CN106279125A - Coumarin derivative and preparation method thereof - Google Patents

Coumarin derivative and preparation method thereof Download PDF

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CN106279125A
CN106279125A CN201510296809.8A CN201510296809A CN106279125A CN 106279125 A CN106279125 A CN 106279125A CN 201510296809 A CN201510296809 A CN 201510296809A CN 106279125 A CN106279125 A CN 106279125A
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formyl
umbelliferone
amino
amino methylpyrimidine
methylpyrimidine
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CN106279125B (en
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张建伟
程凯
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Capital Medical University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The present invention relates to coumarin derivative and preparation method thereof.Specifically, the invention discloses the novel umbelliferone-3-formyl-β-alanylamino acyl-2-amino methylpyrimidine with anti-inflammatory activity of logical formula (I), AA=Ala in logical formula (I), Leu, Val, Met, Phe, Tyr, Asp (OBzl).Further relate to their preparation method, and further disclose its antiinflammatory action.Thus the invention discloses 2-amino methylpyrimidine and the amino acid modified umbelliferone-3-formyl-β-propanoic acid potential applicability in clinical practice as anti-inflammatory drug.

Description

Coumarin derivative and preparation method thereof
Invention field
The invention belongs to biomedicine field, particularly the present invention relates to the novel 7-hydroxyl perfume with anti-inflammatory activity The preparation method and applications of legumin-3-formyl-β-alanylamino acyl-2-amino methylpyrimidine (9a-g).
Background technology
Inflammation is the defense reaction of a kind of protectiveness, is also the co-channel causing many important human diseasess, And participate in human infection, tumor, cardiovascular and cerebrovascular disease, Alzheimer and nervous system disease, allergy The generation of property other important diseases such as disease, psychosis and evolution.Clinically, anti-inflammatory drug comes often Using medicine second, be only second to anti-infective, typical reaction is red, swollen, hot, pain and dysfunction etc..
Nonsteroidal antiinflammatory drug (NSAIDS) and selective cyclooxygenase-2 (COX-2) inhibitor be for Treat the conventional medicament of acute or chronic inflammation disease, studies have found that NSAIDS can induce serious gastrointestinal Road untoward reaction, including gastrointestinal hemorrhage and induced ulcer, and Selective COX-2 inhibitor can increase patient Myocardial infarction, cardiac sudden death and the risk of apoplexy occur.Therefore, develop new efficient, low toxicity, antiinflammatory One of medicine important topic being always new drug research, and cyclooxygenase and lipoxygenase COX/5-LOX are dual The emphasis that inhibitor is studied especially.
Coumarin (Coumarin) is the natural product that a class has benzo α pyranone parent nucleus, is widely present in and plants Thing circle, is also COX/5-LOX double inhibitor simultaneously.Document once disclosed and reported that coumarin was 10 Good anti-inflammatory activity is shown under μm ol/kg dosage.
Summary of the invention
The compound of a kind of logical formula (I) of present disclosure:
Wherein in logical formula (I), AA is selected from Ala, Leu, Val, Met, Phe, Tyr or Asp (OBzl).
The coumarin derivative that the present invention obtains is respectively:
9a:7-Hydroxycoumarin-3-formyl-β-alanyl alanyl-2-amino methylpyrimidine
9b:7-Hydroxycoumarin-3-formyl-β-alanyl leucyl-2-amino methylpyrimidine
9c:7-Hydroxycoumarin-3-formyl-β-alanyl valyl-2-amino methylpyrimidine
9d:7-Hydroxycoumarin-3-formyl-β-alanyl methinyl-2-amino methylpyrimidine
9e:7-Hydroxycoumarin-3-formyl-β-alanyl phenylalanyl-2-amino methylpyrimidine
9f:7-Hydroxycoumarin-3-formyl-β-alanyl tyrosyl-2-amino methylpyrimidine
9g:7-Hydroxycoumarin-3-formyl-β-alanyl aspartoyl benzyl ester-2-amino methylpyrimidine
The invention still further relates to the preparation method of logical formula (I), the method comprises the following steps:
By 2,4-4-dihydroxy benzaldehyde generates umbelliferone-3-carboxylic acid with diethyl malonate condensation under piperidines is catalyzed Ethyl ester,
Described umbelliferone-3-the carboxylic acid, ethyl ester obtained generates umbelliferone-3-under concentrated hydrochloric acid effect Carboxylic acid,
Described umbelliferone-3-the carboxylic acid obtained and beta-amino acids-OBzl coupling obtain umbelliferone-3- Formyl-Beta-alanine benzyl ester,
Described umbelliferone-3-formyl-Beta-alanine the benzyl ester obtained hydrogenolysis under the catalysis of palladium carbon generates 7- Hydroxycoumarin-3-formyl-Beta-alanine,
Described umbelliferone-3-formyl-the Beta-alanine obtained and l-amino acid benzyl ester coupling obtain 7-hydroxyl Coumarin-3-formyl-β-alanylamino acid benzyl ester,
Described umbelliferone-3-formyl-β-alanylamino acid benzyl ester the hydrogenolysis under the catalysis of palladium carbon obtained Generate umbelliferone-3-formyl-β-alanylamino acid,
Described umbelliferone-3-formyl-the β obtained-alanylamino acid obtains with 2-amino methylpyrimidine coupling To umbelliferone-3-formyl-β-alanylamino acyl-2-amino methylpyrimidine,
Tertiary fourth oxygen amic acid and 2-amino methylpyrimidine coupling are obtained tertiary fourth oxygen acyl aminoacyl-2-amino methyl phonetic Pyridine,
The described tertiary fourth oxygen acyl aminoacyl-2-amino methylpyrimidine obtained generates N-in HCl/EtOAc (4N) solution Aminoacyl-2-amino methylpyrimidine,
N-aminoacyl-2-amino methylpyrimidine and umbelliferone-3-formyl-Beta-alanine coupling are obtained 7-hydroxyl Coumarin-3-formyl-β-alanylamino acyl-2-amino methylpyrimidine.
