CN114853628A - Docosahexaenoic acid ester derivative and preparation method and application thereof - Google Patents

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

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CN114853628A
CN114853628A CN202210496100.2A CN202210496100A CN114853628A CN 114853628 A CN114853628 A CN 114853628A CN 202210496100 A CN202210496100 A CN 202210496100A CN 114853628 A CN114853628 A CN 114853628A
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ester
acid
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docosahexenoyl
dichloroethane
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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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Abstract

The invention discloses a docosahexenoyl ester derivative, a preparation method and application thereof, wherein the structural formula of the derivative is shown in the specification
Figure DDA0003631870380000011
Wherein n is an integer of 0 to 4, and R is
Figure DDA0003631870380000012
Figure DDA0003631870380000013
Or
Figure DDA0003631870380000014
The invention has certain down-regulation effect on mRNA expression of proinflammatory mediators induced by Lipopolysaccharide (LPS) in macrophage RAW264.7 of a mouse, down-regulates the exocrine level of Nitric Oxide (NO), and can inhibit protein expression of proinflammatory cytokines.

Description

Docosahexaenoic acid 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 ester derivative as well as 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 pathogens and toxins. Acute inflammation is less dangerous to the body and can cause edema and intracellular flow as well as changes in vascular permeability and local hemodynamics, while chronic inflammation can lead to diseases such as asthma, rheumatoid arthritis, and cancer.
Omega-3 polyunsaturated fatty acid is enriched in cell membrane, can affect intracellular signal conduction, and inhibit the transcriptional activity of inflammation-related transcription factor NF-kB, thereby reducing the expression of proinflammatory cytokines TNF-alpha, IL-6, IL-1 beta and the like. Omega-3 polyunsaturated fatty acid is metabolized to generate derivatives with physiological activities of diminishing inflammation, relieving pain and the like, such as resolvins and protectins generated by enzyme catalysis, and can stimulate neutrophils, macrophages and the like to secrete anti-inflammatory cytokines IL-10, IL-4, IL-13 and the like to weaken inflammatory reaction and regulate the level of inflammation of an organism.
Disclosure of Invention
The invention aims to provide a docosahexenoyl ester derivative.
Another object of the present invention is to provide a process for producing the docosahexaenoic acid ester derivative.
The invention also aims to provide application of the docosahexenoyl ester derivative.
The technical scheme of the invention is as follows:
a docosahexenoyl ester derivative with the structural formula
Figure BDA0003631870360000011
Wherein n is an integer of 0 to 4, and R is
Figure BDA0003631870360000012
Figure BDA0003631870360000013
The preparation method of the docosahexenoyl ester derivative comprises the following steps:
(1) mixing methyl docosahexenoate and alcohol amine, heating and stirring at 80 ℃ for reaction for 15 hours, stirring with silica gel, and purifying by silica gel column chromatography to obtain docosahexaenoic acid alcohol amine;
(2) mixing the docosahexenoyl alcohol amine with organic acid, stirring and reacting at 0-5 deg.C for 8-24h under the action of ester condensing agent, extracting twice with 1, 2-dichloroethane, anhydrous MgSO 4 Drying, concentrating, purifying by silica gel column chromatography and high performance liquid chromatography to obtain the docosahexenoyl 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 (cresylic 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 and the alcohol amine is 1: 2.
Further preferably, in the step (2), the molar ratio of the docosahexaenoyl alcohol amine to the organic acid is 1: 1.1.
Still more preferably, the ratio of the docosahexaenoic acid alcohol amine, the organic acid and the ester condensing agent is 1.0 mmol: 1.1 mmol: 10 mL.
Still further preferably, in the ester condensing agent, the ratio of N, N' -dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, 4-dimethylaminopyridine and dichloroethane is 206.0-247.2 mg: 148.5-175.5 mg: 18.3-30.5 mg: 10 mL.
In a preferred embodiment of the present invention, in said step (2), the characteristic retention time t of the high performance liquid chromatography purification 1/2 Between 4.58 and 16.47 min.
The docosahexenoyl ester derivative is applied as an anti-inflammatory micromolecule drug.
The application of the docosahexenoyl ester derivative in preparing an anti-inflammatory composition.
An anti-inflammatory composition contains the docosahexaenoic acid ester derivative as the effective component.
The invention has the beneficial effects that:
1. the invention introduces a molecular fragment with anti-inflammatory activity into a hydroxyl position of fatty acyl alcohol amine, has certain down-regulation effect on mRNA expression of proinflammatory 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 proinflammatory cytokines (TNF-a and IL-1 beta).
2. The invention has high bioavailability and good safety.
Drawings
FIG. 1 is a drawing showing a scheme for preparing Compound 2a in the example of the present invention 1 H NMR chart.
