CN114853628B - Docosahexaenoic acid acyl ester derivative and preparation method and application thereof - Google Patents

Docosahexaenoic acid acyl ester derivative and preparation method and application thereof Download PDF

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CN114853628B
CN114853628B CN202210496100.2A CN202210496100A CN114853628B CN 114853628 B CN114853628 B CN 114853628B CN 202210496100 A CN202210496100 A CN 202210496100A CN 114853628 B CN114853628 B CN 114853628B
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docosahexaenoic acid
acid
ester
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CN114853628A (en
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方华
李孟昱
陈伟珠
晋文慧
张怡评
陈晖�
洪专
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Third Institute of Oceanography MNR
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/20—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a docosahexaenoic acid acyl ester derivative, a preparation method and application thereof, and the structural formula isWherein n is an integer of 0 to 4, R is Or (b)The invention has a certain down-regulating effect on the mRNA expression of pro-inflammatory mediators induced by lipopolysaccharide LPS in the mouse macrophage RAW264.7, and down-regulates the exocrine level of nitric oxide NO, and can inhibit the protein expression of pro-inflammatory cytokines.

Description

Docosahexaenoic acid acyl ester derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a docosahexaenoic acid acyl ester derivative, a preparation method and application thereof.
Background
Inflammation, a physiological or pathological response of the body to external stimuli, is involved in the development and progression of a variety of major diseases, and is a fundamental defense mechanism of the immune system, which protects the human body from such things as pathogens and toxins. Acute inflammation is less dangerous to the body and can cause oedema and intracellular flow and vascular permeability and local hemodynamic changes, while chronic inflammation can lead to diseases such as asthma, rheumatoid arthritis and cancer.
Omega-3 polyunsaturated fatty acids are enriched in cell membranes and can influence intracellular signaling and inhibit the transcriptional activity of inflammatory related transcription factors NF- κB, thereby reducing the expression of pro-inflammatory cytokines TNF- α, IL-6, IL-1β, etc. Omega-3 polyunsaturated fatty acids are metabolized to produce derivatives with physiological activities such as anti-inflammatory and analgesic effects, such as enzymatic production of resolvins and protectins (protectins), which stimulate secretion of neutrophils and macrophages to produce anti-inflammatory cytokines such as IL-10, IL-4, IL-13, etc., to attenuate inflammatory responses and regulate body inflammatory levels.
Disclosure of Invention
The invention aims to provide a docosahexaenoic acid ester derivative.
Another object of the present invention is to provide a process for producing the above docosahexaenoic acid ester derivative.
It is a further object of the present invention to provide the use of the above docosahexaenoic acid ester derivative.
The technical scheme of the invention is as follows:
a docosahexaenoic acid acyl ester derivative has a structural formula ofWherein n is an integer of 0 to 4, R is +.>
The preparation method of the docosahexaenoic acid ester derivative comprises the following steps:
(1) Mixing methyl docosahexaenoic acid and alcohol amine, heating and stirring at 80 ℃ for reaction for 15 hours, then stirring a sample with silica gel, and then performing silica gel column chromatography purification to obtain docosahexaenoic acid alcohol amine;
(2) Mixing the above docosahexaenoic acid alcohol amine with organic acid, stirring at 0-5deg.C under the action of ester condensing agent for 8-24 hr, extracting with 1, 2-dichloroethane twice, and anhydrous MgSO 4 Drying, concentrating, purifying by silica gel column chromatography and purifying by high performance liquid chromatography to obtain the docosahexaenoic acid ester derivative;
the alcohol amine is ethanolamine, propanolamine, butanolamine, pentanolamine and hexanolamine, the organic acid is 2- (6-methoxy-2-naphthyl) -propionic acid (naproxen, S1), 2- (4-isobutyl-phenyl) -propionic acid (ibuprofen, S2), 3- (4-hydroxy-3-methoxy-phenyl) -acrylic acid (ferulic acid, S3), 2- (2, 3-xylylamino) -benzoic acid (cresol-fenamic acid, S4) or 2-acetoxy-benzoic acid (aspirin, S5), and the ester condensing agent is a dichloroethane solution containing N, N' -dicyclohexylcarbodiimide, 1-hydroxybenzotriazole and 4-dimethylaminopyridine.
In a preferred embodiment of the present invention, in the step (1), the molar ratio of methyl docosahexaenoic acid to alcohol amine is 1:2.
Further preferably, in the step (2), the molar ratio of the docosahexaenoic acid alcohol amine to the organic acid is 1:1.1.
Still more preferably, the ratio of docosahexaenoic acid alcohol amine, organic acid and ester condensing agent is 1.0mmol:1.1mmol:10 mL.
Still further preferably, the ratio of N, N' -dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, 4-dimethylaminopyridine and dichloroethane in the ester condensing agent is 206.0-247.2mg:148.5-175.5mg:18.3-30.5mg:10 mL.
In a preferred embodiment of the present invention, in said step (2), the characteristic retention time t of the HPLC purification is 1/2 Between 4.58 and 16.47 min.
The application of the docosahexaenoic acid ester derivative as an anti-inflammatory small molecule drug.
Use of the above-mentioned docosahexaenoic acid ester derivative for preparing an anti-inflammatory composition.
An anti-inflammatory composition comprises the above docosahexaenoic acid ester derivative as active ingredient.
The beneficial effects of the invention are as follows:
1. the invention introduces a molecular fragment with anti-inflammatory activity at the hydroxyl position of fatty acyl alcohol amine, has a certain down-regulating effect on mRNA expression of pro-inflammatory mediators (TNF-a, IL-6 and IL-1 beta) induced by lipopolysaccharide LPS in mouse macrophage RAW264.7, and down-regulates the exocrine level of nitric oxide NO, and can inhibit protein expression of pro-inflammatory cytokines (TNF-a and IL-1 beta).
2. The invention has high bioavailability and good safety.
Drawings
FIG. 1 is a schematic diagram of Compound 2a in the examples of the present invention 1 H NMR hydrogen spectrum.
FIG. 2 is a schematic diagram of Compound 2a in the examples of the present invention 13 C NMR carbon spectrum.
FIG. 3 is a diagram showing the synthetic general formula of the docosahexaenoic acid ester derivative (2 a-2 y) according to the embodiment of the present invention.
FIG. 4 is a graph showing the experimental results of inhibiting NO production in RAW264.7 cells by using a docosahexaenoic acid ester derivative (2 a-2 y) according to the embodiment of the invention, wherein S1 is naproxen, S2 is ibuprofen, S3 is ferulic acid, S4 is cresol fenamic acid, S5 is aspirin, and DHEA is docosahexaenoic acid ethanolamine.
FIG. 5 is a graph showing the results of down-regulating the mRNA expression of the pro-inflammatory mediator TNF- α by the docosahexaenoic acid derivative (2 a-2 y) according to the present invention, wherein S1 is naproxen, S2 is ibuprofen, S3 is ferulic acid, S4 is cresol, S5 is aspirin, and DHEA is docosahexaenoic acid ethanolamine.
FIG. 6 is a graph showing the results of down-regulating mRNA expression of the pro-inflammatory mediator IL-6 by the docosahexaenoic acid derivative (2 a-2 y) according to the present invention, wherein S1 is naproxen, S2 is ibuprofen, S3 is ferulic acid, S4 is cresol fenamic acid, S5 is aspirin, and DHEA is docosahexaenoic acid ethanolamine.
