A method for large-scale safe and efficient synthesis of cyclopentadecanone

Abstract

A large-scale, safe, and efficient method for synthesizing cyclopentadecanone, belonging to the field of musk in fragrances and flavorings, comprises the following steps: Step 1: Hexadecanoic acid monoester, inorganic base A, trichloroacetyl chloride, 1,2-dimethylimidazole, titanium tetrachloride, and an organic base undergo a Claisen ring-closing condensation reaction in an aprotic solvent to obtain a 2-carboxylate cyclopentadecanone intermediate; Step 2: Adding inorganic base B and the 2-carboxylate cyclopentadecanone intermediate to methanol for hydrolysis to obtain 2-carboxylate cyclopentadecanone, followed by acidification with an inorganic acid to obtain cyclopentadecanone; This invention utilizes hexadecanoic acid monoester as a starting material to obtain cyclopentadecanone in high yield; Compared with existing processes, this invention has the advantages of shorter steps, safe and controllable reaction conditions, fewer side reactions, high reaction yield, and ease of industrial scale-up production.

Description

Technical Field

[0001] This invention belongs to the field of musk in fragrances and flavorings, and specifically relates to a method for the large-scale, safe and efficient synthesis of cyclopentadecanone. Background Technology

[0002] Cyclopentadecanone, also known as Exaltone, is naturally found in the glands of male musk deer and the secretions of North American muskrats. It emits a sweet and powerful fragrance very similar to natural musketone, with a soft, pure, and elegant aroma, strong diffusion, long-lasting scent, and excellent fragrance-enhancing and fixing effects. As an excellent fixative agent to replace musketone, cyclopentadecanone is widely used in high-end face powders, perfumes, essential oils, soaps, and cosmetics in the daily chemical industry; it is also used in the fragrances of tobacco, candies, beverages, and oral hygiene products. In addition, it is an important intermediate in the synthesis of the pharmaceutical raw material musketone, precious fragrances, and other macrocyclic muscin lactones. Currently, the extraction of cyclopentadecanone from the glandular secretions of wild musk deer can no longer meet consumer demand. Since Professor Lutzka of Switzerland first synthesized cyclopentadecanone artificially in 1926, despite the development of various synthetic routes, the price of cyclopentadecanone remains high due to limitations such as limited raw material sources, long process routes, harsh synthesis conditions, and low overall yield. Therefore, developing a synthetic route that is short, has a high yield, and is economical and environmentally friendly not only meets the needs of social and industrial development but also has good market prospects.

[0003] Among the many methods for synthesizing cyclopentadecanones, the conjugation method is generally considered to be a relatively simple synthetic method. Zhou Zijin et al. used sodium metal as a reducing catalyst to catalyze the inco-condensation of ethyl pentadecanedicarboxylate in xylene solvent, obtaining 2-hydroxycyclopentadecanone in 75% yield (Zhou Zijin, Cai Gui, Synthesis of Cyclopentadecanone, Journal of Jiangxi University (Natural Science Edition), 1991, 15(3): 91-94); Song Na used sodium sand as a catalyst to catalyze the inco-condensation of methyl pentadecanedicarboxylate in xylene solvent, obtaining 2-hydroxycyclopentadecanone in 68% crude yield (Song Na, Synthesis of Cyclopentadecanone, Master's Thesis of Tianjin University, 2008); under the same conditions, Fang Meiqin used butyl pentadecanedicarboxylate to catalyze the inco-condensation of 3-hydroxycyclopentadecanone in 57.9% yield (Fang Meiqin, Research on the Synthesis of Cyclopentadecanone, Master's Thesis of East China University of Science and Technology, 2012); Zhao Yang added trimethylchlorosilane to the same inco-condensation reaction to inhibit the intramolecular Dieckmann condensation reaction, increasing the yield of 2-hydroxycyclopentadecanone to 90%. Although this reaction system requires only two steps to synthesize cyclopentadecanone, it necessitates the use of a very large amount of xylene to reduce the intermolecular reactions between pentadecyl dicarboxylate molecules. This not only introduces a very cumbersome solvent removal process in the post-processing but also poses a significant disadvantage for scale-up of the reaction. Furthermore, the amount of sodium used, which is more than five equivalents compared to that used in straight-chain dicarboxylate esters, also presents numerous safety and post-processing challenges. These disadvantages limit the large-scale industrial application of this method.