The present invention is further directed to the antiinflammatory using the mouse ear swelling model of dimethylbenzene induction to evaluate them Effect.Thus the invention discloses Novel 2 Amino methylpyrimidine and amino acid modified umbelliferone-3- Formyl-β-propanoic acid is as the potential applicability in clinical practice of anti-inflammatory drug.
By the further research of the present invention, present inventors have recognized that, using 7-coumarin as lead compound, Umbelliferone-3-formyl-Beta-alanine after modifying with Beta-alanine is as parent nucleus, with aminoacid for connecting Arm, the cox 2 inhibitor 2-amino methylpyrimidine with another with stronger anti-inflammatory activity is stitched together, no Only can reduce the toxic and side effects of the most existing compound, can improve simultaneously lead compound coumarin and The 2-amino methylpyrimidine shortcoming that dissolubility is bad in organic solvent and aqueous solution, improves the biology of compound Availability, greatly reduces the oral dose of compound, strengthen compound anti-inflammatory activity.Repaiied by this Decorations, it is thus achieved that there is the compound of more preferable anti-inflammatory activity, there is good potential applicability in clinical practice.
Accompanying drawing explanation
Fig. 1 represents the synthetic route of 7-coumarin-3-formyl-β-propanoic acid, wherein, i) piperidines, diethyl oxalate； Ii) concentrated hydrochloric acid, H2O；Iii) Beta-alanine-OBzl, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimine Hydrochlorate (EDC HCl) I-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), THF；Iv) 5%Pd, H2, methanol.
Fig. 2 represents the synthetic route of logical formula (I) coumarin derivative (9a-g), wherein, v) Boc-AA-OH, 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC HCl), I-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), THF；vi)4N HCl/EtOAc；Vii) 1-(3-dimethylamino third Base)-3-ethyl-carbodiimide hydrochloride (EDC HCl), I-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), THF.
Detailed description of the invention
In order to the present invention is expanded on further, a series of embodiment is given below.These embodiments are entirely illustratively , they are only used for being specifically described the present invention, are not construed as limitation of the present invention.
Embodiment 1 prepares umbelliferone-3-Ethyl formate (2)
At a temperature of 90 DEG C, weigh 2,4-4-dihydroxy benzaldehyde (0.500g, 3.60mmol) and measure malonic acid two Ethyl ester (0.70ml, 4.00mmol) is placed in 100ml eggplant bottle, is dissolved in 95% ethanol (20ml), this Time solution colour be rufous transparency liquid；Adding piperidines (0.40ml, 4.00mmol), solution surface is green tinged Coloured light, starts backflow, and after reacting about 6h, solution becomes dark-brown.It is cooled to room temperature, is evaporated to red Color is thick, ethyl alcohol recrystallization, is filtrated to get compound 3 (0.758g, 3.24mmol), and character is faint yellow Solid, productivity is 90%.ESI-MS m/z 233(M-1).
Embodiment 2 prepares umbelliferone-3-carboxylic acid (3)
At a temperature of 90 DEG C, Weigh Compound 3 (2.00g, 8.55mmol) is dissolved in water (20ml), adds After entering concentrated hydrochloric acid (6ml), reflux 8h.Reactant liquor is cooled to room temperature, filters, washing, obtain compound 4 (1.32g, 6.41mmol), character is light red solid, and productivity is 75%.ESI-MS m/z 205(M-1).