FIG. 7 is a graph showing the results of down-regulating the mRNA expression of the pro-inflammatory mediator IL-1β by the docosahexaenoic acid derivative (2 a-2 y) according to the present invention, wherein S1 is naproxen, S2 is ibuprofen, S3 is ferulic acid, S4 is cresol, S5 is aspirin, and DHEA is docosahexaenoic acid ethanolamine.
FIG. 8 is a graph showing the results of the inhibition of protein expression of pro-inflammatory cytokines IL-1. Beta. And TNF-alpha by docosahexaenoic acid ester derivatives according to an embodiment of the present invention.
Detailed Description
The following further describes and illustrates the technical solution of the present invention by means of specific embodiments in conjunction with the drawings.
The general synthetic formula of compounds 2a-2y in the examples below is shown in FIG. 3.
Example 1: preparation of the Compound 2- (6-methoxy-2-naphthyl) -propionic acid- (docosahexaenoic acid-2-ethylamino) -ester (2 a)
The structural formula of the compound (2 a) is as follows:
1.0mmol of docosahexaenoic acid ethanolamine and 1.1mmol of naproxen are uniformly mixed, and an ester condensing agent is slowly dripped, which comprises a mixed solution of DCC (1.0 mmol,206 mg), HOBt (1.1 mmol,148.5 mg) and DMAP (0.15 mmol,18.3 mg) in 10mL of 1, 2-dichloroethane. Stirring at 0-5deg.C for reacting for 8 hr, extracting 1, 2-dichloroethane twice after the reaction, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid preparative chromatography, collecting characteristic retention time t 1/2 The fraction=6.46 min was concentrated to give pale yellow viscous product 2a.
As shown in fig. 1 and 2, the main physical and chemical properties of the compound (2 a) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d6)：7.81(br)，7.79-7.76(m)，7.71(s)，7.41-7.38(m)，7.29-7.7.28(m)，7.16-7.14(m)，5.36-5.27(m)，4.15-4.06(m)，3.90-3.87(m)，3.86(s)，3.26-3.25(m)，2.81-2.76(m)，2.23-2.21(m)，2.07-2.01(m)，1.49-1.44(m)，0.91(t). 13 C NMR(100MHz，DMSO-d6)：174.34，172.17，157.66，157.58，136.07，133.78，132.00，129.60，129.24，128.86，128.57，128.54，128.51，128.35，128.30，128.22，128.15，127.40，127.30，126.87，126.73，126.07，119.19，106.16，63.38，55.62，45.05，37.93，35.57，33.82，25.79，25.66，25.61，25.57，24.93，23.50，20.50，18.90，14.56.MS m/z：584[M+H] + ，606[M+Na] + ，552，374.
example 2: the preparation of compound 2- (6-methoxy-2-naphthyl) -propionic acid- (docosahexaenoic acyl-3-propanolamino) -ester (2 b) compound (2 b) has the structural formula:
1.0mmol of docosahexaenoic acid propanolamine and 1.1mmol of naproxen were mixed uniformly and slowly dropwise into an ester condensing agent comprising DCC (1.1 mmol,226.6 mg), HOBt (1.2 mmol,162 mg) and DMAP (0.20 mmol,24.4 mg) in 10mL of 1, 2-dichloroethane. Stirring at 0-5deg.C for reacting for 12 hr, extracting 1, 2-dichloroethane twice after the reaction, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid preparative chromatography, collecting characteristic retention time t 1/2 The fraction=6.83 min was concentrated to give pale yellow viscous product 2b.
The main physical and chemical properties of compound (2 b) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ7.81-7.77(m)，7.72(s)，7.41-7.38(m)，7.29-7.28(m)，7.17-7.14(m)，5.35-5.29(m)，4.03-4.02(m)，3.92-3.90(m)，3.86(s)，3.04-3.03(m)，2.83-2.78(m)，2.25-2.23(m)，2.09-2.01(m)，1.66-1.63(m)，1.48-1.47(m)，0.91(t). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ174.35，171.85，157.66，136.18，133.77，132.00，129.61，129.32，128.88，128.58，128.54，128.36，128.34，128.31，128.20，128.16，127.42，127.40，126.69，126.03，119.20，106.18，62.67，55.62，44.94，35.66，35.63，28.83，25.67，25.62，25.58，23.61，20.50，18.93，14.56.MS m/z：598[M+H] + ，620[M+Na] + ，566，274.
example 3: preparation of the Compound 2- (6-methoxy-2-naphthyl) -propionic acid- (docosahexaenoic acid-4-butanol-amino) -ester (2 c)
The structural formula of the compound (2 c) is as follows:
1.0mmol of docosahexaenoic acid butanolamine and 1.1mmol of naproxen were mixed uniformly and slowly dropwise into an ester condensing agent comprising DCC (1.1 mmol,226.6 mg), HOBt (1.3 mmol,175.5 mg) and DMAP (0.25 mmol,30.5 mg) in 10mL of 1, 2-dichloroethane. Stirring at 0-5deg.C for 24 hr, extracting 1, 2-dichloroethane twice, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1: 1) And further purifying by high performance liquid chromatography, collecting characteristic retention time t 1/2 The fraction=6.99 min was concentrated to give pale yellow viscous product 2c.
The main physical and chemical properties of compound (2 c) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d6)： 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ7.81-7.73(m)，7.71(s)，7.40-7.37(m)，7.29-7.28(m)，7.17-7.14(m)，5.35-5.29(m)，4.02-4.01(m)，3.91-3.89(m)，3.86(s)，2.99-2.97(m)，2.82-2.76(m)，2.25-2.23(m)，2.09-2.01(m)，1.52-1.46(m)，1.35-1.33(m)，0.91(t). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ174.36，171.70，157.66，136.18，133.77，132.00，129.59，129.36，128.87，128.58，128.54，128.52，128.36，128.34，128.31，128.19，128.16，127.42，127.40，126.66，126.03，119.20，106.17，64.41，55.62，44.96，35.70，33.82，26.04，25.99，25.67，25.63，25.58，23.64，20.50，18.88，14.56.MS m/z：612[M+H] + ，634[M+Na] + ，580，334.
example 4: preparation of the Compound 2- (6-methoxy-2-naphthyl) -propionic acid- (docosahexaenoic acid-5-pentanoylamino) -ester (2 d)
The structural formula of the compound (2 d) is as follows:
1.0mmol of docosahexaenoic acid pentanol amine and 1.1mmol of naproxen are uniformly mixed, and an ester condensing agent is slowly dripped, which comprises 10mL of 1, 2-dichloroethane mixed solution of DCC (1.2 mmol,247.2 mg), HOBt (1.3 mmol,175.5 mg) and DMAP (0.15 mmol,30.5 mg). Stirring at 0-5deg.C for reacting for 20 hr, extracting 1, 2-dichloroethane twice after the reaction, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid preparative chromatography, collecting characteristic retention time t 1/2 The fraction=7.37 min was concentrated to give pale yellow viscous product 2d.