[0004] The Dieckmann condensation reaction of linear diacid diesters is considered another shorter process route for preparing cyclopentadecanone. BASF, a globally renowned company, heated a tetrahydrofuran solution of dimethyl hexadecanoate to 270°C, vaporized it, and then heated the resulting gas to 350°C. This gas was then carried by a nitrogen stream to the surface of a titanium dioxide-supported solid catalyst containing 2% potassium oxide for the reaction, achieving a final yield of cyclopentadecanone of 78% (WO2004009524, 2004:1-29). However, the high temperature required for this process causes partial decomposition and carbonization of the raw material, dimethyl hexadecanoate. The carbonized particles easily deactivate the catalyst, and frequent catalyst replacements hinder large-scale application of this process.

[0005] Firmenich developed a five-step process to synthesize cyclopentadecanone from readily available cyclododecane using ring expansion (Dowd, P., Choi, SC Homologation of largerings. Tetrahedron, 1992, 48:4773). However, this process requires the use of the high-risk, expensive strong base sodium hydride and highly toxic tin reagents, limiting its synthetic applications. Furthermore, the low overall yield makes this route uneconomical.

[0006] The dienone method reported by Blomquist et al. uses α,ω-hexadecanoic acid chloride as a starting material. After treatment with an ether solution containing triethylamine, chloride ions leave to obtain α,ω-hexadecanoic acid dienone. Dimerization then occurs to give an unsaturated β-lactone, which is hydrolyzed and deacidified to give cyclopentadecanone (Blomquist, AT, Spencer, RD A new synthetic method for many membered carbon rings. J. Am. Chem. Soc., 1947, 69:472-473). However, the overall yield of cyclopentadecanone in the above five steps is only 20%, which is not industrially viable.

[0007] Wanhua Chemical Group Co., Ltd.'s patent CN107915610A discloses a four-step reaction using cyclododecene and acryloyl chloride as starting materials to obtain cyclopentadecanone in a 48% yield. Wang Xianquan's patent CN107445813A discloses a process using garlic fruit oil rich in nervonic acid as a starting material, extracting the nervonic acid, ozonating it to obtain pentadecadecanoic acid, and then performing esterification, cyclization, and reduction. Based on pentadecadecanoic acid, the yield of cyclopentadecanone is less than 42%. Charles F's patent US4296258 discloses a reaction between pentadecadecanone and bicyclopentadecanone to obtain cyclopentadecanylene, which is then reduced to yield cyclopentadecanone in a 65% yield. Although the reaction conditions of these inventions are not demanding, the bicyclopentadecanone raw material is difficult to obtain, and the yield is low, thus lacking industrial application value.

[0008] In summary, the cyclopentadecanedioic acid diester-based synthesis method is limited by the use of more than 5 equivalents of sodium and large amounts of xylene solvent, resulting in high process safety risks, cumbersome operation, numerous side reactions, and difficult purification. The Dieckmann condensation reaction using hexadecanoic acid diester-based synthesis is limited by expensive strong base sodium hydride and highly toxic tin reagents, resulting in high environmental risks and low yield. Using cyclododecene or nervonic acid as starting materials is limited by numerous synthetic steps, difficult separation, and low yield. All these processes for preparing cyclopentadecanedioic acid have many shortcomings, while the application prospects of cyclopentadecanedioic acid are becoming increasingly broad. Therefore, developing cyclopentadecanedioic acid with short synthetic steps, safety, environmental friendliness, and high yield has significant industrial application value and importance. Summary of the Invention