FIG. 2 is a drawing of Compound 2a in an example of the present invention 13 C NMR carbon spectrum.
FIG. 3 is a general synthesis diagram of the docosahexaenoic acid ester derivative (2a-2y) according to the embodiment of the present invention.
FIG. 4 is a graph showing the results of experiments in which the docosahexaenoic acid ester derivative (2a-2y) according to the present invention inhibits the production of NO in RAW264.7 cells, wherein S1 is naproxen, S2 is ibuprofen, S3 is ferulic acid, S4 is cresylic acid, S5 is aspirin, and DHEA is docosahexaenoic acid ethanolamine.
FIG. 5 is a graph showing the result of the docosahexenoyl ester derivative (2a-2y) down-regulating the expression of mRNA of proinflammatory mediator TNF-alpha in the example of the present invention, wherein S1 is naproxen, S2 is ibuprofen, S3 is ferulic acid, S4 is cresylic acid, S5 is aspirin, and DHEA is docosahexenoyl ethanolamine.
FIG. 6 is a graph showing the result of the docosahexenoyl ester derivative (2a-2y) down-regulating the expression of mRNA of proinflammatory mediator IL-6 in the example of the present invention, wherein S1 is naproxen, S2 is ibuprofen, S3 is ferulic acid, S4 is cresylic acid, S5 is aspirin, and DHEA is docosahexenoyl ethanolamine.
FIG. 7 is a graph showing the result of the docosahexenoyl ester derivative (2a-2y) down-regulating the expression of mRNA of proinflammatory mediator IL-1 β in the example of the present invention, wherein S1 is naproxen, S2 is ibuprofen, S3 is ferulic acid, S4 is cresylic acid, S5 is aspirin, and DHEA is docosahexenoyl ethanolamine.
FIG. 8 is a graph showing the results of the inhibition of protein expression of the proinflammatory cytokines IL-1 β and TNF- α by docosahexaenoic acid ester derivatives according to an embodiment of the present invention.
Detailed Description
The technical solution of the present invention will be further illustrated and described below with reference to the drawings by means of specific embodiments.
The general synthetic formulae of compounds 2a-2y in the following examples are shown in FIG. 3.
Example 1: preparation of the Compound 2- (6-methoxy-2-naphthyl) -propionic acid- (docosahexenoyl-2-ethanolamine) -ester (2a)
The structural formula of the compound (2a) is:
Figure BDA0003631870360000031
1.0mmol of docosahexaenoic acid ethanolamine and 1.1mmol of naproxen were mixed uniformly, and an ester condensing agent comprising a mixed solution of DCC (1.0mmol, 206mg), HOBt (1.1mmol, 148.5mg) and DMAP (0.15mmol, 18.3mg) in 10mL of 1, 2-dichloroethane was slowly dropped. Stirring at 0-5 deg.C for 8 hr, extracting with 1, 2-dichloroethane twice, and collecting the extractive solution with anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Ethyl acetate ∶V Petroleum ether 1: 1) and high performance liquid chromatography, collecting characteristic retention time t 1/2 The fractions were concentrated for 6.46min to give the product 2a as a pale yellow viscous product.
As shown in fig. 1 and 2, the main physical and chemical properties of compound (2a) are as follows:
a light yellow sticky 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: preparation of compound 2- (6-methoxy-2-naphthyl) -propionic acid- (docosahexenoyl-3-propanolamino) -ester (2b) compound (2b) has the formula:
Figure BDA0003631870360000041
1.0mmol of docosahexaenoylpropanolamine and 1.1mmol of naproxen are mixed homogeneouslyUniformly, an ester condensing agent comprising a mixed solution of DCC (1.1mmol, 226.6mg), HOBt (1.2mmol, 162mg) and DMAP (0.20mmol, 24.4mg) in 10mL of 1, 2-dichloroethane was slowly dropped. Stirring at 0-5 deg.C for 12 hr, extracting with 1, 2-dichloroethane twice, and collecting the extractive solution with anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Ethyl acetate ∶V Petroleum ether 1: 1) and HPLC for further purification, collecting characteristic retention time t 1/2 The mixture was concentrated for 6.83min to give a pale yellow viscous product 2 b.
The main physical and chemical properties of compound (2b) are as follows:
a light yellow sticky 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- (docosahexenoyl-4-butanolamino) -ester (2c)
The structural formula of the compound (2c) is:
Figure BDA0003631870360000051
1.0mmol of docosahexaenoic acid butanolamine and 1.1mmol of naproxen were mixed uniformly, and an ester condensing agent comprising a mixed solution of DCC (1.1mmol, 226.6mg), HOBt (1.3mmol, 175.5mg) and DMAP (0.25mmol, 30.5mg) in 10mL of 1, 2-dichloroethane was slowly dropped. Stirring and reacting at 0-5 DEG C24h, after the reaction is finished, extracting 1, 2-dichloroethane twice, and anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Ethyl acetate ∶V Petroleum ether 1: 1) and further purifying by high performance liquid chromatography, collecting characteristic retention time t 1/2 Concentrating for 6.99min to obtain yellowish viscous product 2 c.