The main physical and chemical properties of compound (2 d) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ7.81-7.79(m)，7.77-7.75(m)，7.71(s)，7.39-7.37(m)，7.29-7.28(m)，7.16-7.14(m)，5.35-5.29(m)，4.02-4.00(m)，3.98-3.89(m)，3.86(s)，2.94-2.92(m)，2.82-2.76(m)，2.25-2.23(m)，2.08-2.03(m)，1.51-1.46(m)，1.33-1.31(m)，1.30-1.29(m)，0.91(t). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ174.38，171.65，157.65，136.20，133.77，132.00，129.59，129.37，128.86，128.57，128.54，128.51，128.35，128.33，128.30，128.19，128.15，127.40，126.66，126.03，119.22，113.72，106.16，64.56，55.62，44.95，38.62，35.70，29.11，28.19，25.66，25.63，25.57，23.66，20.50，18.84，14.57.MS m/z：626[M+H] + ，648[M+Na] + ，594，481.
example 5: preparation of the Compound 2- (6-methoxy-2-naphthyl) -propionic acid- (docosahexaenoic acid-6-hexanolamino) -ester (2 e)
The structural formula of the compound (2 e) is as follows:
1.0mmol of docosahexaenoic acid hexanolamine and 1.1mmol of naproxen are uniformly mixed, and an ester condensing agent comprising DCC (1.0 mmol,206 mg), HOBt (1.2 mmol,162 mg) and DMAP (0.15 mmol,18.3 mg) in 10mL of 1, 2-dichloroethane is slowly added dropwise. Stirring at 0-5deg.C for 16 hr, extracting 1, 2-dichloroethane twice, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid preparative chromatography, collecting characteristic retention time t 1/2 The fraction=7.91 min was concentrated to give pale yellow viscous product 2e.
The main physical and chemical properties of compound (2 e) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ7.80-7.76(m)，7.71(s)，7.39-7.37(m)，7.29-7.28(m)，7.16-7.14(m)，5.35-5.29(m)，4.01-3.99(m)，3.91-3.89(m)，3.86(s)，2.95-2.93(m)，2.82-2.76(m)，2.26-2.24(m)，2.10-2.01(m)，1.48-1.46(m)，1.26-1.24(m)，1.16-1.14(m)，0.91(t). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ174.37，171.61，157.65，136.21，133.78，132.00，129.58，129.38，128.86，128.57，128.55，128.50，128.36，128.33，128.30，128.18，128.15，127.40，126.65，126.03，119.21，106.16，64.54，55.61，44.96，35.71，29.44，28.47，26.39，25.67，25.63，25.57，25.40，23.68，20.50，18.79，14.57.MS m/z：640[M+H] + ，662[M+Na] + ，608，312.
example 6: the preparation of compound 2- (4-isobutyl-phenyl) -propionic acid- (docosahexaenoic acyl-2-ethanolamine) -ester (2 f) compound (2 f) has the structural formula:
1.0mmol of docosahexaenoic acid ethanolamine and 1.1mmol of ibuprofen are uniformly mixed, and an ester condensing agent is slowly dripped, wherein the ester condensing agent comprises 10mL of 1, 2-dichloroethane mixed solution of DCC (1.0 mmol,206 mg), HOBt (1.1 mmol,148.5 mg) and DMAP (0.15 mmol,18.3 mg). Stirring at 0-5deg.C for reacting for 20 hr, extracting 1, 2-dichloroethane twice after the reaction, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid preparative chromatography, collecting characteristic retention time t 1/2 The fraction=8.69 min was concentrated to give pale yellow viscous product 2f.
The main physical and chemical properties of compound (2 f) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ7.89(s)，7.19-7.17(m)，7.10-7.08(m)，5.37-5.29(m)，4.05-4.04(m)，3.95-3.93(m)，3.73-3.71(m)，3.24-3.23(m)，2.83-2.77(m)，2.42-2.40(m)，2.29-2.22(m)，2.10-2.02(m)，1.80-1.78(m)，1.38-1.37(m)，0.94-0.92(m)，0.90-0.86(m). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ174.34，172.15，140.21，138.26，132.01，129.49，129.25，128.58，128.51，128.35，128.31，128.23，128.16，127.54，127.40，63.29，44.68，37.90，35.59，30.06，25.67，25.63，25.58，23.52，22.64，20.51，18.99，14.58.MS m/z：560[M+H] + ，582[M+Na] + ，516，184.
example 7: preparation of the compound 2- (4-isobutyl-phenyl) -propionic acid- (docosahexaenoic acyl-3-propanolamino) -ester (2 g) the compound (2 g) has the formula:
1.0mmol of docosahexaenoic acid propanolamine and 1.1mmol of ibuprofen were mixed uniformly and slowly dropped into an ester condensing agent comprising DCC (1.1 mmol,226.6 mg), HOBt (1.2 mmol,162 mg) and DMAP (0.20 mmol,24.4 mg) in 10mL of 1, 2-dichloroethane. Stirring at 0-5deg.C for 24 hr, extracting 1, 2-dichloroethane twice, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ：V Petroleum ether =1:1) and high performance liquid preparative chromatography, collecting characteristic retention time t 1/2 The fraction=8.93 min was concentrated to give 2g of a pale yellow viscous product.
The main physical and chemical properties of compound (2 g) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ7.79(s)，7.18(d)，7.10(d)，5.37-5.29(m)，4.01-3.99(m)，3.74-3.72(m)，3.03-3.01(m)，2.82-2.79(m)，2.42-2.40(m)，2.26-2.24(m)，2.10-2.02(m)，1.82-1.77(m)，1.65-1.62(m)，1.38-1.36(m)，0.94-0.90(m)，0.87-0.84(m). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ174.34，171.82，140.18，138.37，131.99，129.51，129.41，129.32，128.57，128.53，128.36，128.33，128.31，128.19，128.15，127.48，127.40，62.59，44.68，35.67，35.61，30.06，28.82，25.67，25.62，25.58，23.62，22.61，20.50，18.96，14.56.MS m/z：574[M+H] + ，596[M+Na] + ，530，517.
example 8: the structural formula for preparing the compound 2- (4-isobutyl-phenyl) -propionic acid- (docosahexaenoic acyl-4-butanol amino) -ester (2 h) compound (2 h) is as follows:
1.0mmol of docosahexaenoic acid butanolamine and 1.1mmol of ibuprofen are uniformly mixed, and an ester condensing agent is slowly dripped, which comprises DCC (1.1 mmol,226.6 mg), HOBt (1.3 mmol,175.5 mg), DMAP (0.25 mmol,30.5 mg) in 10mL of 1, 2-dichloroethane. Stirring at 0-5deg.C for reacting for 8 hr, extracting 1, 2-dichloroethane twice after the reaction, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid 75 phase preparative chromatography for further purification, collecting characteristic retention time t 1/2 The fraction=9.15 min was concentrated to give a pale yellow viscous product for 2h.