[0009] To overcome the shortcomings of the prior art, this invention discloses a large-scale, safe, and efficient method for synthesizing cyclopentadecanone. Using hexadecanoic acid monoester as the starting material, a Claisen ring-closing condensation reaction is carried out with the assistance of inorganic base A, trichloroacetyl chloride, 1,2-dimethylimidazole (DMI), titanium tetrachloride (TiCl4), and an organic base. Hydrolysis is then performed using inorganic base B, followed by acidification with an inorganic acid to obtain cyclopentadecanone in high yield. Compared with existing processes, this invention has the advantages of shorter steps, safer and more controllable reaction conditions, fewer side reactions, higher reaction yield, and ease of industrial scale-up.

[0010] To achieve the aforementioned objective, the present invention employs the following technical solution: A method for the large-scale, safe, and efficient synthesis of cyclopentadecanone includes the following steps: Step 1: Hexadecanoic acid monoester, inorganic base A, trichloroacetyl chloride, 1,2-dimethylimidazole, titanium tetrachloride and organic base undergo Claisen cyclization condensation reaction in an aprotic solvent to obtain 2-carbamate cyclopentadecanone intermediate; Step 2: Add inorganic base B and 2-carboxylate cyclopentadecanone intermediate to methanol for hydrolysis to obtain 2-carboxylate cyclopentadecanone. Add inorganic acid to 2-carboxylate cyclopentadecanone for acidification to obtain cyclopentadecanone. In the above process, the R group in hexadecanoic acid monoester is an alkyl group.

[0011] The method for preparing cyclopentadecanone on a large scale, safely and efficiently is described above, wherein the alkyl group is any one of methyl, ethyl, propyl, or butyl groups.

[0012] In the method for the large-scale, safe and efficient synthesis of cyclopentadecanone, the inorganic base A in step one is any one of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, and sodium hydride, or any two or more in any proportion.

[0013] In the method for the large-scale, safe and efficient synthesis of cyclopentadecanone, the molar ratio of hexadecanoic acid monoester to inorganic base A in step one is 1:(1~1.6).

[0014] In the large-scale, safe, and efficient method for synthesizing cyclopentadecanone, the molar ratio of hexadecanoic acid monoester to trichloroacetyl chloride in step one is 1:(1~1.6).

[0015] In the large-scale, safe, and efficient method for synthesizing cyclopentadecanone, the molar ratio of hexadecanoic acid monoester to 1,2-dimethylimidazolium in step one is 1:(1~1.6).

[0016] In the large-scale, safe, and efficient method for synthesizing cyclopentadecanone, the molar ratio of hexadecanoic acid monoester to titanium tetrachloride in step one is 1:(2~5).

[0017] In the large-scale, safe, and efficient method for preparing cyclopentadecanone, the molar ratio of hexadecanoic acid monoester to organic base in step one is 1:(2~6).

[0018] The method for preparing cyclopentadecanone in a large-scale, safe and efficient manner, wherein the organic base in step one is any one of triethylamine, tri-n-butylamine, or 1,8-diazabicyclo[5,4,0]undec-7-ene, or any two or more in any proportion.

[0019] The method for the large-scale, safe and efficient synthesis of cyclopentadecanone, wherein the aprotic solvent in step one is any one of dichloromethane, chloroform, toluene, methyl tert-butyl ether, 1,2-dichloroethane, tetrahydrofuran, and methyltetrahydrofuran, or any two or more in any proportion.

[0020] In the large-scale, safe, and efficient method for the preparation of cyclopentadecanone, the reaction concentration of hexadecanoic acid monoester in step one is 10~1000 mM.

[0021] In the large-scale, safe, and efficient method for preparing cyclopentadecanone, the molar ratio of the 2-carboxylate cyclopentadecanone intermediate to inorganic base B in step two is 1:(1.2~4).

[0022] In the method for the large-scale, safe and efficient synthesis of cyclopentadecanone, the inorganic base B in step two is any one of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate, or any two or more in any proportion.