The main physical and chemical properties of compound (2c) are as follows:
a light yellow sticky 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- (docosahexenoyl-5-pentanoylamino) -ester (2d)
The structural formula of the compound (2d) is:
Figure BDA0003631870360000052
1.0mmol of docosahexaenoic acid pentolamine and 1.1mmol of naproxen were mixed uniformly, and an ester condensing agent comprising a mixed solution of DCC (1.2mmol, 247.2mg), HOBt (1.3mmol, 175.5mg) and DMAP (0.15mmol, 30.5mg) in 10mL of 1, 2-dichloroethane was slowly dropped. Stirring at 0-5 deg.C for 20 hr, extracting with 1, 2-dichloroethane twice, and collecting the extractive solution with anhydrous MgSO 4 Drying, concentrating, and purifying by rapid silica gel column chromatographyTransformation (V) Ethyl acetate ∶V Petroleum ether 1: 1) and high performance liquid chromatography, collecting characteristic retention time t 1/2 Concentrating for 7.37min to obtain yellowish viscous product 2 d.
The main physical and chemical properties of compound (2d) are as follows:
a light yellow sticky 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- (docosahexenoyl-6-hexanolamino) -ester (2e)
The structural formula of compound (2e) is:
Figure BDA0003631870360000061
1.0mmol of docosahexaenoic acid hexanolamine and 1.1mmol of naproxen were mixed uniformly, and an ester condensing agent comprising a mixed solution of DCC (1.0mmol, 206mg), HOBt (1.2mmol, 162mg) and DMAP (0.15mmol, 18.3mg) in 10mL of 1, 2-dichloroethane was slowly dropped. Stirring and reacting at 0-5 deg.C for 16h, extracting with 1, 2-dichloroethane twice after reaction, and collecting the extract over anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Ethyl acetate ∶V Petroleum ether 1: 1) and high performance liquid chromatography, collecting characteristic retention time t 1/2 Concentrating for 7.91min to obtain yellowish viscous product 2 e.
The main physical and chemical properties of compound (2e) are as follows:
a light yellow sticky 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: preparation of compound 2- (4-isobutyl-phenyl) -propionic acid- (docosahexenoyl-2-ethanolamine) -ester (2f) compound (2f) the structural formula of compound (2f) is:
Figure BDA0003631870360000071
1.0mmol of docosahexaenoic acid ethanolamine and 1.1mmol of ibuprofen were mixed uniformly, and an ester condensing agent comprising a mixed solution of DCC (1.0mmol, 206mg), HOBt (1.1mmol, 148.5mg) and DMAP (0.15mmol, 18.3mg) in 10mL of 1, 2-dichloroethane was slowly dropped. Stirring at 0-5 deg.C for 20 hr, extracting with 1, 2-dichloroethane twice, and collecting the extractive solution with anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Ethyl acetate ∶V Petroleum ether 1: 1) and high performance liquid chromatography, collecting characteristic retention time t 1/2 Concentrating for 8.69min to obtain yellowish viscous product 2 f.
The main physical and chemical properties of compound (2f) are as follows:
a light yellow sticky 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- (docosahexenoyl-3-propanolamino) -ester (2g) the formula for compound (2g) is:
Figure BDA0003631870360000072
1.0mmol of docosahexenoylpropanolamine and 1.1mmol of ibuprofen were mixed well and an ester condensing agent comprising a 10mL mixed solution of 1, 2-dichloroethane of DCC (1.1mmol, 226.6mg), HOBt (1.2mmol, 162mg) and DMAP (0.20mmol, 24.4mg) was slowly dropped. Stirring at 0-5 deg.C for 24 hr, extracting with 1, 2-dichloroethane twice, and collecting the extractive solution with anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Ethyl acetate ：V Petroleum ether 1: 1) and high performance liquid chromatography, collecting characteristic retention time t 1/2 The mixture was concentrated for 8.93min to give 2g of a pale yellow viscous product.