The main physical and chemical properties of compound (2 h) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ7.76(s)，7.17(d)，7.09(d)，5.36-5.29(m)，4.01-3.97(m)，3.73-3.71(m)，2.99-2.98(m)，2.99-2.97(m)，2.83-2.77(m)，2.42-2.40(m)，2.26-2.24(m)，2.10-2.02(m)，1.85-1.74(m)，1.50-1.48(m)，1.38-1.35(m)，1.34-1.30(m)，0.94-0.90(m)，0.87-0.84(m). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ174.34，171.69，140.19，138.38，131.99，129.49，129.36，128.57，128.54，128.51，128.35，128.33，128.30，128.19，128.15，127.56，127.46，127.39，64.29，44.68，38.29，35.70，30.06，26.02，25.96，25.67，25.63，25.58，23.66，22.60，20.51，18.90，14.56.MSm/z：588[M+H] + ，610[M+Na] + ，544，330.
example 9: the preparation of compound 2- (4-isobutyl-phenyl) -propionic acid- (docosahexaenoic acyl-5-pentanoylamino) -ester (2 i) compound (2 i) has the structural formula:
1.0mmol of docosahexaenoic acid pentanol amine and 1.1mmol of ibuprofen are mixed uniformly, and an ester condensing agent is slowly dripped, which comprises 10mL of 1, 2-dichloroethane mixed solution of DCC (1.2 mmol,247.2 mg), HOBt (1.3 mmol,175.5 mg) and DMAP (0.15 mmol,18.3 mg). Stirring at 0-5deg.C for 16 hr, extracting 1, 2-dichloroethane twice, and anhydrous MgSO 4 DryingConcentration, flash column chromatography purification on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid preparative chromatography, collecting characteristic retention time t 1/2 The fraction=9.71 min was concentrated to give pale yellow viscous product 2i.
The main physical and chemical properties of compound (2 i) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ7.75(s)，7.17(d)，7.10(d)，5.36-5.30(m)，3.98-3.97(m)，3.73-3.71(m)，2.97-2.95(m)，2.82-2.79(m)，2.42-2.40(m)，2.26-2.24(m)，2.10-2.02(m)，1.86-1.79(m)，1.49-1.47(m)，1.38-1.36(m)，1.33-1.32(m)，1.19-1.70(m)，0.94-0.90(m)，0.87-0.84(m). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ174.35，171.61，140.20，138.39，131.99，129.49，129.38，128.57，128.54，128.49，128.36，128.33，128.31，128.18，128.15，127.56，127.46，127.40，64.43，44.67，38.65，35.71，33.82，30.06，29.11，28.18，25.80，25.67，25.63，25.58，24.94，23.67，23.10，22.60，20.50，18.99，14.56.MS m/z：602[M+H] + ，624[M+Na] + ，558，381.
example 10: preparation of the Compound 2- (4-isobutyl-phenyl) -propionic acid- (docosahexaenoic acid-6-hexanolamino) -ester (2 j)
The structural formula of the compound (2 j) is as follows:
1.0mmol of docosahexaenoic acid hexanolamine and 1.1mmol of ibuprofen are mixed uniformly, and an ester condensing agent is slowly dripped, which comprises a mixed solution of DCC (1.0 mmol,206 mg), HOBt (1.2 mmol,148 mg) and DMAP (0.15 mmol,18.3 mg) in 10mL of 1, 2-dichloroethane. Stirring at 0-5deg.C for reacting for 12 hr, extracting 1, 2-dichloroethane twice after the reaction, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid preparative chromatography,collection of characteristic retention time t 1/2 The fraction=10.46 min was concentrated to give pale yellow viscous product 2j.
The main physical and chemical properties of the compound (2 j) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ7.74(s)，7.17(d)，7.10(d)，5.37-5.29(m)，4.00-3.97(m)，3.73-3.71(m)，2.98-2.96(m)，2.82-2.77(m)，2.42-2.40(m)，2.26-2.24(m)，2.10-2.02(m)，1.82-1.79(m)，1.49-1.45(m)，1.37-1.35(m)，1.33-1.30(m)，1.28-1.26(m)，1.16-1.1.15(m)，0.94-0.90(m)，0.86-0.83(m). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ174.36，171.59，140.20，138.42，132.00，129.49，129.42，129.38，128.57，128.55，128.49，128.36，128.33，128.31，128.18，128.15，127.57，127.46，127.40，64.41，44.74，38.75，35.72，30.28，30.07，29.48，28.45，26.39，25.67，25.64，25.58，25.37，23.69，22.60，20.51，18.82，14.58.MS m/z：616[M+H] + ，638[M+Na] + ，572，431.
example 11: preparation of the Compound 3- (4-hydroxy-3-methoxy-phenyl) -acrylic acid- (docosahexaenoic acid-2-ethylamino) -ester (2 k)
The structural formula of the compound (2 k) is as follows:
1.0mmol of docosahexaenoic acid ethanolamine and 1.1mmol of ferulic acid were uniformly mixed, and an ester condensing agent comprising a 10mL 1, 2-dichloroethane mixed solution of DCC (1.0 mmol,206 mg), HOBt (1.1 mmol,148.5 mg) and DMAP (0.15 mmol,18.3 mg) was slowly dropped. Stirring at 0-5deg.C for reacting for 20 hr, extracting 1, 2-dichloroethane twice after the reaction, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid preparative chromatography, collecting characteristic retention time t 1/2 The fraction=4.58 min was concentrated to give the pale yellow viscous product 2k.
The main physical and chemical properties of compound (2 k) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ9.63(s)，8.02(s)，7.56(d)，7.30(s)，7.10(d)，6.79(d)，6.45(d)，5.37-5.26(m)，4.13-4.10(m)，3.82(s)，3.35-3.32(m)，2.82-2.78(m)，2.28-2.24(m)，2.15-2.11(m)，2.05-2.01(m)，0.92(t). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ172.22，167.02，149.85，148.40，145.66，132.01，129.27，128.58，128.51，128.35，128.31，128.23，128.16，127.41，126.01，123.59，115.97，114.75，111.57，62.95，56.13，38.21，35.60，25.67，25.63，25.58，23.55，20.51，14.58.MS m/z：548[M+H] + ，570[M+Na] + ，516，304.
example 12: preparation of the Compound 3- (4-hydroxy-3-methoxy-phenyl) -acrylic acid- (docosahexaenoic acid-3-propanolamino) -ester (21)
The structural formula of the compound (21) is as follows:
1.0mmol of docosahexaenoic acid propanolamine and 1.1mmol of ferulic acid were mixed uniformly, and an ester condensing agent comprising DCC (1.1 mmol,226.6 mg), HOBt (1.2 mmol,162 mg) and DMAP (0.20 mmol,24.4 mg) in 10mL of 1, 2-dichloroethane was slowly added dropwise. Stirring at 0-5deg.C for 24 hr, extracting 1, 2-dichloroethane twice, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid preparative chromatography, collecting characteristic retention time t 1/2 The fraction=4.60 min was concentrated to give 2l of pale yellow viscous product.
