A preparation method of N-hexanoyl-phytosphingosine

Abstract

The invention discloses a method for preparing N-hexanoyl-phytosphingosine, comprising: using phytosphingosine and caproic acid as raw materials, and carrying out a condensation reaction in an organic solvent under the action of a condensing agent and an organic base to obtain N-hexanoyl-phytosphingosine. The method avoids the use of enzyme catalysis and acyl chloride. A high-quality product can be obtained without column chromatography, the operation steps are simple, and the process is suitable for large-scale production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and more specifically to a method for preparing N-hexanoyl-phytosphingosine. Background Art

[0002] N-hexanoyl-phytosphingosine is a member of the ceramide family. Ceramides containing short-chain fatty acyl groups are more likely to enter cells. Ceramides exist in all eukaryotic cells and play an important regulatory role in life activities such as cell differentiation, proliferation, apoptosis, and aging. As the main component of intercellular lipids in the stratum corneum of the skin, ceramides not only act as second messenger molecules in the sphingomyelin pathway, but also play an important role in the formation process of the epidermal stratum corneum. They have the functions of maintaining the skin barrier, moisturizing, anti-aging, whitening, and treating diseases.

[0003] Phytosphingosine contains one amino group and three hydroxyl groups. Unlike other amino compounds that only contain amino groups but no hydroxyl groups, the amino groups and hydroxyl groups of phytosphingosine compete with the transition state of the condensation agent during the condensation reaction. It is challenging to improve the selectivity of the reaction site in the preparation of N-hexanoyl-phytosphingosine from phytosphingosine.

[0004] The prior art often uses acyl halides or anhydrides to prepare amide structures, such as Yang-Tae Chang, J. Am. Chem. Soc. 2002, 124, 9, 1856–1857 This article reports the synthesis of short-chain ceramide using acyl chloride as raw material. The method is relatively complicated. There are few existing literature reports, and the method is not simple enough and is not suitable for large-scale production.

[0005] Due to the widespread demand for functional ceramides in the market, it is very necessary to quickly construct ceramide derivatives through chemical synthesis to further improve the properties of ceramides and enhance their efficacy. Summary of the invention

[0006] The invention aims to solve the shortcomings of the existing N-hexanoyl-phytosphingosine synthesis method, such as complicated operation, expensive reagents, immature method and unsuitability for large-scale production, and provides a preparation method of N-hexanoyl-phytosphingosine with mild reaction, simple treatment and suitable for large-scale production.

[0007] To achieve the above object, the present invention adopts the following technical solution: A method for preparing N-hexanoyl-phytosphingosine comprises the following steps: With phytosphingosine (CAS No. 554-62-1) and caproic acid as raw materials, a condensation reaction is carried out in an organic solvent under the action of a condensation agent and an organic base to obtain N-hexanoyl-phytosphingosine.

[0008] The reaction formula of the condensation reaction is as follows: .

[0009] Preferably, the condensing agent is an onium phosphonium salt condensing agent or a carbodiimide condensing agent, more preferably a carbodiimide condensing agent, and most preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl).

[0010] Preferably, the organic base is triethylamine (TEA), N,N-diisopropylethylamine (DIPEA) or 4-dimethylaminopyridine (DMAP).

[0011] Preferably, the organic solvent is N,N-dimethylformamide, dichloromethane, acetonitrile or tetrahydrofuran, more preferably N,N-dimethylformamide.

[0012] Preferably, the temperature of the condensation reaction is 10-35°C, more preferably 25-35°C.

[0013] Preferably, the condensation reaction time is 8 to 24 hours, more preferably 16 to 20 hours.

[0014] Preferably, the phytosphingosine is of industrial grade.

[0015] Preferably, the molar ratio of the phytosphingosine to the caproic acid is 1:1.0-1.2, more preferably 1:1.

[0016] Preferably, the preparation method further comprises a post-reaction treatment step, and the post-reaction treatment comprises extraction, solvent removal and recrystallization.

[0017] Preferably, the solvent used for the recrystallization is one or more of ethyl acetate, acetonitrile, dichloromethane, ethanol, methanol or n-heptane, preferably a mixed solvent of ethyl acetate and n-heptane.

[0018] Preferably, the solvent used in the recrystallization is 5 to 10 times the mass of the crystals.

[0019] The beneficial effects of the present invention are: The present invention adopts EDCI as a condensation agent, has few reaction impurities, mild reaction, simple treatment and purification, and is suitable for large-scale production.