The main physical and chemical properties of compound (2g) are as follows:
a light yellow sticky 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: preparation of compound 2- (4-isobutyl-phenyl) -propionic acid- (docosahexenoyl-4-butanolamino) -ester (2h) compound (2h) the structural formula of compound (2h) is:
Figure BDA0003631870360000081
1.0mmol of docosahexaenoic acid butanolamine and 1.1mmol of ibuprofen were mixed uniformly, and an ester condensing agent comprising a mixed solution of DCC (1.1mmol, 226.6mg), HOBt (1.3mmol, 175.5mg), DMAP (0.25mmol, 30.5mg) in 10mL of 1, 2-dichloroethane was slowly dropped. Stirring at 0-5 deg.C for 8 hr, extracting with 1, 2-dichloroethane twice, and collecting the extractive solution with anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Ethyl acetate ∶V Petroleum ether 1: 1) and high performance liquid 75 phase preparative chromatography, collecting characteristic retention time t 1/2 Concentrating for 9.15min to obtain yellowish viscous product for 2 h.
The main physical and chemical properties of compound (2h) are as follows:
a light yellow sticky 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: preparation of compound 2- (4-isobutyl-phenyl) -propionic acid- (docosahexenoyl-5-pentanoylamino) -ester (2i) compound (2i) the structural formula of compound (2i) is:
Figure BDA0003631870360000091
1.0mmol of docosahexaenoic acid pentolamine and 1.1mmol of ibuprofen were mixed uniformly, and an ester condensing agent comprising a mixed solution of DCC (1.2mmol, 247.2mg), HOBt (1.3mmol, 175.5mg), DMAP (0.15mmol, 18.3mg) in 10mL of 1, 2-dichloroethane was slowly dropped. Stirring and reacting at 0-5 deg.C for 16h, extracting with 1, 2-dichloroethane twice after reaction, and collecting the extract over anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Ethyl acetate ∶V Petroleum ether 1: 1) and high performance liquid chromatography, collecting characteristic retention time t 1/2 Concentrating for 9.71min to obtain yellowish viscous product 2 i.
The main physical and chemical properties of compound (2i) are as follows:
a light yellow sticky 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- (docosahexenoyl-6-hexanolamino) -ester (2j)
The structural formula of the compound (2j) is:
Figure BDA0003631870360000092
1.0mmol of docosahexaenoic acid hexanolamine and 1.1mmol of ibuprofen were mixed uniformly, and an ester condensing agent comprising a 10mL mixed solution of 1, 2-dichloroethane (DCC (1.0mmol, 206mg), HOBt (1.2mmol, 148mg), DMAP (0.15mmol, 18.3mg) was slowly dropped. Stirring at 0-5 deg.C for 12 hr, extracting with 1, 2-dichloroethane twice, and collecting the extractive solution with anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Ethyl acetate ∶V Petroleum ether 1: 1) and high performance liquid chromatography, collecting characteristic retention time t 1/2 Concentrating for 10.46min to obtain yellowish viscous product 2 j.
The main physical and chemical properties of compound (2j) are as follows:
a light yellow sticky 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- (docosahexenoyl-2-ethanolamine) -ester (2k)
The structural formula of compound (2k) is:
Figure BDA0003631870360000101
1.0mmol of docosahexaenoic acid ethanolamine and 1.1mmol of ferulic acid were mixed uniformly, and an ester condensing agent comprising a mixed solution of DCC (1.0mmol, 206mg), HOBt (1.1mmol, 148.5mg) and DMAP (0.15mmol, 18.3mg) in 10mL of 1, 2-dichloroethane was slowly dropped. Stirring at 0-5 deg.C for 20 hr, extracting with 1, 2-dichloroethane twice, and collecting the extractive solution with anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Ethyl acetate ∶V Petroleum ether 1: 1) and high performance liquid chromatography, collecting characteristic retention time t 1/2 Concentrating for 4.58min to obtain yellowish viscous product 2 k.
The main physical and chemical properties of compound (2k) are as follows:
a light yellow sticky 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- (docosahexenoyl-3-propanolamino) -ester (21)
The structural formula of the compound (21) is:
Figure BDA0003631870360000111
1.0mmol of docosahexaenoic acid propanolamine and 1.1mmol of ferulic acid were mixed uniformly, and an ester condensing agent comprising a mixed solution of DCC (1.1mmol, 226.6mg), HOBt (1.2mmol, 162mg) and DMAP (0.20mmol, 24.4mg) in 10mL of 1, 2-dichloroethane was slowly dropped. Stirring at 0-5 deg.C for 24 hr, extracting with 1, 2-dichloroethane twice, and collecting the extractive solution with anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Ethyl acetate ∶V Petroleum ether 1: 1) and high performance liquid chromatography, collecting characteristic retention time t 1/2 The fractions were concentrated for 4.60min to give 2l of a pale yellow viscous product.