[0023] In the large-scale, safe, and efficient method for synthesizing cyclopentadecanone, the molar ratio of 2-carboxylic acid cyclopentadecanone to inorganic acid in step two is 1:(1~1.5).

[0024] In the method for the large-scale, safe and efficient synthesis of cyclopentadecanone, the inorganic acid in step two is any one of hydrochloric acid, acetic acid, sulfuric acid, and ammonium chloride, or any two or more in any proportion.

[0025] Due to the adoption of the above technical solution, the present invention has the following beneficial effects: The present invention describes a large-scale, safe, and efficient method for the synthesis of cyclopentadecanone. Using hexadecanoic acid monoester as the starting material, a Claisen ring-closing condensation reaction is carried out with the assistance of inorganic base A, trichloroacetyl chloride, 1,2-dimethylimidazole (DMI), titanium tetrachloride (TiCl4), and an organic base. Hydrolysis is then performed using inorganic base B, followed by acidification with an inorganic acid to achieve a high yield of cyclopentadecanone. Compared with existing methods, this invention has the following advantages: 1. The starting material, hexadecanoic acid monoester, is readily available, and its bio-preparation technology is very advanced and mature; 2. The synthesis steps are not only concise but also have short reaction times, mild and safe reaction conditions, and do not require the addition of large amounts of sodium or potassium; the reaction product separation is simple (recrystallization), requires no hydrogen reduction, has a high reaction yield, significant environmental benefits, and is safe and efficient, making it highly suitable for large-scale industrial production. Attached Figure Description

[0026] Figure 1 This is a schematic diagram of the structure of the present invention.

[0027] In the diagram: 1. Hexadecanoic acid monoester; 2. 2-Carbamate cyclopentadecanone intermediate; 3. 2-Carbamate cyclopentadecanone; 4. Cyclopentadecanone. Detailed Implementation

[0028] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. Parts not described in detail in the following embodiments of the present invention, such as thin-layer chromatography tracking reaction, NMR nuclear magnetic resonance detection technology, gas chromatography technology and recrystallization technology, should all be existing technologies known or should be known by those skilled in the art. Example 1

[0029] Step 1: Add 1 equivalent of hexadecanoic acid monoester 1 containing a propyl group, 1 equivalent of sodium hydroxide, and 1 equivalent of trichloroacetyl chloride to an appropriate amount of dichloromethane solvent to make the reaction concentration of hexadecanoic acid monoester 1 10 mM. Under nitrogen protection, react at 0℃ for 10 min. After cooling to -45℃, add 1 equivalent of 1,2-dimethylimidazole to the above solution and react for 10 min. Then add 2 equivalents of titanium tetrachloride and 2 equivalents of triethylamine in sequence, stir for 30 min, and remove the solvent and low-boiling triethylamine by vacuum distillation to obtain 2-methyl carbamate cyclopentadecanone intermediate 2 with a yield of 78%. Step 2: Add 1 equivalent of 2-carbamate-based cyclopentadecanone intermediate 2 and 1.2 equivalents of sodium hydroxide to methanol for hydrolysis to obtain 2-carbamate-based cyclopentadecanone 3. Heat to 70 °C and react for 20 min. Then add 1 equivalent of hydrochloric acid to the solution and stir for 10 min to obtain cyclopentadecanone 4 with a yield of 93%. Example 2