The main physical and chemical properties of compound (2 l) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ9.72(br)，7.88(s)，7.55(d)，7.32(s)，7.12(d)，6.79(d)，6.46(d)，5.37-5.28(m)，4.13-4.10(m)，3.82(s)，3.17-3.13(m)，2.83-2.76(m)，2.27-2.24(m)，2.13-2.09(m)，2.05-2.01(m)，1.78-1.74(m)，0.92(t). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ171.91，167.12，149.87，148.41，145.48，132.01，129.32，128.58，128.54，128.36，128.35，128.31，128.21，128.16，127.40，125.99，123.63，115.95，114.84，111.59，62.18，56.14，35.87，35.70，28.98，25.67，25.63，25.58，23.64，20.51，14.58.MS m/z：562[M+H] + ，584[M+Na] + ，530，466.
example 13: preparation of the Compound 3- (4-hydroxy-3-methoxy-phenyl) -acrylic acid- (docosahexaenoic acid-4-butanol amino) -ester (2 m)
The structural formula of the compound (2 m) is as follows:
1.0mmol of docosahexaenoic acid butanolamine and 1.1mmol of ferulic acid were mixed uniformly, and an ester condensing agent comprising 10mL of a 1, 2-dichloroethane mixed solution of DCC (1.1 mmol,226.6 mg), HOBt (1.3 mmol,175.5 mg) and DMAP (0.25 mmol,30.5 mg) was slowly added dropwise. Stirring at 0-5deg.C for reacting for 8 hr, extracting 1, 2-dichloroethane twice after the reaction, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid preparative chromatography, collecting characteristic retention time t 1/2 The fraction=4.63 min was concentrated to give a pale yellow viscous product 2m.
The main physical and chemical properties of compound (2 m) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ9.66(br)，7.82(s)，7.54(d)，7.32(s)，7.10(d)，6.78(d)，6.46(d)，5.36-5.29(m)，4.13-4.10(m)，3.82(s)，3.08-3.06(m)，2.82-2.77(m)，2.27-2.25(m)，2.12-2.01(m)，1.62-1.60(m)，1.49-1.47(m)，0.92(t). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ171.76，167.13，149.80，148.39，145.44，132.01，129.36，128.58，128.55，128.37，128.35，128.32，128.21，128.16，127.41，126.03，123.61，115.94，114.91，111.61，63.91，56.15，38.47，35.73，26.25，25.67，25.64，25.58，23.66，20.51，14.58.MS m/z：576[M+H] + ，598[M+Na] + ，544，340.
example 14: preparation of the Compound 3- (4-hydroxy-3-methoxy-phenyl) -acrylic acid- (docosahexaenoic acid-5-pentanoylamino) -ester (2 n)
The structural formula of the compound (2 n) is as follows:
1.0mmol of docosahexaenoic acid pentanol amine and 1.1mmol of ferulic acid are uniformly mixed, and an ester condensing agent is slowly dripped, which comprises 10mL of 1, 2-dichloroethane mixed solution of DCC (1.2 mmol,247.2 mg), HOBt (1.3 mmol,175.5 mg) and DMAP (0.15 mmol,18.3 mg). Stirring at 0-5deg.C for 16 hr, extracting 1, 2-dichloroethane twice, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid preparative chromatography, collecting characteristic retention time t 1/2 The fraction=5.05 min was concentrated to give pale yellow viscous product 2n.
The main physical and chemical properties of compound (2 n) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ9.61(br)，7.79(s)，7.54(d)，7.32(s)，7.10(d)，6.78(d)，6.46(d)，5.37-5.29(m)，4.12-4.08(m)，3.82(s)，3.05-3.03(m)，2.82-2.78(m)，2.26-2.24(m)，2.11-2.03(m)，1.64-1.63(m)，1.42-1.41(m)，1.35-1.34(m)，0.92(t). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ171.69，167.15，149.79，148.39，145.41，132.01，129.36，128.58，128.55，128.52，128.36，128.34，128.31，128.18，128.16，127.40，126.04，123.59，115.93，114.94，111.61，64.11，56.14，38.73，35.73，29.29，28.47，25.67，25.63，25.58，23.68，23.39，20.51，14.58.MS m/z：590[M+H] + ，612[M+Na] + ，558，380.
example 15: preparation of the Compound 3- (4-hydroxy-3-methoxy-phenyl) -acrylic acid- (docosahexaenoic acid-6-hexanolamino) -ester (2 o)
The structural formula of the compound (2 o) is:
1.0mmol of docosahexaenoic acid caprolamine and 1.1mmol of ferulic acid are uniformly mixed, and an ester condensing agent comprising a 10mL 1, 2-dichloroethane mixed solution of DCC (1.0 mmol,206 mg), HOBt (1.2 mmol,162 mg) and DMAP (0.15 mmol,24.4 mg) is slowly dripped. Stirring at 0-5deg.C for reacting for 12 hr, extracting 1, 2-dichloroethane twice after the reaction, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid preparative chromatography, collecting characteristic retention time t 1/2 The fraction=5.27 min was concentrated to give the pale yellow viscous product 2o.
The main physical and chemical properties of compound (2 o) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ9.61(br)，7.76(s)，7.54(d)，7.32(s)，7.10(d)，6.78(d)，6.47(d)，5.35-5.29(m)，4.12-4.09(m)，3.82(s)，3.03-3.02(m)，2.82-2.76(m)，2.26-2.24(m)，2.11-2.01(m)，1.64-1.60(m)，1.41-1.28(m)，0.92(t). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ171.66，167.16，149.78，148.39，145.40，132.01，129.38，128.57，128.55，128.51，128.36，128.33，128.31，128.18，128.16，127.40，126.05，123.61，115.93，114.95，111.61，64.12，56.14，38.79，35.73，29.53，28.73，26.54，25.67，25.64，25.58，23.69，20.51，14.58.MS m/z：604[M+H] + ，626[M+Na] + ，572，412.
example 16: preparation of the Compound 2- (2, 3-xylylamino) -benzoic acid- (docosahexaenoic acid-2-ethylamino) -ester (2 p)
The structural formula of the compound (2 p) is as follows:
1.0mmol of docosahexaenoic acid ethanolamine and 1.1mmol of cresol are uniformly mixed, and an ester condensing agent is slowly dripped, which comprises a 10mL 1, 2-dichloroethane mixed solution of DCC (1.0 mmol,206 mg), HOBt (1.1 mmol,148.5 mg) and DMAP (0.15 mmol,30.5 mg). Stirring at 0-5deg.C for reacting for 12 hr, extracting 1, 2-dichloroethane twice after the reaction, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid preparative chromatography, collecting characteristic retention time t 1 / 2 The fraction=10.89 min was concentrated to give the pale yellow viscous product 2p.
The main physical and chemical properties of compound (2 p) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ9.16(s)，8.11-8.09(m)，7.97-7.94(m)，7.35-7.32(m)，7.13-7.11(m)，7.06-7.05(m)，6.72-6.66(m)，5.36-5.25(m)，4.29-4.26(m)，3.46-3.44(m)，2.81-2.76(m)，2.29(s)，2.27-2.24(m)，2.15-2.12(m)，2.09(s)，2.04-2.00(m)，0.91(t). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ172.30，168.35，149.08，138.61，138.39，135.00，132.06，132.00，131.94，129.23，128.57，128.50，128.35，128.30，128.20，128.15，127.40，127.13，126.53，122.94，116.74，113.69，110.96，63.78，38.12，35.66，25.66，25.61，25.57，23.60，20.68，20.50，14.57，14.11.MS m/z：595[M+H] + ，617[M+Na] + ，476，326.
example 17: preparation of the Compound 2- (2, 3-xylylamino) -benzoic acid- (docosahexaenoic acid-3-propanolamino) -ester (2 q)
The structural formula of the compound (2 q) is as follows:
1.0mmol of docosahexaenoic acid propanolamine and 1.1mmol of cresol were mixed uniformly and slowly dropwise into an ester condensing agent comprising DCC (1.1 mmol,226.6 mg), HOBt (1.2 mmol,162 mg) and DMAP (0.20 mmol,24.4 mg) in 10mL of 1, 2-dichloroethane. Stirring at 0-5deg.C for 16 hr, extracting 1, 2-dichloroethane twice, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid preparative chromatography, collecting characteristic retention time t 1/2 The fraction=12.01 min was concentrated to give a pale yellow viscous product 2q.