The main physical and chemical properties of compound (2l) are as follows:
a light yellow sticky 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- (docosahexenoyl-4-butanolamino) -ester (2m)
The structural formula of the compound (2m) is:
Figure BDA0003631870360000112
mixing 1.0mmol of docosahexaenoyl butanolamine and 1.1mmol of ferulic acid uniformly and slowlyAn ester condensing agent comprising a mixed solution of DCC (1.1mmol, 226.6mg), HOBt (1.3mmol, 175.5mg) and DMAP (0.25mmol, 30.5mg) in 10mL of 1, 2-dichloroethane was slowly dropped. Stirring at 0-5 deg.C for 8 hr, extracting with 1, 2-dichloroethane twice, and collecting the extractive solution with anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Acetic acid ethyl ester ∶V Petroleum ether 1: 1) and high performance liquid chromatography, collecting characteristic retention time t 1/2 Concentrating for 4.63min to obtain yellowish viscous product 2 m.
The main physical and chemical properties of compound (2m) are as follows:
a light yellow sticky 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- (docosahexenoyl-5-pentanoylamino) -ester (2n)
The structural formula of the compound (2n) is:
Figure BDA0003631870360000121
1.0mmol of docosahexaenoic acid pentolamine and 1.1mmol of ferulic acid were mixed uniformly, and an ester condensing agent comprising a mixed solution of DCC (1.2mmol, 247.2mg), HOBt (1.3mmol, 175.5mg) and DMAP (0.15mmol, 18.3mg) in 10mL of 1, 2-dichloroethane was slowly dropped. Stirring and reacting for 16h at 0-5 ℃, and extracting 1, 2-dichloroethane after the reaction is finishedTwice, anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Ethyl acetate ∶V Petroleum ether 1: 1) and high performance liquid chromatography, collecting characteristic retention time t 1/2 Concentrating for 5.05min to obtain yellowish viscous product 2 n.
The main physical and chemical properties of compound (2n) are as follows:
a light yellow sticky 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- (docosahexenoyl-6-hexanolamino) -ester (2o)
The structural formula of compound (2o) is:
Figure BDA0003631870360000131
1.0mmol of docosahexaenoic acid hexanolamine and 1.1mmol of ferulic acid were mixed uniformly, and an ester condensing agent comprising a 10mL 1, 2-dichloroethane mixed solution of DCC (1.0mmol, 206mg), HOBt (1.2mmol, 162mg), DMAP (0.15mmol, 24.4mg) was slowly dropped. Stirring at 0-5 deg.C for 12 hr, extracting with 1, 2-dichloroethane twice, and collecting the extractive solution with anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Ethyl acetate ∶V Petroleum ether 1: 1) and high performance liquid chromatography for further purification,collected feature retention time t 1/2 The fractions were concentrated for 5.27min to give a pale yellow viscous product 2 o.
The main physical and chemical properties of compound (2o) are as follows:
a light yellow sticky 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-Dixylylamino) -benzoic acid- (docosahexenoyl-2-ethanolamine) -ester (2p)
The structural formula of compound (2p) is:
Figure BDA0003631870360000132
1.0mmol of docosahexaenoic acid ethanolamine and 1.1mmol of cresylic acid were mixed uniformly, and an ester condensing agent comprising a mixed solution of DCC (1.0mmol, 206mg), HOBt (1.1mmol, 148.5mg) and DMAP (0.15mmol, 30.5mg) in 10mL of 1, 2-dichloroethane was slowly dropped. Stirring at 0-5 deg.C for 12 hr, extracting with 1, 2-dichloroethane twice, and collecting the extractive solution with anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Ethyl acetate ∶V Petroleum ether 1: 1) and high performance liquid chromatography, collecting characteristic retention time t 1 / 2 Concentrating for 10.89min to obtain yellowish viscous product 2 p.
The main physical and chemical properties of compound (2p) are as follows:
a light yellow sticky 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-Dixylylamino) -benzoic acid- (docosahexenoyl-3-propanolamino) -ester (2q)
The structural formula of compound (2q) is:
Figure BDA0003631870360000141
1.0mmol of docosahexaenoic acid propanolamine and 1.1mmol of cresylic acid were mixed uniformly, and an ester condensing agent comprising a mixed solution of DCC (1.1mmol, 226.6mg), HOBt (1.2mmol, 162mg) and DMAP (0.20mmol, 24.4mg) in 10mL of 1, 2-dichloroethane was slowly dropped. Stirring and reacting at 0-5 deg.C for 16h, extracting with 1, 2-dichloroethane twice after reaction, and collecting the extract over anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Ethyl acetate ∶V Petroleum ether 1: 1) and high performance liquid chromatography, collecting characteristic retention time t 1/2 Concentrating for 12.01min to obtain yellowish viscous product 2 q.