Embodiment 3 prepares umbelliferone-3-formyl-β-benzyl propionate (4)
Weigh 3 (1.00g, 4.85mmol) to be placed in 100ml eggplant bottle, under ice bath cooling condition, add tetrahydrochysene furan Mutter (30ml), is sequentially added into N-hydroxybenzotriazole (HOBt) (0.720g, 5.33mmol), 1-(3-dimethylamino Base propyl group)-3-ethyl-carbodiimide hydrochloride (EDC HCl) (1.02g, 5.33mmol), reacts 30 minutes. Compound Tos Beta-alanine-OBzl (1.87g, 5.33mmol) that addition oxolane (20ml) dissolves, Dropping N-methylmorpholine (NMM) (0.60ml) adjusts pH value to 8.Reaction whole process carries out TLC detection, and about 8 Hour reaction is completely.Filter, be evaporated to do, add ethyl acetate (100ml) and make residue dissolve, Solution is joined in the separatory funnel of 250ml, use saturated sodium bicarbonate aqueous solution to wash (50 successively ML × 3), saturated sodium-chloride water solution washes (50mL × 3), 5% aqueous potassium hydrogen sulfate washes (50mL × 3), full Wash (50mL × 3) with sodium-chloride water solution, saturated sodium bicarbonate aqueous solution washes (50mL × 3), saturated sodium-chloride Aqueous solution washes (50mL × 3), obtain three kinds of aqueous solutions is re-used ethyl acetate and carries out back extraction respectively, closes And the ethyl acetate layer of each time, add anhydrous Na2SO4It is dried about 30 minutes, filters, by filtrate reduced in volume To dry, silica gel column chromatography is used residue to carry out isolated and purified (dichloromethane: methanol=50: 1), in obtaining Intermediate compounds therefor 4 (1.07g, 2.93mmol), character is faint yellow solid, and productivity is 55%. ESI-MS m/z 364(M-1)。
Embodiment 4 prepares umbelliferone-3-formyl-β-propanoic acid (5)
In 50ml eggplant bottle, add 4 (1.29g, 3.29mmol), add methanol (20ml) and dissolve, add Pd/C (5%) (65mg), is passed through H after evacuation2Carry out reacting overnight under room temperature, monitor through TLC plate, reaction Completely.Filtering, be evaporated to do, obtain compound 5 (620mg, 2.24mmol), character is faint yellow Solid, productivity is 68%.ESI-MS m/z 276(M-1).
Embodiment 5 prepares tertiary fourth oxygen acyl alanyl-2-amino methylpyrimidine (7a)
Weigh Boc-A-OH (300mg, 3.03mmol) to be placed in 100ml eggplant bottle, add oxolane (40 Ml) dissolve, under ice bath, be sequentially added into N-hydroxybenzotriazole (HOBt) (405g, 3.03mmol), 1-(3-bis- Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC HCl) (573mg, 3.03mmol), drip N- Methyl morpholine (NMM) (0.50ml) regulation PH is 8, reacts 30 minutes.Weigh 2-amino methylpyrimidine hydrochloric acid Salt (401mg, 2.50mmol) is placed in small beaker, adds oxolane (10ml) and dissolves, is simultaneously added dropwise N-methylmorpholine (NMM) (0.20ml) regulation PH is 8.Solution in small beaker is added in eggplant bottle, room temperature Reaction, through TLC monitoring reaction, reaction in about 10 hours is completely.It is evaporated to do by reactant liquor, adds 50ml ethyl acetate extracts, and uses saturated sodium bicarbonate aqueous solution to wash (30mL × 3), saturated chlorine successively Sodium water solution washes (30mL × 3), 5% aqueous potassium hydrogen sulfate washes (30mL × 3), saturated sodium-chloride water solution in change Wash (30mL × 3), saturated sodium bicarbonate aqueous solution washes (30mL × 3), saturated sodium-chloride water solution washes (30 ML × 3), obtain three kinds of aqueous solutions are re-used ethyl acetate back extraction, merges the ethyl acetate layer of each time, Add anhydrous Na2SO4It is dried about 30 minutes, filters, concentrate filtrate to do, use silica gel column chromatography Residue is carried out isolated and purified (dichloromethane: methanol=40: 1), obtain compound 7a (560mg, 2.00 Mmol), character is colorless oil, and productivity is=72%.ESI-MS m/z 281(M+1).
Embodiment 6 prepares tertiary fourth oxygen acyl leucyl-2-amino methylpyrimidine (7b)
According to the operation of embodiment 5, by Boc-L-OH (500mg, 2.16mmol), and HOBt (292mg, 2.16 Mmol) and EDC HCl (413g, 2.16mmol) and 2-amino methylpyrimidine hydrochlorate (287mg, 1.97 Mmol) being condensed to yield 7b (460mg, 1.43mmol) at anhydrous THF (50ml), character is colorless oil, Productivity is 70%.ESI-MS m/z 323(M+1).
Embodiment 7 prepares tertiary fourth oxygen acyl valyl-2-amino methylpyrimidine (7c)
According to the operation of embodiment 5, by Boc-V-OH (500mg, 2.30mmol), and HOBt (311mg, 2.30 Mmol) and EDC HCl (440mg, 2.30mmol) and 2-amino methylpyrimidine hydrochlorate (305mg, 2.09 Mmol) being condensed to yield 7c (487mg, 1.58mmol) at anhydrous THF (50ml), character is colorless oil, Productivity is 75%.ESI-MS m/z 309(M+1).
