Synthesis method of heptadecane-9-yl-8-((2-ethoxyl) (6-oxo-6-((undecyloxy) hexyl) amino) octanoate)

Abstract

The invention relates to the field of organic synthesis, in particular to a synthetic method of heptadecane-9-yl-8-((2-ethoxyl) (6-oxo-6-((undecyloxy) hexyl) amino) octanoate). The synthesis method comprises the following steps: carrying out condensation reaction on 9-heptadecanol and 8-bromocaprylic acid to obtain 8-bromocaprylic acid-9-heptadecanol ester; the preparation method comprises the following steps: carrying out substitution reaction on 8-bromocaprylic acid-9-heptadecanol ester, 6-bromohexanoic acid undecanol ester and ethanolamine to obtain a crude product; and refining the crude product, so as to obtain the heptadecane-9-yl-8-((2-ethoxyl) (6-oxo-6-((undecyloxy) hexyl) amino) octanoate). The synthesis method provided by the invention has the characteristics of simplicity and convenience in operation, short route, high repeatability, relatively high total yield and facilitation of industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and more specifically, to a method for synthesizing heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate). Background Technology

[0002] Heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate) (SM-102) is an ionizable cationic amino lipid that plays a crucial role in mRNA vaccine delivery technology. It is a pale yellow oily substance, soluble in organic solvents such as ethanol and DMSO. It is neutral at physiological pH, but protonates and becomes positively charged in acidic environments, binding to mRNA via electrostatic interactions to form stable lipid nanoparticles (LNPs). Through ester hydrolysis, the aliphatic head group is cleared via the bile duct and kidneys, exhibiting rapid clearance and low immunogenicity. The cationic head binds to mRNA, and the hydrophobic chain anchors the lipid bilayer, forming an LNP structure that protects the mRNA from nuclease degradation. After endocytosis into the cell, the acidic endosome environment triggers protonation, promoting endosome escape and releasing mRNA into the cytoplasm. Compared to other cationic lipids, SM-102 combines high delivery efficiency with low cytotoxicity. Summary of the Invention

[0003] In view of this, the present invention aims to provide a heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate) to solve the problems of complex preparation processes and low yield and low purity of cationic lipid compounds in the prior art.

[0004] To solve the above-mentioned technical problems, this application is implemented as follows:

[0005] This invention provides a method for synthesizing heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate), comprising the following steps:

[0006] 9-Heptadecanol and 8-bromooctanoic acid are condensed to give 8-bromooctanoic acid-9-heptadecyl ester;

[0007] 8-Bromooctanoic acid-9-heptadecyl ester, 6-bromohexanoic acid-undecanyl ester and ethanolamine were subjected to a substitution reaction to give crude heptadecyl-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoic acid ester);

[0008] The crude product of heptadecanyl-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate was purified to obtain heptadecanyl-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate).

[0009] Preferably, the condensation reaction process includes:

[0010] A condensation reaction is carried out by mixing 9-heptadecyl alcohol, 8-bromooctanoic acid, an organic base, and a first solvent.

[0011] In this invention, the condensation reaction pathway is as follows:

[0012]

[0013] Preferably, the molar ratio of 9-heptadecyl alcohol, 8-bromooctanoic acid and organic base is 1:(1-1.4):(0.01-0.1).

[0014] Preferably, the organic base comprises 4-dimethylaminopyridine and / or triethylamine.

[0015] In this invention, 4-dimethylaminopyridine (DMAP) and triethylamine are organic compounds with strong selective reducing properties and are commonly used as condensing agents. Both DMAP and triethylamine are non-nucleophilic bases, which only react with protons and cannot undergo other nucleophilic reactions. They have good chemoselectivity. Therefore, the use of DMAP and triethylamine can play a deprotonating role, which can better promote the condensation reaction and achieve docking under very mild conditions.

[0016] Preferably, the first solvent includes chloroform and / or dichloroform.