[0030] Step 1: Add 1 equivalent of hexadecanoic acid monoester 1 containing a butyl group, 1.35 equivalents of a mixture of potassium hydroxide and potassium carbonate, and 1.35 equivalents of trichloroacetyl chloride to an appropriate amount of a mixture of chloroform and toluene to make the reaction concentration of hexadecanoic acid monoester 1 500 mM. Under nitrogen protection, react at 0℃ for 20 min. After cooling to -45℃, add 1.35 equivalents of 1,2-dimethylimidazole to the above solution and react for 10 min. Then add 3.5 equivalents of titanium tetrachloride and 4 equivalents of a mixture of tri-n-butylamine and 1,8-diazabicyclo[5,4,0]undec-7-ene in sequence. Stir for 30 min. Remove the solvent and the low-boiling-point tri-n-butylamine and 1,8-diazabicyclo[5,4,0]undec-7-ene by vacuum distillation to obtain 2-methyl carbamate cyclopentadecanone intermediate 2 with a yield of 82%. Step 2: Add 1 equivalent of 2-carboxylate cyclopentadecanone intermediate 2 and 2.6 equivalents of potassium carbonate and sodium carbonate compound to methanol for hydrolysis to obtain 2-carboxylate cyclopentadecanone 3. Heat to 70 °C and react for 20 min. Then add 1.3 equivalents of sulfuric acid and ammonium chloride compound to the solution and stir for 10 min to obtain cyclopentadecanone 4 with a yield of 96%. Example 3

[0031] Step 1: Add 1 equivalent of hexadecanoic acid monoester 1 containing a propyl group, 1.6 equivalents of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, and sodium hydride (any two or more in any proportion), and 1.6 equivalents of trichloroacetyl chloride to an appropriate amount of dichloromethane, chloroform, toluene, methyl tert-butyl ether, 1,2-dichloroethane, tetrahydrofuran, and methyltetrahydrofuran (any two or more in any proportion) in a compound solvent to make the reaction concentration of hexadecanoic acid monoester 1 1000 mM. Under nitrogen protection, react at 0℃ for 30 min. After cooling to -45℃, add 1.6 equivalents of 1,2-dimethylimidazole to the above solution and react for 10 min. Then, add 5 equivalents of titanium tetrachloride and 6 equivalents of triethylamine, tri-n-butylamine, and 1,8-diazabicyclo[5,4,0]undec-7-ene (any two or more in any proportion) in a compound solvent to the above solution and stir for 30 minutes. The solvent and any two or more of the following low-boiling-point compounds, triethylamine, tri-n-butylamine, and 1,8-diazabicyclo[5,4,0]undec-7-ene, were removed by vacuum distillation to obtain intermediate 2, methyl carbamate-cyclopentadecanone, with a yield of 77%. Step 2: Add 1 equivalent of 2-carboxylate cyclopentadecanone intermediate 2 and 4 equivalents of any two or more of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate in any proportion to methanol for hydrolysis to obtain 2-carboxylate cyclopentadecanone 3. Heat to 70 °C and react for 20 min. Then add 1.5 equivalents of any two or more of hydrochloric acid, acetic acid, sulfuric acid, and ammonium chloride in any proportion to the solution and stir for 10 min to obtain cyclopentadecanone 4 with a yield of 91%. Example 4

[0032] Step 1: Add 1 equivalent of hexadecanoic acid monoester 1 containing a methyl group, 1.2 equivalents of potassium carbonate, and 1.2 equivalents of trichloroacetyl chloride to an appropriate amount of dichloromethane solvent to make the reaction concentration of hexadecanoic acid monoester 1 100 mM. Under nitrogen protection, react at 0℃ for 10 min. After cooling to -45℃, add 1.2 equivalents of 1,2-dimethylimidazole to the above solution and react for 10 min. Then add 3.2 equivalents of titanium tetrachloride and 4 equivalents of triethylamine in sequence, stir for 30 min, and remove the solvent and low-boiling triethylamine by vacuum distillation to obtain 2-methyl carbamate cyclopentadecanone intermediate 2 with a yield of 86%. Step 2: Add 1 equivalent of 2-carbamate-based cyclopentadecanone intermediate 2 and 3.2 equivalents of sodium hydroxide to methanol for hydrolysis to obtain 2-carbamate-based cyclopentadecanone 3. Heat to 70 °C and react for 20 min. Then add 1.02 equivalents of hydrochloric acid to the solution and stir for 10 min to obtain cyclopentadecanone 4 with a yield of 99%. Example 5