Embodiment 8 prepares tertiary fourth oxygen acyl methinyl-2-amino methylpyrimidine (7d)
According to the operation of embodiment 5, by Boc-M-OH (500mg, 2.01mmol), and HOBt (270mg, 2.00 Mmol) and EDC HCl (382mg, 2.00mmol) and 2-amino methylpyrimidine hydrochlorate (266mg, 1.83 Mmol) being condensed to yield 7d (440mg, 1.29mmol) at anhydrous THF (50ml), character is colorless oil, Productivity is 70%.ESI-MS m/z 341(M+1).
Embodiment 9 prepares tertiary fourth oxygen acyl phenylalanyl-2-amino methylpyrimidine (7e)
According to the operation of embodiment 5, by Boc-F-OH (500mg, 1.89mmol), and HOBt (255mg, 1.88 Mmol) and EDC HCl (360mg, 1.88mmol) and 2-amino methylpyrimidine hydrochlorate (250mg, 1.72 Mmol) being condensed to yield 7e (320mg, 0.90mmol) at anhydrous THF (50ml), character is colorless oil, Productivity is 52%.ESI-MS m/z 357(M+1).
Embodiment 10 prepares tertiary fourth oxygen acyl tyrosyl-2-amino methylpyrimidine (7f)
According to the operation of embodiment 5, by Boc-Y-OH (500mg, 1.78mmol), and HOBt (240mg, 1.78 Mmol) and EDC HCl (340mg, 1.78mmol) and 2-amino methylpyrimidine hydrochlorate (236mg, 1.62 Mmol) being condensed to yield 7f (379mg, 1.02mmol) at anhydrous THF (50ml), character is colorless oil, Productivity is 62%.ESI-MS m/z 373(M+1).
Embodiment 11 prepares tertiary fourth oxygen acyl benzyl ester aspartoyl-2-amino methylpyrimidine (7g)
According to the operation of embodiment 5, by Boc-D (OBzl)-OH (500mg, 1.55mmol), HOBt (209mg, 1.55mmol) and EDC HCl (296mg, 1.55mmol) and 2-amino methylpyrimidine hydrochlorate (205mg, 1.41mmol) being condensed to yield 7g (380mg, 0.92mmol) at anhydrous THF (50ml), character is colorless oil Thing, productivity is 65%.ESI-MS m/z 415(M+1).
Embodiment 12 prepares umbelliferone-3-formyl-β-alanyl alanyl-2-amino methylpyrimidine (9a)
In 100ml eggplant bottle, add 7a (742mg, 2.65mmol), add 4N HCl/EA (30ml), ice The lower reaction of bath, TLC monitors, and reacts about 3 hours completely.Decompressing and extracting solvent, obtain compound 8a (286mg, 1.59mmol), it is dissolved in oxolane (40ml), dropping N-methylmorpholine (NMM) (0.30ml) Regulation PH is 8.Weigh 5 (400mg, 1.44mmol) to be dissolved in oxolane (30ml), under ice bath successively Add N-hydroxybenzotriazole (HOBt) (215mg, 1.59mmol), 1-(3-dimethylaminopropyl)-3-ethyl Carbodiimide hydrochloride (EDC HCl) (303mg, 1.59mmol), dropping N-methylmorpholine (NMM) (0.30 Ml) regulation PH is 8, reacts 30 minutes.Solution in small beaker is added in eggplant bottle, room temperature reaction, warp TLC monitors reaction, and about 8h reaction is completely.It is evaporated to do by reactant liquor, uses silica gel column chromatography to residual Excess carries out isolated and purified (dichloromethane: methanol=20: 1), obtain target compound 9a (334mg, 0.76 Mmol), character is faint yellow solid, and productivity is=53%.Mp 252.6-254.4℃；[α]D 25=-12.1 (c= 0.10, CH3OH)；IR (KBr): 3287,2875,1700,1633,1567,1526,1439,1410,1365, 1317,1216,1138,795,639cm-1；ESI-MS(m/e)438[M-H]-；1H-NMR (300MHz, DMSO-d6): δ/ppm 11.05 (s, 1H, O-H), 8.81 (t, J=6.0Hz, 1H, N-H), 8.78 (s, 1H, CH), 8.73 (d, J=5.1Hz, 2H, CH, CH), 8.35 (t, J=5.7Hz, 1H, N-H), 8.19 (d, J=7.8 Hz, 1H, N-H), 7.80 (d, J=8.7Hz, 1H, Ar-H), 7.35 (t, J=5.1Hz, 1H, CH), 6.87 (dd, J1=8.4Hz, J2=2.1Hz, 1H, Ar-H), 6.78 (d, J=2.1Hz, 1H, Ar-H), 4.60 (d, J= 5.7Hz, 2H, CH2), 4.41 (m, 1H, CH), 3.56-3.49 (m, 2H, CH2), 2.43 (t, J=6.6Hz, 2H, CH2), 1.24 (d, J=6.9Hz, 3H, CH3)；13C-NMR (75MHz, DMSO-d6): δ/ppm 172.81, 170.80,167.13,164.07,161.89,161.34,157.75 (2C), 156.71,148.50,132.44,120.21, 114.76,113.99,111.55,102.23,48.48,45.20,35.97,35.30,18.73.