The main physical and chemical properties of compound (2q) are as follows:
a light yellow sticky 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-Dixylylamino) -benzoic acid- (docosahexenoyl-4-butanolamino) -ester (2r)
The structural formula of compound (2r) is:
Figure BDA0003631870360000151
1.0mmol of docosahexaenoic acid butanolamine and 1.1mmol of cresylic acid were mixed uniformly, and an ester condensing agent comprising a mixed solution of DCC (1.1mmol, 226.6mg), HOBt (1.3mmol, 175.5mg) and DMAP (0.25mmol, 30.5mg) in 10mL of 1, 2-dichloroethane was slowly dropped. Stirring at 0-5 deg.C for 8 hr, extracting with 1, 2-dichloroethane twice, and collecting the extractive solution with anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Ethyl acetate ∶V Petroleum ether 1: 1) and high performance liquid chromatography, collecting characteristic retention time t 1/2 Concentrating for 12.95min to obtain yellowish viscous product 2 r.
The main physical and chemical properties of compound (2r) are as follows:
a light yellow sticky 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- (docosahexenoyl-5-pentanoylamino) -ester (2s)
The structural formula of compound (2s) is:
Figure BDA0003631870360000161
1.0mmol of docosahexaenoic acid pentolamine and 1.1mmol of cresolic acid were mixed uniformly, and an ester condensing agent comprising a mixed solution of DCC (1.2mmol, 247.2mg), HOBt (1.3mmol, 175.5mg) and DMAP (0.15mmol, 18.3mg) in 10mL of 1, 2-dichloroethane was slowly dropped. Stirring at 0-5 deg.C for 20 hr, extracting with 1, 2-dichloroethane twice, and collecting the extractive solution with anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Ethyl acetate ∶V Petroleum ether 1: 1) and high performance liquid chromatography, collecting characteristic retention time t 1/2 Concentrating for 14.41min to obtain yellowish viscous product 2 s.
The main physical and chemical properties of compound (2s) are as follows:
a light yellow sticky 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- (docosahexenoyl-6-hexanolamino) -ester (2t)
The structural formula of compound (2t) is:
Figure BDA0003631870360000162
1.0mmol of docosahexaenoic acid hexanolamine and 1.1mmol of cresylic acid were mixed uniformly, and an ester condensing agent comprising a mixed solution of DCC (1.0mmol, 206mg), HOBt (1.2mmol, 162mg) and DMAP (0.15mmol, 18.3mg) in 10mL of 1, 2-dichloroethane was slowly dropped. Stirring at 0-5 deg.C for 24 hr, extracting with 1, 2-dichloroethane twice, and collecting the extractive solution with anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Ethyl acetate ∶V Petroleum ether 1: 1) and high performance liquid chromatography, collecting characteristic retention time t 1/2 Concentrating for 16.47min to obtain yellowish viscous product 2 t.
The main physical and chemical properties of compound (2t) are as follows:
a light yellow sticky 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: preparation of compound 2-acetoxy-benzoic acid- (docosahexenoyl-2-ethanolamine) -ester (2u) compound (2u) the structural formula of compound (2u) is:
Figure BDA0003631870360000171
1.0mmol of docosahexaenoic acid ethanolamine and 1.1mmol of aspirin were mixed uniformly, and an ester condensing agent comprising a mixed solution of DCC (1.0mmol, 206mg), HOBt (1.1mmol, 148.5mg) and DMAP (0.15mmol, 18.3mg) in 10mL of 1, 2-dichloroethane was slowly dropped. Stirring and reacting at 0-5 deg.C for 16h, extracting with 1, 2-dichloroethane twice after reaction, and collecting the extract over anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Ethyl acetate ∶V Petroleum ether 1: 1) and high performance liquid chromatography, collecting characteristic retention time t 1/2 Concentrating for 6.46min to obtain yellowish viscous product 2 u.
The main physical and chemical properties of compound (2u) are as follows:
a light yellow sticky 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: preparation of compound 2-acetoxy-benzoic acid- (docosahexenoyl-3-propanolamino) -ester (2v) compound (2v) the formula of compound (2v) is:
Figure BDA0003631870360000181
1.0mmol of docosahexaenoic acid propanolamine and 1.1mmol of aspirin were mixed uniformly, and an ester condensing agent comprising a 10mL mixed solution of 1, 2-dichloroethane of DCC (1.1mmol, 226.6mg), HOBt (1.2mmol, 162mg) and DMAP (0.20mmol, 24.4mg) was slowly dropped. Stirring at 0-5 deg.C for 20 hr, extracting with 1, 2-dichloroethane twice, and collecting the extractive solution with anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Ethyl acetate ∶V Petroleum ether 1: 1) and high performance liquid chromatography, collecting characteristic retention time t 1/2 The fractions were concentrated for 6.83min to give 2v as a pale yellow viscous product.