The main physical and chemical properties of compound (2 q) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ9.21(s)，7.92-7.90(m，2H，NH，ArH)，7.34-7.31(m)，7.13-7.11(m)，7.06-7.05(m)，6.74-6.67(m)，5.36-5.28(m)，4.29-4.26(m)，3.24-3.20(m)，2.81-2.76(m)，2.29(s)，2.28-2.24(m)，2.13-2.11(m)，2.10(s，3H，CH 3 )，1.88-1.84(m)，0.91(t). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ171.94，168.38，149.05，138.62，138.39，134.96，131.99，131.88，129.32，128.57，128.53，128.35，128.32，128.30，128.19，128.15，127.40，127.09，126.53，122.87，116.85，113.76，111.06，62.77，35.84，35.73，28.85，25.66，25.63，25.57，23.65，20.68，20.50，14.56，14.11.MS m/z：609[M+H] + ，631[M+Na] + ，490，488.
example 18: preparation of the Compound 2- (2, 3-xylylamino) -benzoic acid- (docosahexaenoic acid-4-butanol amino) -ester (2 r)
The structural formula of the compound (2 r) is as follows:
1.0mmol of docosahexaenoic acid butanolamine and 1.1mmol of cresol were mixed uniformly and slowly added dropwise to an ester condensing agent comprising DCC (1.1 mmol,226.6 mg), HOBt (1.3 mmol,175.5 mg) and DMAP (0.25 mmol,30.5 mg) in 10mL of 1, 2-dichloroethane. Stirring at 0-5deg.C for reacting for 8 hr, extracting 1, 2-dichloroethane twice after the reaction, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid preparative chromatography, collecting characteristic retention time t 1/2 The fraction=12.95 min was concentrated to give pale yellow viscous product 2r.
The main physical and chemical properties of the compound (2 r) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ9.21(s)，7.90-7.89(m)，7.88-7.83(m)，7.33-7.30(m)，7.13-7.11(m)，7.05-7.04(m)，6.71-6.68(m)，5.34-5.28(m)，4.30-4.26(m)，3.12-3.11(m)，2.81-2.76(m)，2.29(s)，2.28-2.26(m)，2.12(s)，2.11-2.00(m)，1.73-1.71(m)，1.56-1.52(m)，0.91(t). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ171.77，168.38，149.08，138.61，138.38，134.93，131.98，131.87，129.36，128.56，128.53，128.35，128.32，128.30，128.17，128.14，127.39，127.08，126.51，122.85，116.86，113.78，111.05，64.63，38.46，35.75，26.31，26.19，25.66，25.64，25.57，23.68，20.67，20.50，14.56，14.10.MS m/z：623[M+H] + ，645[M+Na] + ，504，492.
example 19: preparation of the Compound 2- (2, 3-xylylamino) -benzoic acid- (docosahexaenoic acid-5-pentanoylamino) -ester (2 s)
The structural formula of the compound (2 s) is as follows:
will be 1.0mmol of docosahexaenoic acid pentanol amine and 1.1mmol of cresol are uniformly mixed, and an ester condensing agent is slowly dripped, which comprises a mixed solution of DCC (1.2 mmol,247.2 mg), HOBt (1.3 mmol,175.5 mg) and DMAP (0.15 mmol,18.3 mg) in 10mL of 1, 2-dichloroethane. Stirring at 0-5deg.C for reacting for 20 hr, extracting 1, 2-dichloroethane twice after the reaction, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid preparative chromatography, collecting characteristic retention time t 1/2 The fraction=14.41 min was concentrated to give a pale yellow viscous product 2s.
The main physical and chemical properties of compound (2 s) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ9.21(s)，7.90-7.88(m)，7.82-7.79(m)，7.34-7.32(m)，7.13-7.11(m)，7.05-7.03(m)，6.71-6.67(m)，5.35-5.28(m)，4.28-4.25(m)，3.07-3.06(m)，2.82-2.76(m)，2.29(s)，2.26-2.24(m)，2.11(s)，2.10-2.07(m)，1.73-1.71(m)，1.46-1.42(m)，0.91(t). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ171.69，168.41，149.07，138.62，138.38，134.92，131.99，131.87，131.62，129.37，128.56，128.51，128.35，128.32，128.30，128.17，128.15，127.40，127.08，126.52，122.85，116.88，113.79，111.09，64.83，38.69，35.75，29.27，28.33，25.66，25.64，25.57，23.70，20.68，20.50，14.56，14.10.MS m/z：637[M+H] + ，659[M+Na] + ，518，504.
example 20: preparation of the Compound 2- (2, 3-xylylamino) -benzoic acid- (docosahexaenoic acid-6-hexanolamino) -ester (2 t)
The structural formula of the compound (2 t) is as follows:
mixing 1.0mmol of docosahexaenoic acid hexylamine and 1.1mmol of cresol acid uniformly, slowly dripping into ester condensing agent, which comprises DCC (1.0 m)mol,206 mg), HOBt (1.2 mmol,162 mg), DMAP (0.15 mmol,18.3 mg) in 10mL of 1, 2-dichloroethane. Stirring at 0-5deg.C for 24 hr, extracting 1, 2-dichloroethane twice, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid preparative chromatography, collecting characteristic retention time t 1/2 The fraction=16.47 min was concentrated to give 2t as a pale yellow viscous product.
The main physical and chemical properties of compound (2 t) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ9.20(s)，7.90-7.88(m)，7.87(s)，7.34-7.32(m)，7.13-7.11(m)，7.05-7.04(m)，6.71-6.67(m)，5.35-5.28(m)，4.29-4.25(m)，3.04-3.03(m)，2.81-2.75(m，8H，4CH 2 )，2.29(s)，2.26-2.24(m)，2.10(s)，2.09-2.07(m)，2.04-2.00(m)，1.72-1.70(m)，1.43-1.41(m)，1.39-1.32(m)，0.91(t). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ171.69，168.41，149.04，138.62，138.39，134.93，131.99，131.85，131.61，129.37，128.54，128.35，128.31，128.30，128.16，128.14，127.39，127.08，126.53，122.83，116.92，113.80，111.09，64.85，38.78，35.73，29.52，28.58，26.52，25.74，25.66，25.57，23.70，20.68，20.50，14.56，14.10.MS m/z：651[M+H] + ，673[M+Na] + ，532，402.
example 21: the preparation of compound 2-acetoxy-benzoic acid- (docosahexaenoic acyl-2-ethanolamine) -ester (2 u) compound (2 u) has the structural formula:
1.0mmol of docosahexaenoic acid ethanolamine and 1.1mmol of aspirin were mixed uniformly, and an ester condensing agent comprising a 10mL 1, 2-dichloroethane mixed solution of DCC (1.0 mmol,206 mg), HOBt (1.1 mmol,148.5 mg) and DMAP (0.15 mmol,18.3 mg) was slowly added dropwise. Stirring and reacting for 16h at 0-5 DEG CAfter the reaction, 1, 2-dichloroethane is extracted twice, anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid preparative chromatography, collecting characteristic retention time t 1/2 The fraction=6.46 min was concentrated to give 2u as a pale yellow viscous product.