Embodiment 13 prepares umbelliferone-3-formyl-β-alanyl leucyl-2-amino methylpyrimidine (9b)
According to the operation of embodiment 12,7b (708mg, 2.20mmol) obtains in 4N HCl/EA (30ml) 8b (292mg, 1.32mmol), and HOBt (195mg, 1.45mmol), EDC HCl (276mg, 1.45 Mmol) and 5 (400mg, 1.44mmol) are condensed to yield 9b (221mg, 0.46mmol), and character is pale yellow colored solid Body, productivity is=35%.Mp 215.3-216.8℃；[α]D 25=-24.4 (c=0.10, CH3OH)；IR (KBr): 3296,2959,1700,1635,1566,1530,1437,1416,1366,1321,1214,1144,794,637 cm-1；ESI-MS(m/e)480[M-H]-；1H-NMR (300MHz, DMSO-d6): δ/ppm 11.09 (s, 1H, O-H), 8.80 (m, 2H, N-H, CH), 8.73 (d, J=4.8Hz, 2H, CH, CH), 8.38 (t, J=5.7 Hz, 1H, N-H), 8.13 (d, J=8.4Hz, 1H, N-H), 7.82 (d, J=8.7Hz, 1H, Ar-H), 7.35 (t, J=4.8Hz, 1H, CH), 6.87 (dd, J1=8.4Hz, J2=2.1Hz, 1H, Ar-H), 6.78 (d, J=2.1 Hz, 1H, Ar-H), 4.42 (m, 3H, CH2, CH), 3.53 (m, 2H, CH2), 2.42 (m, 2H, CH2), 1.64-1.39 (m, 3H, CH2, CH), 0.82 (t, J=6.0Hz, 6H, CH3, CH3)；13C-NMR (75MHz, DMSO-d6): δ/ppm 172.61,170.93,167.16,164.14,161.88,161.33,157.71 (2C), 156.73,148.48,132.43,120.19,114.80,113.95,111.57,102.24,51.33,45.27,41.35, 36.08,35.40,24.65,23.49,21.98.
Embodiment 14 prepares umbelliferone-3-formyl-β-alanyl valyl-2-amino methylpyrimidine (9c)
According to the operation of embodiment 12,7c (611mg, 1.98mmol) obtains in 4N HCl/EA (30ml) 8c (248mg, 1.19mmol), with HOBt (161mg, 1.19mmol), EDC HCl (228mg, 1.19mmol) Being condensed to yield 9c (243mg, 0.52mmol) with 5 (300mg, 1.08mmol), character is faint yellow solid, produces Rate is=48%.Mp 249.6-251.3℃；[α]D 25=-10.2 (c=0.10, CH3OH)；IR (KBr): 3290, 2968,1702,1636,1568,1527,1453,1370,1218,1142,794,639cm-1；ESI-MS(m/e) 466[M-H]-；1H-NMR (300MHz, DMSO-d6): δ/ppm 11.07 (s, 1H, O-H), 8.83 (t, J= 5.7Hz, 1H, N-H), 8.79 (s, 1H, CH), 8.73 (d, J=4.8Hz, 2H, CH, CH), 8.46 (t, J=5.4 Hz, 1H, N-H), 7.99 (d, J=9.0Hz, 1H, N-H), 7.82 (d, J=8.7Hz, 1H, Ar-H), 7.36 (t, J=5.1Hz, 1H, CH), 6.87 (dd, J1=8.4Hz, J2=2.1Hz, 1H, Ar-H), 6.79 (d, J=1.8 Hz, 1H, Ar-H), 4.46 (t, J=5.4Hz, 2H, CH2), 4.30 (m, 1H, CH), 3.52 (m, 2H, CH2), 2.46 (m, 2H, CH2), 2.01 (m, 2H, CH2), 0.86 (t, J=6.9Hz, 6H, CH3, CH3)；13C-NMR (75MHz, DMSO-d6): δ/ppm 171.59,171.08,167.25,164.09,161.85,161.33, 157.71 (2C), 156.72,148.52,132.45,120.21,114.77,113.96,111.55,102.24,58.01, 45.30,36.11,35.30,30.94,19.71,18.44.