[0033] Step 1: Add 1 equivalent of hexadecanoic acid monoester 1 containing an ethyl group, 1.2 equivalents of potassium carbonate, and 1.2 equivalents of trichloroacetyl chloride to an appropriate amount of dichloromethane solvent to make the reaction concentration of hexadecanoic acid monoester 1 100 mM. Under nitrogen protection, react at 0℃ for 10 min. After cooling to -45℃, add 1.2 equivalents of 1,2-dimethylimidazole to the above solution and react for 10 min. Then add 3.2 equivalents of titanium tetrachloride and 4 equivalents of triethylamine in sequence, stir for 30 min, and remove the solvent and low-boiling triethylamine by vacuum distillation to obtain 2-methyl carbamate cyclopentadecanone intermediate 2 with a yield of 84%. Step 2: Add 1 equivalent of 2-carbamate-based cyclopentadecanone intermediate 2 and 3.2 equivalents of sodium hydroxide to methanol for hydrolysis to obtain 2-carbamate-based cyclopentadecanone 3. Heat to 70 °C and react for 20 min. Then add 1.02 equivalents of hydrochloric acid to the solution and stir for 10 min to obtain cyclopentadecanone 4 with a yield of 99%. Comparative Example 1

[0034] Step 1: Add 1 equivalent of hexadecanoic acid monoester 1 containing a methyl group, 0.8 equivalents of sodium hydroxide, and 0.8 equivalents of trichloroacetyl chloride to an appropriate amount of dichloromethane solvent to make the reaction concentration of hexadecanoic acid monoester 1 8 mM. Under nitrogen protection, react at 0℃ for 8 min. After cooling to -45℃, add 0.8 equivalents of 1,2-dimethylimidazole to the above solution and react for 10 min. Then add 1.5 equivalents of titanium tetrachloride and 1.5 equivalents of triethylamine sequentially, stir for 30 min, and remove the solvent and low-boiling triethylamine by vacuum distillation to obtain 2-methyl carbamate cyclopentadecanone intermediate 2 with a yield of 69%. Step 2: Add 1 equivalent of 2-carbamate-based cyclopentadecanone intermediate 2 and 1 equivalent of sodium hydroxide to methanol for hydrolysis to obtain 2-carbamate-based cyclopentadecanone 3. Heat to 70 °C and react for 20 min. Then add 0.8 equivalent of sulfuric acid to the solution and stir for 10 min to obtain cyclopentadecanone 4 with a yield of 87%. Comparative Example 2

[0035] Step 1: Add 1 equivalent of hexadecanoic acid monoester 1 containing an ethyl group, 1.8 equivalents of a mixture of cesium carbonate and sodium hydride, and 1.8 equivalents of trichloroacetyl chloride to an appropriate amount of a mixture of tetrahydrofuran and methyltetrahydrofuran to make the reaction concentration of hexadecanoic acid monoester 1 1100 mM. Under nitrogen protection, react at 0℃ for 40 min. After cooling to -45℃, add 1.8 equivalents of 1,2-dimethylimidazolium to the above solution and react for 10 min. Then add 6 equivalents of titanium tetrachloride and 7 equivalents of a mixture of triethylamine and tri-n-butylamine in sequence. Stir for 30 min. Remove the solvent and the low-boiling-point triethylamine and tri-n-butylamine mixture by vacuum distillation to obtain 2-methyl carbamate cyclopentadecanone intermediate 2 with a yield of 66%. Step 2: Add 1 equivalent of 2-carboxylate cyclopentadecanone intermediate 2 and 1 equivalent of sodium bicarbonate and potassium bicarbonate compound to methanol for hydrolysis to obtain 2-carboxylate cyclopentadecanone 3. Heat to 70 °C and react for 20 min. Then add 0.8 equivalent of acetic acid and sulfuric acid compound to the solution and stir for 10 min to obtain cyclopentadecanone 4 with a yield of 83%.

[0036] The parts of this invention not described in detail are prior art.