The main physical and chemical properties of compound (2 u) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ8.06(s)，8.01-7.99(m)，7.69-7.66(m)，7.43-7.41(m)，7.39-7.23(m)，5.37-5.26(m)，4.22-4.19(m)，3.41-3.37(m)，2.83-2.76(m)，2.27(s)，2.25-2.24(m)，2.15-2.11(m)，2.05-2.01(m)，0.92(t). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ172.30，169.54，164.22，150.63，134.77，132.01，131.88，129.23，128.58，128.51，128.36，128.31，128.22，128.16，127.40，126.58，124.45，123.36，63.99，38.02，35.60，25.67，25.61，25.58，23.53，21.18，20.50，14.58.MS m/z：534[M+H] + ，556[M+Na] + ，492，237.
example 22: the preparation of compound 2-acetoxy-benzoic acid- (docosahexaenoic acyl-3-propanolamino) -ester (2 v) compound (2 v) has the structural formula:
1.0mmol of docosahexaenoic acid propanolamine and 1.1mmol of aspirin were mixed uniformly and an ester condensing agent, which included a 10mL 1, 2-dichloroethane mixed solution of DCC (1.1 mmol,226.6 mg), HOBt (1.2 mmol,162 mg) and DMAP (0.20 mmol,24.4 mg), was slowly added dropwise. Stirring at 0-5deg.C for reacting for 20 hr, extracting 1, 2-dichloroethane twice after the reaction, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid preparative chromatography, collecting characteristic retention time t 1/2 Concentrating the component with the concentration of=6.83 min to obtain yellowish sticky componentThe thick product was 2v.
The main physical and chemical properties of compound (2 v) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ7.97-7.95(m)，7.91(s)，7.70-7.66(m)，7.43-7.41(m)，7.25-7.23(m)，5.35-5.29(m)，4.23-4.20(m)，3.17-3.16(m)，2.82-2.76(m)，2.27(s)，2.25-2.24(m)，2.12-2.09(m)，2.05-2.01(m)，1.82-1.79(m)，0.91(t). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ172.00，169.57，164.46，150.44，134.69，132.01，131.68，129.28，128.57，128.52，128.35，128.30，128.20，128.15，127.40，126.70，124.48，123.63，63.29，35.75，35.69，28.78，25.66，25.62，25.57，23.61，21.20，20.50，14.57.MS m/z：548[M+H] + ，570[M+Na] + ，506，389.
example 23: the preparation of compound 2-acetoxy-benzoic acid- (docosahexaenoic acyl-4-butanol amino) -ester (2 w) compound (2 w) has the structural formula:
1.0mmol of docosahexaenoic acid butanolamine and 1.1mmol of aspirin were mixed uniformly and an ester condensing agent, which included a 10mL 1, 2-dichloroethane mixed solution of DCC (1.1 mmol,226.6 mg), HOBt (1.3 mmol,175.5 mg) and DMAP (0.25 mmol,30.5 mg), was slowly added dropwise. Stirring at 0-5deg.C for 24 hr, extracting 1, 2-dichloroethane twice, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid preparative chromatography, collecting characteristic retention time t 1/2 The fraction=6.99 min was concentrated to give a pale yellow viscous product 2w.
The main physical and chemical properties of compound (2 w) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ7.96-7.95(m)，7.93(s)，7.83-7.68(m)，7.42-7.40(m)，7.25-7.23(m)，5.37-5.29(m)，4.23-4.20(m)，3.09-3.07(m)，2.82-2.76(m)，2.28(s)，2.25-2.23(m)，2.12-2.08(m)，2.05-2.03(m)，1.68-1.66(m)，1.50-1.47(m)，0.91(t). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ171.79，169.54，164.49，150.44，134.67，132.00，131.61，129.34，128.57，128.54，128.36，128.33，128.31，128.19，128.15，127.40，126.71，124.50，123.68，113.32，65.07，38.39，35.72，35.69，28.78，25.66，25.62，25.57，23.61，21.20，20.50，14.57.MS m/z：562[M+H] + ，584[M+Na] + ，520，384.
example 24: the structural formula for preparing the compound 2-acetoxy-benzoic acid- (docosahexaenoic acyl-5-amyl alcohol amino) -ester (2 x) compound (2 x) is as follows:
1.0mmol of docosahexaenoic acid pentanol amine and 1.1mmol of aspirin were mixed uniformly, and an ester condensing agent comprising DCC (1.2 mmol,247.2 mg), HOBt (1.3 mmol,175.5 mg) and DMAP (0.15 mmol,18.3 mg) in 10mL of 1, 2-dichloroethane was slowly added dropwise. Stirring at 0-5deg.C for reacting for 12 hr, extracting 1, 2-dichloroethane twice after the reaction, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid preparative chromatography, collecting characteristic retention time t 1/2 The fraction=7.37 min was concentrated to give the pale yellow viscous product 2x.
The main physical and chemical properties of compound (2 x) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ7.93-7.90(m)，7.82(s)，7.70-7.66(m)，7.45-7.41(m)，7.23-7.21(m)，5.34-5.27(m)，4.35-4.22(m)，3.05-3.02(m)，2.83-2.79(m)，2.28(s)，2.26-2.23(m)，2.10-2.08(m)，2.08-2.03(m)，1.75-1.67(m)，1.38-1.24(m)，0.92(t). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ172.41，171.65，170.84，161.62，136.10，132.00，130.72，129.38，128.57，128.55，128.50，128.36，128.33，128.31，128.18，128.16，127.40，119.62，117.54，113.40，64.21，38.77，35.72，29.50，28.54，26.50，25.67，25.64，25.58，23.68，21.17，20.51，14.57.MS m/z：576[M+H] + ，598[M+Na] + ，534，316.
example 25: the preparation of compound 2-acetoxy-benzoic acid- (docosahexaenoic acyl-6-hexanolamino) -ester (2 y) compound (2 y) has the structural formula:
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1.0mmol of docosahexaenoic acid hexanolamine and 1.1mmol of aspirin were mixed uniformly, and an ester condensing agent comprising DCC (1.0 mmol,206 mg), HOBt (1.2 mmol,162 mg) and DMAP (0.15 mmol,24.4 mg) in 10mL of 1, 2-dichloroethane was slowly added dropwise. Stirring at 0-5deg.C for reacting for 8 hr, extracting 1, 2-dichloroethane twice after the reaction, and anhydrous MgSO 4 Drying, concentrating, and purifying by flash column chromatography on silica gel (V Acetic acid ethyl ester ∶V Petroleum ether =1:1) and high performance liquid preparative chromatography, collecting characteristic retention time t 1/2 The fraction=7.91 min was concentrated to give pale yellow viscous product 2y.