Embodiment 15 prepares umbelliferone-3-formyl-β-alanyl methinyl-2-amino methylpyrimidine (9d)
According to the operation of embodiment 12,7d (440mg, 1.33mmol) obtains in 4N HCl/EA (30ml) 8d (183mg, 0.80mmol), and HOBt (107mg, 0.80mmol), EDC HCl (152mg, 0.80 Mmol) and 5 (200mg, 0.72mmol) are condensed to yield 9d (155mg, 0.31mmol), and character is pale yellow colored solid Body, productivity is=43%.Mp 219.0-221.2℃；[α]D 25=-11.9 (c=0.10, CH3OH)；IR (KBr): 3279,2914,1694,1636,1515,1532,1450,1372,1219,1144,794,639cm-1；ESI-MS (m/e)498[M-H]-；1H-NMR (300MHz, DMSO-d6): δ/ppm 11.06 (s, 1H, O-H), 8.81 (t, J=5.7Hz, 1H, N-H), 8.78 (s, 1H, CH), 8.73 (d, J=4.8Hz, 2H, CH, CH), 8.43 (t, J=5.7Hz, 1H, N-H), 8.20 (d, J=8.1Hz, 1H, N-H), 7.81 (d, J=8.7Hz, 1H, Ar-H), 7.36 (t, J=4.8Hz, 1H, CH), 6.87 (dd, J1=8.4Hz, J2=2.1Hz, 1H, Ar-H), 6.78 (d, J= 2.1Hz, 1H, Ar-H), 4.55-4.38 (m, 3H, CH2, CH), 3.53 (m, 2H, CH2), 2.47 (m, 2H, CH2), 2.00 (s, 3H, CH3), 1.97-1.78 (m, 2H, CH2)；13C-NMR (75MHz, DMSO-d6): δ/ppm 171.72,171.15,167.13,164.08,161.91,161.34,157.72 (2C), 156.73,148.48, 132.43,120.22,114.77,114.01,111.56,102.24,52.27,45.25,36.04,35.39,32.41, 30.06,15.06.
Embodiment 16 prepares umbelliferone-3-formyl-β-alanyl phenylalanyl-2-amino methylpyrimidine (9e)
According to the operation of embodiment 12,7e (706mg, 1.98mmol) obtains in 4N HCl/EA (30ml) 8e (305mg, 1.19mmol), with HOBt (161mg, 1.19mmol), EDC HCl (228mg, 1.19mmol) Being condensed to yield 9e (319mg, 0.62mmol) with 5 (300mg, 1.08mmol), character is faint yellow solid, produces Rate is=57%.Mp 194.3-195.7℃；[α]D 25=-11.3 (c=0.10, CH3OH)；IR (KBr): 3270, 2917,1694,1639,1614,1544,1452,1416,1375,1225,1149,1118,850,794,640 cm-1；ESI-MS(m/e)514[M-H]-；1H-NMR (300MHz, DMSO-d6): δ/ppm 11.04 (s, 1H, O-H), 8.76-8.71 (m, 4H, N-H, CH, CH, CH), 8.52 (t, J=5.7Hz, 1H, N-H), 8.23 (d, J=8.7Hz, 1H, N-H), 7.81 (d, J=8.4Hz, 1H, Ar-H), 7.37 (t, J=4.8Hz, 1H, CH), 7.26-7.17 (m, 4H, Ar-H), 7.08 (m, 1H, Ar-H), 6.87 (dd, J1=8.4Hz, J2=2.1Hz, 1H, Ar-H), 6.79 (d, J=2.4Hz, 1H, Ar-H), 4.63 (m, 1H, CH), 4.48 (d, J=6.0Hz, 2H, CH2), 3.42 (m, 2H, CH2), 3.18-2.73 (m, 2H, CH2), 2.35 (m, 2H, CH2)；13C-NMR(75 MHz, DMSO-d6): δ/ppm 171.76,170.90,167.09,164.07,161.84,161.25,157.76 (2C), 156.72,148.43,138.51,132.43,129.59 (2C), 128.38 (2C), 126.49,120.24,114.76, 114.03,111.55,102.23,54.26,45.33,38.08,35.93,35.29.