[0020] Preferably, the condensing agent is an onium phosphonium salt condensing agent or a carbodiimide condensing agent, more preferably a carbodiimide condensing agent, and most preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl).

[0021] Preferably, the organic base is triethylamine (TEA), N,N-diisopropylethylamine (DIPEA) or 4-dimethylaminopyridine (DMAP).

[0022] Preferably, the organic solvent is N,N-dimethylformamide, dichloromethane, acetonitrile or tetrahydrofuran, more preferably N,N-dimethylformamide.

[0023] Preferably, the temperature of the condensation reaction is 10-35°C, more preferably 25-35°C.

[0024] Preferably, the condensation reaction time is 8 to 24 hours, more preferably 16 to 20 hours.

[0025] Preferably, the phytosphingosine is of industrial grade.

[0026] Preferably, the molar ratio of the phytosphingosine to the caproic acid is 1:1.0-1.2, more preferably 1:1.

[0027] Preferably, the preparation method further comprises a post-reaction treatment step, and the post-reaction treatment comprises extraction, solvent removal and recrystallization.

[0028] Preferably, the solvent used for the recrystallization is one or more of ethyl acetate, acetonitrile, dichloromethane, ethanol, methanol or n-heptane, preferably a mixed solvent of ethyl acetate and n-heptane.

[0029] Preferably, the solvent used in the recrystallization is 5 to 10 times the mass of the crystals.

[0030] The beneficial effects of the present invention are: The present invention adopts EDCI as a condensation agent, has few reaction impurities, mild reaction, simple treatment and purification, and is suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 The compound prepared in Example 1 1 HNMR spectrum.

[0032] Figure 2 This is the HPLC chart of the compound prepared in Example 1. DETAILED DESCRIPTION

[0033] In order to better illustrate the present invention, the following embodiments are listed, but the present invention is not limited to the following embodiments.

[0034] Example 1 Dissolve n-hexanoic acid (36.6 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72.5 g) and 4-dimethylaminopyridine (4.0 g) in N,N-dimethylformamide (1000 mL) and stir at 25 °C for 30 minutes. Add phytosphingosine (100.1 g) and react at 30-35 °C for 16 hours. The reaction solution was poured into ice water (3000 mL), and the pH value of the reaction solution was adjusted to 3-4 with 1N hydrochloric acid. The solution was extracted with ethyl acetate (600 mL*3). The organic layer was washed with saturated sodium chloride solution (500 mL*2), dried with anhydrous sodium sulfate (50.6 g), and filtered. The solvent was evaporated under reduced pressure to obtain 128.6 g of crude product. The obtained solid was dispersed in a mixed solvent (ethyl acetate: n-heptane = 1:1 volume ratio, 900 mL), heated to 80 °C to dissolve and clarify, cooled to 30 °C, stirred for 16 hours, filtered, and the filter cake was washed with (ethyl acetate: n-heptane = 1:1 volume ratio, 130 mL) and dried to obtain 94.1 g of N-hexanoyl-phytosphingosine as a white solid with an HPLC purity of 98.03%.

[0035] Example 2

[0036] Dissolve n-hexanoic acid (3.6 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.2 g) and triethylamine (0.3 g) in dichloromethane (100 mL) and stir at 25 °C for 30 minutes. Add phytosphingosine (10.1 g) and react at 25-30 °C for 20 hours. The reaction solution was poured into ice water (300 mL), and the pH value of the reaction solution was adjusted to 3-4 with 1N hydrochloric acid. The solution was extracted with ethyl acetate (60 mL*3). The organic layer was washed with saturated sodium chloride solution (50 mL*2), dried with anhydrous sodium sulfate (5.1 g), and filtered. The solvent was evaporated under reduced pressure to obtain 11.9 g of crude product. The obtained solid was dispersed in acetonitrile (120 mL), heated to reflux for 1 h, and filtered hot. The filtrate was cooled to 30 °C, stirred at this temperature for 14 hours, filtered, and the filter cake was washed with acetonitrile (15 mL) and dried to obtain 8.6 g of N-hexanoyl-phytosphingosine as a white solid with an HPLC purity of 95.91%.