[0017] In this invention, the raw materials can be well dissolved in the first solvent, which can better promote the condensation reaction.

[0018] Preferably, the weight ratio of 9-heptadecyl alcohol to the first solvent is 1:(4-5).

[0019] Preferably, the temperature of the condensation reaction is 10–20°C, and the time of the condensation reaction is 16–20 h.

[0020] Preferably, after the condensation reaction is completed, a first post-processing is also included;

[0021] The first post-processing includes:

[0022] The first product was washed with a saturated sodium chloride solution to remove impurities, and an organic phase was obtained. The organic phase was then subjected to a first vacuum distillation.

[0023] The mass ratio of the first product to the saturated sodium chloride solution is 1:(2-2.5);

[0024] The temperature of the first vacuum distillation is 25℃~35℃, the time of the first vacuum distillation is 1~2h, and the pressure of the first vacuum distillation is -0.06Mpa~-0.1Mpa.

[0025] Preferably, the substitution reaction process includes:

[0026] First, undecyl 6-bromohexanoate, ethanolamine, and a second solvent are mixed to carry out the first reaction. After the first reaction is completed, 8-bromooctanoate-9-heptadecyl ester, N,N-diisopropylethylamine (DIEA), and a third solvent are added and mixed to carry out the second reaction.

[0027] In this invention, N,N-diisopropylethylamine serves to activate the nucleophile, promote the reaction, provide an alkaline environment, promptly and thoroughly neutralize the acid produced in the reaction, prevent the nucleophile from deactivating, promote reaction equilibrium, and inhibit acid-catalyzed side reactions.

[0028] In this invention, the substitution reaction pathway is as follows:

[0029]

[0030] Preferably, the mass ratio of undecyl 6-bromohexanoate, ethanolamine, and heptadecanol 8-bromooctanoate is 1:(1.2-2):(1-1.5).

[0031] The molar ratio of the 8-bromooctanoic acid-9-heptadecyl ester and the N,N-diisopropylethylamine is 1:1.2-3;

[0032] Preferably, the second solvent includes ethanol.

[0033] Preferably, the mass ratio of the undecyl 6-bromohexanoate to the second solvent is 1:(3-6).

[0034] The third solvent includes acetonitrile and / or n-heptane.

[0035] Preferably, the third solvent comprises acetonitrile and n-heptane.

[0036] Preferably, the volume ratio of acetonitrile to n-heptane is 1:1.

[0037] Preferably, the mass ratio of the 8-bromooctanoic acid-9-heptadecyl ester to the third solvent is 1:(2-3).

[0038] Preferably, the temperature of the first reaction is 40–50°C, and the reaction time is 6–8 hours.

[0039] The temperature of the second reaction is 30℃~60℃, and the reaction time is 16~20h.

[0040] Preferably, after the second reaction is completed, a second post-processing is also included;

[0041] The second post-processing includes subjecting the resulting second product to a second vacuum distillation.

[0042] The temperature of the second vacuum distillation is 25℃~40℃, the time of the second vacuum distillation is 1~2h, and the pressure of the second vacuum distillation is -0.06Mpa~-0.1Mpa.

[0043] Preferably, the specific process of refining includes:

[0044] The crude product of heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate was dissolved in a mixed solution of ethyl acetate and n-heptane, and then extracted and separated by saturated sodium chloride solution. Silica gel was added to the separated organic phase, stirred, and filtered. The filtrate was then subjected to a third vacuum distillation.

[0045] The temperature of the third vacuum distillation is 25℃~40℃, the time of the second vacuum distillation is 1~2h, and the pressure of the second vacuum distillation is -0.06Mpa~-0.1Mpa.

[0046] Preferably, the mass ratio of the ethyl acetate to the n-heptane is 1:2.