The main physical and chemical properties of compound (2v) are as follows:
a light yellow sticky 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: preparation of compound 2-acetoxy-benzoic acid- (docosahexenoyl-4-butanolamino) -ester (2w) compound (2w) the formula of compound (2w) is:
Figure BDA0003631870360000182
1.0mmol of docosahexaenoic acid butanolamine and 1.1mmol of aspirin were mixed uniformly, and an ester condensing agent comprising a mixed solution of DCC (1.1mmol, 226.6mg), HOBt (1.3mmol, 175.5mg), DMAP (0.25mmol, 30.5mg) in 10mL of 1, 2-dichloroethane was slowly dropped. Stirring at 0-5 deg.C for 24 hr, extracting with 1, 2-dichloroethane twice, and collecting the extractive solution with anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Ethyl acetate ∶V Petroleum ether 1: 1) and high performance liquid chromatography, collecting characteristic retention time t 1/2 Concentrating for 6.99min to obtain yellowish viscous product 2 w.
The main physical and chemical properties of compound (2w) are as follows:
a light yellow sticky 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: preparation of the compound 2-acetoxy-benzoic acid- (docosahexenoyl-5-pentanoylamino) -ester (2x) the structural formula of the compound (2x) is:
Figure BDA0003631870360000191
mixing 1.0mmol of docosahexenoylpentaolamine with 1.1mmol of aspirin, and slowly dropping ester condensing agent comprising DCC (1.2 mmol)l, 247.2mg), HOBt (1.3mmol, 175.5mg), DMAP (0.15mmol, 18.3mg) in 10mL of a mixed solution of 1, 2-dichloroethane. Stirring at 0-5 deg.C for 12 hr, extracting with 1, 2-dichloroethane twice, and collecting the extractive solution with anhydrous MgSO 4 Drying, concentrating, purifying by flash silica gel column chromatography (V) Ethyl acetate ∶V Petroleum ether 1: 1) and high performance liquid chromatography, collecting characteristic retention time t 1/2 The fractions were concentrated for 7.37min to give a pale yellow viscous product 2 x.
The main physical and chemical properties of compound (2x) are as follows:
a light yellow sticky 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: preparation of compound 2-acetoxy-benzoic acid- (docosahexenoyl-6-hexanolamino) -ester (2y) compound (2y) the formula of compound (2y) is:
Figure BDA0003631870360000201
1.0mmol of docosahexaenoic acid hexanolamine and 1.1mmol of aspirin were mixed uniformly, and an ester condensing agent comprising a 10mL mixed solution of 1, 2-dichloroethane of DCC (1.0mmol, 206mg), HOBt (1.2mmol, 162mg), DMAP (0.15mmol, 24.4mg) was slowly dropped. Stirring at 0-5 deg.C for 8 hr, extracting with 1, 2-dichloroethane twice, and collecting the extractive solution with anhydrous MgSO 4 Drying, concentrating, and quickly separating silica gel column layerPurification by chromatography (V) Ethyl acetate ∶V Petroleum ether 1: 1) and high performance liquid chromatography, collecting characteristic retention time t 1/2 Concentrating for 7.91min to obtain yellowish viscous product 2 y.
The main physical and chemical properties of compound (2y) are as follows:
a light yellow sticky 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: docosahexaenoyl ester derivatives (2a-2y) inhibit NO production in RAW264.7 cells
Macrophage RAW264.7 was seeded in 24-well plates at 1.5 ten thousand per well and cultured overnight. After the cells are attached to the wall, the compound is added in advance for treatment for 2h, and then 0.5 mu L of LPS is added into each hole for induction for 24h, wherein the final concentration of the LPS is 1 mu g/mL, the final concentration of dexamethasone Dex is 10 mu M, and the final concentration of the 2a-2y compound is 10 mu M. Collecting cell supernatant culture medium as a detection sample. And detecting the content of NO secreted by the RAW264.7 cells by using an NO detection kit and detecting an absorbance (OD) value at 560 nm. The experimental results show that 25 detected docosahexaenoic acid ester derivatives can inhibit the generation of NO in RAW264.7 cells. The results are shown in FIG. 4(Con is a blank cell).