Claims

1. A method for the large-scale, safe, and efficient synthesis of cyclopentadecanone, characterized by: Includes the following steps: Step 1: Hexadecanoic acid monoester (1), inorganic base A, trichloroacetyl chloride, 1,2-dimethylimidazole, titanium tetrachloride and organic base undergo Claisen cyclization condensation reaction in an aprotic solvent to obtain 2-carbamate cyclopentadecanone intermediate (2). Step 2: Add inorganic base B and 2-carboxylate cyclopentadecanone intermediate (2) to methanol for hydrolysis to obtain 2-carboxylate cyclopentadecanone (3), and add inorganic acid to 2-carboxylate cyclopentadecanone (3) for acidification to obtain cyclopentadecanone (4). In the above process, the R group in hexadecanoic acid monoester (1) is an alkyl group.

2. The method for large-scale, safe, and efficient synthesis of cyclopentadecanone according to claim 1, characterized in that: The alkyl group is any one of the methyl group, ethyl group, propyl group, and butyl group.

3. The method for large-scale, safe, and efficient synthesis of cyclopentadecanone according to claim 1, characterized in that: In step one, inorganic base A is any one of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, and sodium hydride, or any two or more in any proportion.

4. The method for large-scale, safe, and efficient synthesis of cyclopentadecanone according to claim 1, characterized in that: The molar ratio of hexadecanoic acid monoester (1) to inorganic base A in step one is 1:(1~1.6).

5. The method for large-scale, safe, and efficient synthesis of cyclopentadecanone according to claim 1, characterized in that: The molar ratio of hexadecanoic acid monoester (1) to trichloroacetyl chloride in step one is 1:(1~1.6).

6. The method for large-scale, safe, and efficient synthesis of cyclopentadecanone according to claim 1, characterized in that: The molar ratio of hexadecanoic acid monoester (1) to 1,2-dimethylimidazolium in step one is 1:(1~1.6).

7. The method for large-scale, safe, and efficient synthesis of cyclopentadecanone according to claim 1, characterized in that: The molar ratio of hexadecanoic acid monoester (1) to titanium tetrachloride in step one is 1:(2~5).

8. The method for large-scale, safe, and efficient synthesis of cyclopentadecanone according to claim 1, characterized in that: The molar ratio of hexadecanoic acid monoester (1) to organic base in step one is 1:(2~6).

9. The method for large-scale, safe, and efficient synthesis of cyclopentadecanone according to claim 1, characterized in that: In step one, the organic base is any one of triethylamine, tri-n-butylamine, or 1,8-diazabicyclo[5,4,0]undec-7-ene, or any two or more in any proportion.

10. The method for large-scale, safe, and efficient synthesis of cyclopentadecanone according to claim 1, characterized in that: The aprotic solvent in step one is any one of dichloromethane, chloroform, toluene, methyl tert-butyl ether, 1,2-dichloroethane, tetrahydrofuran, and methyltetrahydrofuran, or any two or more in any proportion.

11. The method for large-scale, safe, and efficient synthesis of cyclopentadecanone according to claim 1, characterized in that: In step one, the reaction concentration of hexadecanoic acid monoester (1) is 10~1000 mM.

12. The method for large-scale, safe, and efficient synthesis of cyclopentadecanone according to claim 1, characterized in that: In step two, the molar ratio of 2-carbamate cyclopentadecanone intermediate (2) to inorganic base B is 1:(1.2~4).

13. The method for large-scale, safe, and efficient synthesis of cyclopentadecanone according to claim 1, characterized in that: In step two Inorganic base B is any one of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate, or any two or more in any proportion.

14. The method for large-scale, safe, and efficient synthesis of cyclopentadecanone according to claim 1, characterized in that: In step two, the molar ratio of 2-carboxylic acid cyclopentadecanone to inorganic acid is 1:(1~1.5).

15. The method for large-scale, safe, and efficient synthesis of cyclopentadecanone according to claim 1, characterized in that: In step two, the inorganic acid is any one of hydrochloric acid, acetic acid, sulfuric acid, and ammonium chloride, or any two or more in any proportion.

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