[0037] Example 3

[0038] Dissolve n-hexanoic acid (1.0 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.2 g) and N,N-diisopropylethylamine (0.1 g) in tetrahydrofuran (30 mL) and stir at 25 °C for 30 minutes. Add phytosphingosine (3.1 g) and react at 10-25 °C for 24 hours. The reaction solution was poured into ice water (100 mL), and the pH value of the reaction solution was adjusted to 3-4 with 1N hydrochloric acid. The solution was extracted with ethyl acetate (30 mL*3). The organic layer was washed with saturated sodium chloride solution (50 mL*2), dried with anhydrous sodium sulfate (2.1 g), and filtered. The solvent was evaporated under reduced pressure to obtain 2.9 g of crude product. The obtained solid was dispersed in dichloromethane (21 mL), heated to 40°C, dissolved and clarified, cooled to 20°C, stirred for 14 hours, filtered, and the filter cake was washed with dichloromethane (5 mL) and dried to obtain 1.9 g of N-hexanoyl-phytosphingosine as a white solid with an HPLC purity of 96.21%.

[0039] Example 4

[0040] Dissolve n-hexanoic acid (1.0 g) and 4-dimethylaminopyridine (0.1 g) in N,N-dimethylformamide (10 mL), add N,N'-carbonyldiimidazole (0.5 g) in batches, and stir at 35 °C for 2 hours. Add phytosphingosine (2.5 g), and stir at 20-25 °C for 8 hours under nitrogen protection. The reaction solution was poured into ice water (40 mL), and the pH value of the reaction solution was adjusted to 3-4 with 1N hydrochloric acid solution. The solution was extracted with ethyl acetate (20 mL*3). The organic layer was washed with saturated sodium chloride solution (20 mL*2), dried with anhydrous sodium sulfate (3.5 g), and filtered. The solvent was evaporated from the filtrate under reduced pressure to obtain 3.2 g of crude product. The obtained solid was dispersed in ethyl acetate (16 mL), heated to 80 °C to dissolve and clarify, cooled to 20 °C, stirred for 3 hours, filtered, and the filter cake was washed with ethyl acetate (4 mL) and dried to obtain 1.8 g of N-hexanoyl-phytosphingosine as a white solid with an HPLC purity of 97.66%.

[0041] Comparative Example 1 Highly active condensing agent HATU was used, and the other steps were the same as those in Example 1. The product was purified by column chromatography with a yield of 35-40%.

[0042] Comparative Example 2 CDI was used as the condensing agent, and the amount of feed was 10 times that of Example 4. The other steps were the same as those of Example 1. The product amide, urea and ester were generated simultaneously, which made purification difficult. The product was purified by column chromatography with a yield of 24%.

[0043] Comparative Example 3 PyBOP was used as the condensing agent, and the other steps were the same as those in Example 1. The product was purified by column chromatography with a yield of 16%.

[0044] Comparative Example 4 Hexanoyl chloride was used as a raw material to react with phytosphingosine and purified by column chromatography with a yield of 35%. As the feed amount increased by 5 times, the yield decreased to 22%.

Claims

1. A method for preparing N-hexanoyl-phytosphingosine, characterized in that: The steps include: With phytosphingosine and caproic acid as raw materials, a condensation reaction is carried out in an organic solvent under the action of a condensation agent and an organic base to obtain N-hexanoyl-phytosphingosine.

2. The preparation method according to claim 1, characterized in that: The condensing agent is an onium phosphonium salt condensing agent or a carbodiimide condensing agent, more preferably a carbodiimide condensing agent, and most preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

3. The preparation method according to claim 1, characterized in that: The organic base is triethylamine, N,N-diisopropylethylamine or 4-dimethylaminopyridine.

4. The preparation method according to claim 1, characterized in that: The organic solvent is N,N-dimethylformamide, dichloromethane, acetonitrile or tetrahydrofuran, more preferably N,N-dimethylformamide.

5. The preparation method according to claim 1, characterized in that The temperature of the condensation reaction is 10-35°C, more preferably 25-35°C.

6. The preparation method according to claim 1, characterized in that: The condensation reaction time is 8 to 24 hours, more preferably 16 to 20 hours.

7. The preparation method according to claim 1, characterized in that: The molar ratio of the phytosphingosine to the caproic acid is 1:1.0-1.2, more preferably 1:

1.

8. The preparation method according to claim 1, characterized in that: The preparation method further comprises a step of post-reaction treatment, which comprises extraction, solvent removal and recrystallization.

9. The preparation method according to claim 8, characterized in that: The solvent used for the recrystallization is one or more of ethyl acetate, acetonitrile, dichloromethane, ethanol, methanol or n-heptane, preferably a mixed solvent of ethyl acetate and n-heptane.

10. The preparation method according to claim 8, characterized in that: The solvent used in the recrystallization is 5 to 10 times the mass of the crystals.

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