The main physical and chemical properties of the compound (2 y) are as follows:
a light yellow viscous substance, which is a light yellow viscous substance, 1 H NMR(400MHz，DMSO-d 6 ，ppm)：δ7.95-7.94(m)，7.76(s)，7.70-7.68(m)，7.44-7.41(m)，7.25-7.23(m)，5.35-5.27(m)，4.23-4.21(m)，3.03-3.00(m)，2.82-2.77(m)，2.28(s)，2.26-2.23(m)，2.10-2.02(m)，1.68-1.64(m)，1.39-1.29(m)，0.92(t). 13 C NMR(100MHz，DMSO-d 6 ，ppm)：δ171.65，169.52，164.54，150.42，134.65，132.01，131.61，129.39，128.58，128.56，128.51，128.36，128.33，128.31，128.18，128.16，127.41，126.74，124.49，123.73，65.29，38.79，35.72，29.52，28.55，26.52，25.67，25.64，23.68，21.22，20.50，14.58.MS m/z：590[M+H] + ，612[M+Na] + ，548，432.
example 26: docosahexaenoic acid ester derivative (2 a-2 y) inhibits NO production in RAW264.7 cells
Macrophages RAW264.7 were seeded in 24 well plates, 1.5 ten thousand per well, and cultured overnight. After the cells are attached, the compound is added in advance for administration for 2 hours, 0.5 mu L of LPS is added in each hole for induction for 24 hours, the final LPS concentration is 1 mu g/mL, the final dexamethasone Dex concentration is 10 mu M, and the final concentration of the 2a-2y compound is 10 mu M. Cell supernatant medium was collected as a test sample. The amount of NO secreted by RAW264.7 cells was measured using the NO detection kit by detecting absorbance (OD) values at 560 nm. Experimental results show that all 25 tested docosahexaenoic acid ester derivatives can inhibit NO production in RAW264.7 cells. The experimental results are shown in FIG. 4 (Con is a blank cell).
Example 27: docosahexaenoic acid ester derivatives down-regulate mRNA expression of pro-inflammatory mediators TNF-alpha, IL-6 and IL-1 beta
RAW264.7 cells in good condition were seeded in 6-well plates at a seeding density of 4.5X10 5 Each well is cultured overnight, after the cells are attached, the compound is added for 2 hours, the final concentration of 2a-2y compound effect is 10 mu M, the final concentration of dexamethasone Dex effect is 5 mu M, LPS is added for induction for 12 hours, and the final concentration of LPS is 1 mu g/mL. After 12h, the cell culture medium is removed, RNA is extracted, reverse transcription reaction is carried out on the RNA, the obtained reverse transcription product is amplified by PCR experiment, and finally 2 of the apparatus Agilent AriaMx PCR is adopted -ΔΔCt The method is used for quantifying the experimental result. The experimental results show that 2b,2d,2j,2p,2q,2k,2l,2m,2o and 2y compounds of the 25 docosahexaenoic acid ester derivatives tested showed different degrees of down-regulated mRNA expression of pro-inflammatory mediators TNF-alpha, IL-6 and IL-1 beta. The experimental results are shown in FIGS. 5 to 7 (Con is a blank cell).
Example 28: docosahexaenoic acid ester derivatives inhibit protein expression of pro-inflammatory cytokines TNF-alpha and IL-1 beta
RAW264.7 cells in good condition were seeded in 6-well plates at a seeding density of 4.5X10 5 Cell culture per wellAfter the cells are attached, the cells are added to be pretreated for 2 hours, 2b,2d,2j,2p,2q,2k,2l,2M,2o and 2y, the final concentration of the compounds is 10 mu M, the final concentration of dexamethasone Dex is 10 mu M, LPS is added to induce for 6 hours, and the final concentration of the LPS is 1 mu g/mL. After 6h, the cell culture medium was removed, and the cells were lysed with a protein lysate to extract the protein. The protein samples obtained were analysed by SDS-PAGE and the proteins were transferred onto PVDF membrane and immobilized by the "sandwich" method under electrotransfer buffer conditions. After electrotransformation, the membrane is blocked for 2 hours by using 5% skimmed milk, some nonspecific protein interference is removed, then primary antibody and secondary antibody are incubated, and the membrane is washed for 3 times and 10 minutes each time after the secondary antibody incubation is finished. Finally, performing exposure detection by using a chemiluminescent imager Biorad. Experimental results show that LPS significantly up-regulates the protein expression of IL-1 beta and TNF-alpha, and 2d,2j,2k,2l,2m,2o and 2y among the 10 tested docosahexaenoic acid ester derivatives significantly down-regulates the protein expression of IL-1 beta, but they do not show a significant down-regulation trend on the protein expression of TNF-alpha. The experimental results are shown in FIG. 8.
The foregoing description is only illustrative of the preferred embodiments of the present invention and is not to be construed as limiting the scope of the invention, i.e., the invention is not to be limited to the details of the invention.

Claims (5)

1. A docosahexaenoic acid ester derivative, characterized in that: the structure is as follows
The preparation method comprises the following steps:
(1) Mixing methyl docosahexaenoic acid and alcohol amine, heating and stirring at 80 ℃ for reaction for 15 hours, then stirring a sample with silica gel, and then performing silica gel column chromatography purification to obtain docosahexaenoic acid alcohol amine, wherein the molar ratio of the methyl docosahexaenoic acid to the alcohol amine is 1:2;
(2) Uniformly mixing the docosahexaenoic acid alcohol amine and the organic acid,stirring and reacting for 8-24h at 0-5 ℃ under the action of ester condensing agent, and extracting twice by 1, 2-dichloroethane, and obtaining anhydrous MgSO 4 Drying, concentrating, purifying by silica gel column chromatography and purifying by high performance liquid chromatography to obtain the docosahexaenoic acid ester derivative, wherein the ratio of the docosahexaenoic acid alcohol amine to the organic acid to the ester condensing agent is 1.0mmol to 1.1mmol to 10mL, and the ratio of the N, N' -dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, 4-dimethylaminopyridine to dichloroethane in the ester condensing agent is 206.0-247.2mg to 148.5-175.5mg to 18.3-30.5mg to 10mL;
the alcohol amine is ethanolamine, propanolamine, butanolamine, pentanolamine and hexanolamine, the organic acid is 2- (6-methoxy-2-naphthyl) -propionic acid, 2- (4-isobutyl-phenyl) -propionic acid, 3- (4-hydroxy-3-methoxy-phenyl) -acrylic acid, 2- (2, 3-xylylamino) -benzoic acid or 2-acetoxy-benzoic acid, and the ester condensing agent is a dichloroethane solution containing N, N' -dicyclohexylcarbodiimide, 1-hydroxybenzotriazole and 4-dimethylaminopyridine.
2. A docosahexaenoic acid ester derivative as claimed in claim 1, wherein: characteristic retention time t of high performance liquid chromatography purification in the step (2) 1/2 Between 4.58 and 16.47 min.
3. Use of the docosahexaenoic acid ester derivative according to claim 1 or 2 for preparing anti-inflammatory small molecule drugs.
4. Use of a docosahexaenoic acid ester derivative according to claim 1 or 2 for the preparation of an anti-inflammatory composition.
5. An anti-inflammatory composition characterized by: the docosahexaenoic acid ester derivative according to claim 1 or 2 as an active ingredient.
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