[0047] The beneficial technical effects of the present invention through the above technical solution are as follows:

[0048] The method for synthesizing heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate) provided by this invention is characterized by simple operation, short route, high reproducibility, high overall yield, and is conducive to industrial production. Attached Figure Description

[0049] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used together with the following detailed description to explain the invention, but do not constitute a limitation thereof.

[0050] Figure 1 The liquid phase content detection chromatogram of heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate) prepared in Example 1 is shown. Detailed Implementation

[0051] Unless otherwise specified, all embodiments and optional embodiments of this application can be combined to form new technical solutions.

[0052] Unless otherwise specified, all technical features and optional technical features of this application may be combined to form new technical solutions.

[0053] Unless otherwise specified, the terms "comprising" and "including" as used in this application can be open-ended or closed-ended. For example, "comprising" and "including" can mean that other components not listed may also be included, or that only the listed components may be included.

[0054] The present invention will be further described in detail below through examples. All raw materials used in the examples are commercially available.

[0055] Example 1

[0056] The synthesis of heptadecano-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate) includes the following steps:

[0057] 50g of 9-heptadecyl alcohol, 45g of 8-bromooctanoic acid and 2g of DMAP were added to 200g of chloroform and reacted at 20℃ for 20h. After the reaction was completed, 100g of saturated sodium chloride solution was added to the product for washing to remove impurities. The obtained organic phase was distilled under reduced pressure at 35℃ for 60min to obtain 83g of 8-bromooctanoic acid-9-heptadecyl alcohol ester, with a yield of 92%.

[0058] 60g of undecyl 6-bromohexanoate and 100g of ethanolamine were mixed and then 300g of ethanol was added. The mixture was reacted at 40℃ for 8h. After the reaction was completed, the product was distilled under reduced pressure at 35℃ for 1h. Then, 80g of 8-bromooctanoate-9-heptadecyl ester, 30g of DIEA, 100g of acetonitrile and 100g of n-hexane were added. The mixture was stirred at 50℃ for 20h. After the reaction was completed, the product was distilled under reduced pressure at 35℃ for 120min to obtain 108g of crude heptadecyl-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate, with a yield of 89%.

[0059] 100g of crude heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate was added to a mixed solution of 500g ethyl acetate and 1000g n-heptane. The mixture was then extracted with 500g saturated sodium chloride solution to obtain an organic phase. 200g of 200-300 mesh silica gel was added to the organic phase, and the mixture was stirred for 2 hours and then filtered. The filtrate was distilled under reduced pressure at 40°C for 1 hour to obtain 93g of heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate, with a yield of 93%.

[0060] The liquid phase content determination chromatogram of heptadecano-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate) prepared in Example 1 above is shown in the figure. Figure 1 As shown. By Figure 1 It is known that the present invention successfully synthesized heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate).

[0061] Example 2

[0062] The synthesis of heptadecano-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate) includes the following steps:

[0063] 50g of 9-heptadecyl alcohol, 45g of 8-bromooctanoic acid and 2g of DMAP were added to 200g of chloroform and reacted at 15℃ for 18h. After the reaction was completed, 100g of saturated sodium chloride solution was added to the product for washing to remove impurities. The separated organic phase was distilled under reduced pressure at 35℃ for 70min to obtain 84g of 8-bromooctanoic acid-9-heptadecyl alcohol ester, with a yield of 93%.

[0064] 60g of undecyl 6-bromohexanoate and 100g of ethanolamine were mixed and then 300g of ethanol was added. The mixture was reacted at 50℃ for 8h. After the reaction was completed, the product was subjected to vacuum distillation at 30℃ for 2h. Then, 80g of 8-bromooctanoate-9-heptadecyl ester, 30g of DIEA, 100g of acetonitrile and 100g of n-hexane were added. The mixture was stirred at 60℃ for 20h. After the reaction was completed, the product was subjected to vacuum distillation at 35℃ for 120min to obtain 110g of crude heptadecyl-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate, with a yield of 91%.