Example 27: dicodecanoyl ester derivatives down-regulate mRNA expression of the pro-inflammatory mediators TNF-alpha, IL-6 and IL-1 beta
The well-conditioned RAW264.7 cells were seeded in 6-well plates at a seeding density of 4.5X 10 5 Per well, cell cultureAnd (4) culturing overnight, adding a compound after the cells are attached to the wall, performing treatment for 2h, wherein the final action concentration of the 2a-2y compound is 10 mu M, the final action concentration of dexamethasone Dex is 5 mu M, and adding LPS for induction for 12h, wherein the final concentration of the LPS is 1 mu g/mL. After 12h, removing the cell culture medium, extracting RNA, carrying out reverse transcription reaction on the RNA, carrying out PCR experimental amplification on the obtained reverse transcription product, and finally carrying out 2 th PCR amplification on the reverse transcription product by using an Agilent ariaMx PCR instrument -ΔΔCt The method quantifies the experimental results. Experimental results show that 2b, 2d, 2j, 2p, 2q, 2k, 2l, 2m, 2o and 2y compounds in 25 detected docosahexaenoyl ester derivatives show different degrees of down-regulation of mRNA expression of proinflammatory mediators TNF-alpha, IL-6 and IL-1 beta. The results are shown in FIGS. 5 to 7(Con is a blank cell).
Example 28: docosahexaenoic acid ester derivatives inhibit protein expression of proinflammatory cytokines TNF-alpha and IL-1 beta
The well-conditioned RAW264.7 cells were seeded in 6-well plates at a seeding density of 4.5X 10 5 After cells adhere to the wall, the compound is added for pretreatment for 2h, 2b, 2d, 2j, 2p, 2q, 2k, 2l, 2M, 2o and 2y, the final acting concentration of the compound is 10 mu M, the final acting concentration of dexamethasone Dex is 10 mu M, and LPS is added for induction for 6h, and the final acting concentration of the LPS is 1 mu g/mL. After 6h, the cell culture medium was removed and the cells were lysed with protein lysate to extract the protein. The protein samples obtained were analyzed by SDS-PAGE, and the proteins were transferred to PVDF membrane and immobilized by the "sandwich" method under the buffer condition of the electrotransfer. After electrotransfer, the cells were blocked with 5% skim milk for 2h to remove some nonspecific protein interference, and then primary antibody and secondary antibody were incubated, and after the secondary antibody incubation was completed, the membranes were washed 3 times for 10min each time. And finally, carrying out exposure detection by using a chemiluminescence imager Biorad. The experimental result shows that the protein expression of IL-1 beta and TNF-alpha is obviously up-regulated by LPS, and the protein expression of IL-1 beta is obviously down-regulated by 2d, 2j, 2k, 2l, 2m, 2o and 2y in 10 detected docosahexenoyl ester derivatives, but the protein expression of the TNF-alpha does not show obvious down-regulation trend. The results of the experiment are shown in FIG. 8.
The above description is only a preferred embodiment of the present invention, and therefore should not be taken as limiting the scope of the invention, which is defined by the appended claims.

Claims (10)

1. A docosahexaenoic acid ester derivative, characterized in that: the structural formula is
Figure FDA0003631870350000011
Wherein n is an integer of 0 to 4, and R is
Figure FDA0003631870350000012
Figure FDA0003631870350000013
2. The method for producing a docosahexaenoic acid ester derivative according to claim 1, wherein: the method comprises the following steps:
(1) mixing methyl docosahexenoate and alcohol amine, heating and stirring at 80 ℃ for reaction for 15 hours, stirring with silica gel, and purifying by silica gel column chromatography to obtain docosahexaenoic acid alcohol amine;
(2) mixing the docosahexenoyl alcohol amine with organic acid, stirring and reacting at 0-5 deg.C for 8-24h under the action of ester condensing agent, extracting twice with 1, 2-dichloroethane, anhydrous MgSO 4 Drying, concentrating, purifying by silica gel column chromatography and high performance liquid chromatography to obtain the docosahexenoyl ester derivative;
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.
3. The method of claim 2, wherein: in the step (1), the mol ratio of the docosahexaenoic acid methyl ester to the alcohol amine is 1: 2.
4. The method of claim 2, wherein: in the step (2), the molar ratio of the docosahexenoyl alcohol amine to the organic acid is 1: 1.1.
5. The method of claim 4, wherein: the ratio of the docosahexenoyl alcohol amine, the organic acid and the ester condensing agent is 1.0 mmol: 1.1 mmol: 10 mL.
6. The method of claim 5, wherein: in the ester condensing agent, the proportion of N, N' -dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, 4-dimethylaminopyridine and dichloroethane is 206.0-247.2 mg: 148.5-175.5 mg: 18.3-30.5 mg: 10 mL.
7. The production method according to any one of claims 2 to 6, characterized in that: in the step (2), the characteristic retention time t of the high performance liquid chromatography purification 1/2 Between 4.58 and 16.47 min.
8. Use of the docosahexaenoic acid ester derivative according to claim 1 as an anti-inflammatory small molecule drug.
9. Use of the docosahexaenoic acid ester derivative according to claim 1 for the preparation of an anti-inflammatory composition.
10. An anti-inflammatory composition characterized by: the effective component of the compound comprises the docosahexenoyl ester derivative of claim 1.
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