The synthesis method according to claim 1, characterized in that: The organic solvent mentioned in step (1) is any one of N,N-dimethylformamide, acetonitrile, or tetrahydrofuran.

4. The synthesis method according to claim 1, characterized in that: The reducing agent mentioned in step (2) is hans ester or tris(trimethylsilyl)silane.

5. The synthesis method according to claim 1, characterized in that: The alkali mentioned in step (3) is barium hydroxide or sodium hydroxide.

6. The synthesis method according to claim 1, characterized in that: The molar ratio of tetradecanoic acid to condensing agent in step (1) is 1:(2.0~3.0).

7. The synthesis method according to claim 1, characterized in that: The molar ratio of tetradecanoic acid active ester to reducing agent in step (2) is 1:(2.0~4.0).

8. The synthesis method according to claim 1, characterized in that: The molar ratio of di-tert-butyl octadecanoate to alkali in step (3) is 1:(2.0~10.0).

9. The synthesis method according to claim 1, characterized in that: The organic solvent mentioned in step (2) is N,N-dimethylacetamide, and the reaction temperature is 60~65 ℃.

10. The synthesis method according to any one of claims 1 to 9, characterized in that: The condensing agent in step (1) is carbonyl diimidazole, the organic solvent is N,N-dimethylformamide, the molar ratio of tetradecanoic acid, carbonyl diimidazole and N-hydroxyphthalimide is 1:2.2:2.2, and the reaction temperature is 20~25 ℃; And / or, the reducing agent in step (2) is hans ester, and the molar ratio of the active tetradecanoic acid ester, hans ester and tert-butyl acrylate is 1:3.0:3.0; And / or, the base in step (3) is barium hydroxide, the molar ratio of the di-tert-butyl octadecanoate to the barium hydroxide is 1:2.2, and the reaction temperature is 40~50 ℃.

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