[0065] 100g of crude heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate was added to a mixed solution of 500g ethyl acetate and 1000g n-heptane. The mixture was then extracted with 500g saturated sodium chloride solution to obtain an organic phase. 200g of 200-300 mesh silica gel was added to the organic phase, and the mixture was stirred for 2 hours. The mixture was then filtered, and the filtrate was distilled under reduced pressure at 30°C for 2 hours to obtain 94g of heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate, with a yield of 94%.

[0066] Example 3

[0067] 50g of 9-heptadecyl alcohol, 45g of 8-bromooctanoic acid and 2g of DMAP were added to 200g of chloroform and reacted at 10℃ for 16h. After the reaction was completed, 100g of saturated sodium chloride solution was added to the product for washing to remove impurities. The separated organic phase was distilled under reduced pressure at 30℃ for 60min to obtain 82g of 8-bromooctanoic acid-9-heptadecyl alcohol ester, with a yield of 91%.

[0068] 60g of undecyl 6-bromohexanoate and 100g of ethanolamine were mixed and then 300g of ethanol was added. The mixture was reacted at 40℃ for 8h. After the reaction was completed, the product was subjected to vacuum distillation at 30℃ for 2h. Then, 80g of 8-bromooctanoate-9-heptadecyl ester, 30g of DIEA, 100g of acetonitrile and 100g of n-hexane were added. The mixture was stirred at 45℃ for 16h. After the reaction was completed, the product was subjected to vacuum distillation at 30℃ for 120min to obtain 107g of crude heptadecyl-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate, with a yield of 88%.

[0069] 100g of crude heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate was added to a mixed solution of 500g ethyl acetate and 1000g n-heptane. The mixture was then extracted with 500g saturated sodium chloride solution to obtain an organic phase. 200g of 200-300 mesh silica gel was added to the organic phase, and the mixture was stirred for 2 hours. The mixture was then filtered, and the filtrate was distilled under reduced pressure at 35°C for 2 hours to obtain 91g of heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate, with a yield of 91%.

[0070] Example 4

[0071] The synthesis of heptadecano-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate) includes the following steps:

[0072] 50g of 9-heptadecyl alcohol, 48g of 8-bromooctanoic acid and 2g of DMAP were added to 200g of chloroform and reacted at 20℃ for 20h. After the reaction was completed, 100g of saturated sodium chloride solution was added to the product for washing to remove impurities. The separated organic phase was distilled under reduced pressure at 35℃ for 120min to obtain 83g of 8-bromooctanoic acid-9-heptadecyl alcohol ester, with a yield of 92%.

[0073] 50g of undecyl 6-bromohexanoate and 100g of ethanolamine were mixed and then 300g of ethanol was added. The mixture was reacted at 40℃ for 8h. After the reaction was completed, the product was subjected to vacuum distillation at 40℃ for 1h. Then, 80g of 8-bromooctanoate-9-heptadecyl ester, 30g of DIEA, 100g of acetonitrile and 100g of n-hexane were added. The mixture was stirred at 30℃ for 20h. After the reaction was completed, the product was subjected to vacuum distillation at 35℃ for 120min to obtain 125g of crude heptadecyl-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate.

[0074] 100g of crude heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate was added to a mixed solution of 500g ethyl acetate and 1000g n-heptane. The mixture was then extracted with 500g saturated sodium chloride solution to obtain an organic phase. 200g of 200-300 mesh silica gel was added to the organic phase, and the mixture was stirred for 2 hours. The mixture was then filtered, and the filtrate was distilled under reduced pressure at 40℃ to obtain 91g of heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate, with a yield of 91%.

[0075] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method of synthesis of heptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6- ((undecyloxy)hexyl)amino)octanoate), characterized by, The method comprises the following steps: 9-heptadecanol is condensed with 8-bromooctanoic acid to obtain 8-bromooctanoic acid-9-heptadecanol ester; 8-bromooctanoic acid-9-heptadecanol ester, 6-bromohexanoic acid undecanol ester and ethanolamine are subjected to substitution reaction to obtain crude heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate; The crude heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate is refined to obtain heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6-((undecyloxy)hexyl)amino)octanoate.