Embodiment 17 makes each umbelliferone-3-formyl-β-alanyl tyrosyl-2-amino methylpyrimidine (9f)
According to the operation of embodiment 12,7f (738mg, 1.98mmol) obtains in 4N HCl/EA (30ml) 8f (324mg, 1.19mmol), with HOBt (161mg, 1.19mmol), EDC HCl (228mg, 1.19mmol) Being condensed to yield 9f (244mg, 0.46mmol) with 5 (300mg, 1.08mmol), character is faint yellow solid, produces Rate is=43%.Mp257.8-259.4℃；[α]D 25=-11.2 (c=0.10, CH3OH)；IR (KBr): 3285, 2982,1702,1625,1543,1516,1442,1419,1370,1267,1216,1149,966,794,636 cm-1；ESI-MS(m/e)530[M-H]-；1H-NMR (300MHz, DMSO-d6): δ/ppm 11.04 (s, 1H, O-H), 9.11 (s, 1H, O-H), 8.77 (m, 2H, N-H, CH), 8.74 (d, J=4.8Hz, 2H, CH, CH), 8.46 (t, J=5.7Hz, 1H, N-H), 8.16 (d, J=8.4Hz, 1H, N-H), 7.80 (d, J=8.7 Hz, 1H, Ar-H), 7.36 (t, J=4.8Hz, 1H, CH), 7.02 (d, J=8.4Hz, 2H, Ar-H), 6.87 (dd, J1=8.4Hz, J2=2.1Hz, 1H, Ar-H), 6.78 (d, J=2.1Hz, 1H, Ar-H), 6.59 (d, J= 8.1Hz, 2H, Ar-H), 4.54 (m, 1H, CH), 4.54 (m, 1H, CH), 4.47 (d, J=5.7Hz, 2H, CH2), 3.43 (m, 2H, CH2), 3.43 (m, 2H, CH2), 3.00-2.94 (m, 2H, CH2), 2.35 (m, 2H, CH2)；13C-NMR (75MHz, DMSO-d6): δ/ppm 171.87,170.87,167.10,164.04,161.87, 161.29,157.75 (2C), 156.73,156.13,148.46,132.43,130.51 (2C), 128.51, 120.23,115.25 (2C), 114.73,114.01,111.56,102.24,54.64,45.30,37.32,35.97, 35.31。
Embodiment 18 prepares umbelliferone-3-formyl-β-alanyl aspartoyl benzyl ester-2-amino methylpyrimidine (9g)
According to the operation of embodiment 12,7g (821mg, 1.98mmol) obtains in 4N HCl/EA (30ml) 8g (374mg, 1.19mmol), and HOBt (161mg, 1.19mmol), EDC HCl (228mg, 1.19 Mmol) and 5 (300mg, 1.08mmol) are condensed to yield 9g (241mg, 0.42mmol), and character is pale yellow colored solid Body, productivity is=39%.Mp 213.7-215.5℃；[α]D 25=-16.1 (c=0.10, CH3OH)；IR (KBr): 3287,2942,1706,1647,1616,1570,1525,1425,1367,1326,1217,1178,1137,822, 793,637cm-1；ESI-MS(m/e)530[M-H]-；ESI-MS(m/e)572[M-H]-；1H-NMR (300MHz, DMSO-d6): δ/ppm 11.08 (s, 1H, O-H), 8.82 (t, J=5.7Hz, 1H, N-H), 8.76 (s, 1H, CH), 8.72 (d, J=5.1Hz, 2H, CH, CH), 8.41 (d, J=8.1Hz, 1H, N-H), 8.34 (t, J=5.7Hz, 1H, N-H), 7.79 (d, J=8.7Hz, 1H, Ar-H), 7.37-7.28 (m, 6H, Ar-H, CH), 6.87 (dd, J1=8.7Hz, J2=2.1Hz, 1H, Ar-H), 6.77 (d, J=2.1Hz, 1H, Ar-H), 5.06 (s, 2H, CH2), 4.82 (m, 1H, CH), 4.45 (t, J=6.0Hz, 2H, CH2), 3.60-3.50 (m, 2H, CH2), 2.91-2.59 (m, 2H, CH2), 2.44 (m, 2H, CH2)；13C-NMR (75MHz, DMSO-d6): δ/ppm 171.28,170.85,170.52,166.84,164.07,161.96,161.30,157.72 (2C), 156.71, 148.41,136.52,132.40,128.79 (2C), 128.35,128.23 (2C), 120.19,114.77,114.07, 111.04,102.24,66.06,49.72,45.37,36.72,36.00,35.48.
Experimental example 1 antiinflammatory action is tested
1) experimental technique
18-22g ICR male mice is randomly divided into blank group, aspirin positive drug group, tested chemical combination Thing administration group, mice uses front tranquillization 1 day, and operation room keeps indoor temperature 22 DEG C, often group mice 12.One Secondary property is left ear gabarit painting dimethylbenzene (0.03mL) of past white mice after being administered 30 minutes, by mice second after 2 hours After etherization, cervical dislocation is put to death.By a left side for mice, auris dextra is cut, with the card punch of diameter 7mm two The same position of ear, takes circular auricle, weighs respectively, obtains the weight difference of two circle auricles as swelling.Swollen Expansibility=left ear disk weight-auris dextra disk weight, suppression ratio (%)=(blank group swelling-test-compound Swelling)/blank group swelling.
2) medication and dosage
Administering mode is gastric infusion.Blank: the CMC of 0.5%, dosage is 0.2mL/20g； Positive control: aspirin, dosage is 1.11mmol/kg；The dosage of test-compound is 1 Umol/kg and 0.1umol/kg.
3) statistical method
This experimental data statistics all use t inspection and variance analysis, swelling withRepresent.
4) experimental result lists table 1 in.