2. The process for the synthesis of heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6- ((undecyloxy)hexyl)amino)octanoate) according to claim 1, characterized in that, The condensation reaction comprises the following steps: 9-heptadecanol, 8-bromooctanoic acid, an organic base and a first solvent are mixed to perform condensation reaction.

3. The method of synthesis of heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6- ((undecyloxy)hexyl)amino)octanoate) according to claim 2, characterized in that, The molar ratio of 9-heptadecanol, 8-bromooctanoic acid and the organic base is 1:(1-1.4):(0.01-0.1); The organic base comprises 4-dimethylaminopyridine and / or triethylamine; The first solvent comprises chloroform and / or dichloromethane.

4. The method of synthesis of heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6- ((undecyloxy)hexyl)amino)octanoate) according to claim 2, characterized in that, The condensation reaction is performed at a temperature of 10-20℃ for 16-20 hours.

5. The method of synthesis of heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6- ((undecyloxy)hexyl)amino)octanoate) according to claim 2, characterized in that, After the condensation reaction, a first post-treatment is further performed. The first post-treatment comprises the following steps: The obtained first product is washed with saturated sodium chloride solution to remove impurities to obtain an organic phase, and the organic phase is subjected to first vacuum distillation. The first vacuum distillation is performed at a temperature of 25-35℃ for 1-2 hours under a pressure of-0.06Mpa to-0.1Mpa.

6. The method of synthesis of heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6- ((undecyloxy)hexyl)amino)octanoate) according to claim 1, characterized in that, The substitution reaction comprises the following steps: First, 6-bromohexanoic acid undecanol ester, ethanolamine and a second solvent are mixed to perform first reaction, and then 8-bromooctanoic acid-9-heptadecanol ester, N,N-diisopropylethylamine and a third solvent are added to perform second reaction.

7. The method of synthesis of heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6- ((undecyloxy)hexyl)amino)octanoate) according to claim 6, characterized in that, The mass ratio of 6-bromohexanoic acid undecanol ester, ethanolamine and 8-bromooctanoic acid-9-heptadecanol ester is 1:(1.2-2):(1-1.5); The molar ratio of 8-bromooctanoic acid-9-heptadecanol ester and N,N-diisopropylethylamine is 1:1.2-3; The second solvent comprises ethanol; The third solvent comprises acetonitrile and / or n-heptane.

8. The method of synthesis of heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6- ((undecyloxy)hexyl)amino)octanoate) according to claim 6, characterized in that, The first reaction is performed at a temperature of 40-50℃ for 6-8 hours. The second reaction is performed at a temperature of 30-60℃ for 16-20 hours.

9. The method of synthesis of heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6- ((undecyloxy)hexyl)amino)octanoate) according to claim 6, characterized in that, After the second reaction, a second post-treatment is further performed. The second post-treatment comprises the following steps: The second vacuum distillation is performed at a temperature of 25-40℃ for 1-2 hours under a pressure of-0.06Mpa to-0.1Mpa.

10. The method of synthesis of heptadecan-9-yl-8-((2-hydroxyethyl)(6-oxo-6- ((undecyloxy)hexyl)amino)octanoate) according to claim 1, characterized in that, The refining process comprises the following steps: The crude product of heptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6- ((undecyloxy)hexyl)amino)octanoate is dissolved in a mixed solution of ethyl acetate and n-heptane, then extracted with saturated sodium chloride solution, silica gel is added to the separated organic phase, stirred and filtered, and the obtained filtrate is subjected to a third vacuum distillation; The temperature of the third vacuum distillation is 25-40°C, the time of the third vacuum distillation is 1-2h, and the pressure of the third vacuum distillation is -0.06Mpa to -0.1Mpa.

Images