As can be seen from Table 1, dosage is when 1 μm ol/kg, and test-compound removes 9a, outside 9g, remaining 6 Target compound has significant anti-inflammatory activity, has significant difference (p ＜ 0.05)；Dosage is in 0.1 μm ol/kg Time, 9e and 9f still has significant anti-inflammatory activity, has significant difference (p ＜ 0.05), the parent nucleus in reporting with document Coumarin anti-inflammatory activity (suppression ratio is 30.2%) under 10 μm ol/kg is suitable, and having of compound 9e and 9f is described Dosage is low reaches 0.1 μm ol/kg for effect, and this effective dose is than effective agent of once disclosed parent nucleus coumarin in document Measure 10 μm ol/kg low 100 times.
The mouse ear inflammation inhibitory activity of table 1 dimethylbenzene induction
N=12.
A) compared with blank group (CMC), P ＜ 0.05；
B) compared with blank group (CMC), P ＞ 0.05.

Claims (6)

1. lead to the compound of formula (I):
Wherein in logical formula (I), AA is selected from Ala, Leu, Val, Met, Phe, Tyr or Asp (OBzl).
The compound of logical formula (I) the most according to claim 1, it is characterised in that it is selected from following chemical combination Thing,
9a:7-Hydroxycoumarin-3-formyl-β-alanyl alanyl-2-amino methylpyrimidine,
9b:7-Hydroxycoumarin-3-formyl-β-alanyl leucyl-2-amino methylpyrimidine,
9c:7-Hydroxycoumarin-3-formyl-β-alanyl valyl-2-amino methylpyrimidine,
9d:7-Hydroxycoumarin-3-formyl-β-alanyl methinyl-2-amino methylpyrimidine,
9e:7-Hydroxycoumarin-3-formyl-β-alanyl phenylalanyl-2-amino methylpyrimidine,
9f:7-Hydroxycoumarin-3-formyl-β-alanyl tyrosyl-2-amino methylpyrimidine,
9g:7-Hydroxycoumarin-3-formyl-β-alanyl aspartoyl benzyl ester-2-amino methylpyrimidine,
The preparation method of the compound of logical formula (I) the most according to claim 1, the method includes following Step:
By 2,4-4-dihydroxy benzaldehyde generates umbelliferone-3-with diethyl malonate condensation under piperidines is catalyzed Carboxylic acid, ethyl ester,
Described umbelliferone-3-the carboxylic acid, ethyl ester obtained generates umbelliferone-3-under concentrated hydrochloric acid effect Carboxylic acid,
Described umbelliferone-3-the carboxylic acid obtained and β the-the third aminoacid-OBzl coupling obtain umbelliferone -3-formyl-Beta-alanine benzyl ester,
Described umbelliferone-3-formyl-Beta-alanine the benzyl ester obtained hydrogenolysis under the catalysis of palladium carbon generates 7- Hydroxycoumarin-3-formyl-Beta-alanine,
Described umbelliferone-3-formyl-the Beta-alanine obtained and l-amino acid benzyl ester coupling obtain 7-hydroxyl Coumarin-3-formyl-β-alanylamino acid benzyl ester,
Described umbelliferone-3-formyl-β-alanylamino acid benzyl ester the hydrogenolysis under the catalysis of palladium carbon obtained Generate umbelliferone-3-formyl-β-alanylamino acid,
Described umbelliferone-3-formyl-the β obtained-alanylamino acid obtains with 2-amino methylpyrimidine coupling To umbelliferone-3-formyl-β-alanylamino acyl-2-amino methylpyrimidine,
Tertiary fourth oxygen amic acid and 2-amino methylpyrimidine coupling are obtained tertiary fourth oxygen acyl aminoacyl-2-amino methyl phonetic Pyridine,
The described tertiary fourth oxygen acyl aminoacyl-2-amino methylpyrimidine obtained generates N-in HCl/EtOAc (4N) solution Aminoacyl-2-amino methylpyrimidine,
N-aminoacyl-2-amino methylpyrimidine and umbelliferone-3-formyl-Beta-alanine coupling are obtained 7-hydroxyl Coumarin-3-formyl-β-alanylamino acyl-2-amino methylpyrimidine.
The compound the most according to claim 1 application in the pseudo-peptide of synthesis.
The compound the most according to claim 1 application in preparation treatment anti-inflammatory drug.
6. a Pharmaceutical composition, it is characterised in that it include treat effective dose according to claim 1 institute The compound stated and pharmaceutically acceptable carrier.
CN201510296809.8A 2015-06-03 2015-06-03 Coumarin derivative and its preparation method Expired - Fee Related CN106279125B (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013159078A1 (en) * 2012-04-21 2013-10-24 Indiana University Research And Technology Corporation Compositions for in situ labeling of bacterial cell walls with fluorophores and methods of use thereof
CN104159595A (en) * 2012-02-15 2014-11-19 爱勒让治疗公司 Peptidomimetic macrocycles

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104159595A (en) * 2012-02-15 2014-11-19 爱勒让治疗公司 Peptidomimetic macrocycles
WO2013159078A1 (en) * 2012-04-21 2013-10-24 Indiana University Research And Technology Corporation Compositions for in situ labeling of bacterial cell walls with fluorophores and methods of use thereof

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