CN107446015B - Coumarin derivative and preparation method and application thereof - Google Patents
Coumarin derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN107446015B CN107446015B CN201610371668.6A CN201610371668A CN107446015B CN 107446015 B CN107446015 B CN 107446015B CN 201610371668 A CN201610371668 A CN 201610371668A CN 107446015 B CN107446015 B CN 107446015B
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- CN
- China
- Prior art keywords
- hydroxycoumarin
- formylphenylalanyl
- phenylalanyl
- preparation
- general formula
- Prior art date
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- 150000001875 compounds Chemical class 0.000 claims abstract description 48
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- 229940126650 Compound 3f Drugs 0.000 description 1
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- 230000004071 biological effect Effects 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
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- 229910052799 carbon Inorganic materials 0.000 description 1
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- AEULIVPVIDOLIN-UHFFFAOYSA-N cep-11981 Chemical compound C1=C2C3=C4CNC(=O)C4=C4C5=CN(C)N=C5CCC4=C3N(CC(C)C)C2=CC=C1NC1=NC=CC=N1 AEULIVPVIDOLIN-UHFFFAOYSA-N 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
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- 229960004544 cortisone Drugs 0.000 description 1
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- DBUMITZHDMTTNX-UHFFFAOYSA-N gtpl6365 Chemical compound C1=CC(OC)=CC=C1N1C(=O)C(SC=2C3=C(NC4CC4)N=CN=2)=C3N=C1 DBUMITZHDMTTNX-UHFFFAOYSA-N 0.000 description 1
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- 239000003112 inhibitor Substances 0.000 description 1
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- 238000010253 intravenous injection Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- MUJNAWXXOJRNGK-UHFFFAOYSA-N n-[3-(6-methyl-1,2,3,4-tetrahydrocarbazol-9-yl)propyl]cyclohexanamine Chemical compound C1=2CCCCC=2C2=CC(C)=CC=C2N1CCCNC1CCCCC1 MUJNAWXXOJRNGK-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
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- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
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- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- FWQHRZXEQNUCSY-UHFFFAOYSA-N tert-butyl N-[2-(ethoxycarbonylamino)-5-[(4-fluorophenyl)methyl-prop-2-ynylamino]phenyl]carbamate Chemical compound CCOC(=O)NC1=C(C=C(C=C1)N(CC#C)CC2=CC=C(C=C2)F)NC(=O)OC(C)(C)C FWQHRZXEQNUCSY-UHFFFAOYSA-N 0.000 description 1
- FRACPXUHUTXLCX-BELIEFIBSA-N tert-butyl N-{1-[(1S)-1-{[(1R,2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-2-cyclopropylethyl]-2-oxopyridin-3-yl}carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CN(C1=O)[C@@H](CC2CC2)C(=O)N[C@@H](C[C@@H]3CCNC3=O)[C@H](C(=O)NCC4=CC=CC=C4)O FRACPXUHUTXLCX-BELIEFIBSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
The invention relates to a coumarin derivative, a preparation method and application thereof. In particular, the invention relates to compounds of general formula (I) or pharmaceutically acceptable salts thereof, wherein AA is an amino acid; n is 0 or 1; r1、R3、R4、R5、R6、R7Each independently selected from hydrogen, benzyl, benzoyl, C1‑10Alkanoyl radical, C1‑10Alkyl radical, C1‑10Alkoxy radical, C6‑14Aryl or C5‑14Heterocyclyl, wherein the alkyl is optionally substituted by C6‑14Aryl or C5‑14Heteroaryl substitution; and R2Selected from hydroxyl groups. The invention also relates to a preparation method of the compound shown in the general formula (I), a pharmaceutical composition containing the compound shown in the general formula (I) and application of the compound in preparing anti-inflammatory drugs.
Description
Technical Field
The invention relates to 2-aminomethyl pyrimidine modified coumarin derivatives, a preparation method thereof, a pharmaceutical composition containing the same and application thereof in preparing anti-inflammatory drugs.
Background
There are two broad classes of anti-inflammatory drugs: one is a steroidal anti-inflammatory drug, namely glucocorticoid hydrocortisone secreted by adrenal cortex and its artificially synthesized derivatives. Another class is non-steroidal anti-inflammatory drugs such as aspirin, phenylbutazone, and the like.
Steroidal anti-inflammatory drugs are glucocorticoids, either natural or synthetic in their chemical nature. In 1949, Hench et al first used cortisone to treat arthritis, rheumatism, etc., and found that it has a strong anti-inflammatory effect, but its side effects were severe, and especially when applied at a large dose, it may not only cause dependency but also cause deterioration of adrenocortical function. At present, the more commonly used non-steroidal anti-inflammatory drugs have the respective anti-inflammatory or antipyretic and analgesic effects, and most of the non-steroidal anti-inflammatory drugs reduce adverse reactions to a certain extent, but the side effects are still obvious, particularly the toxic reaction of gastrointestinal tracts, and people hope to develop anti-inflammatory drugs with small adverse reactions.
Coumarin (Coumarin) is a natural product with a benzo alpha-pyrone mother nucleus, widely exists in the plant world, and is a COX/5-LOX dual inhibitor. In the literature (see Chen S. Natural products triggeringbiological Targets e a review of the anti-inflammatory-pathological acid pathological in alloreactive and rhematolytic Targets,2011,12: 288-301. and Kontogiogenisis CA, Hadjiptalou-Litina DJ. Synthesis and anti-inflammatory activity of coumarine derivatives. JMed. Chem. 2005,48:6400-6408.) it has been reported that coumarin shows good anti-inflammatory activity.
The anti-inflammatory activity of pyrimidines and their use as Cyclooxygenase (COX) inhibitors have been the focus of research (see Caroline C, clinical M. Dual inhibition of cycloosygenase-2 (COX-2) and5-lipoxygenase (5-LOX) as new strand to pro-enzyme not-steric anti-inflammatory-inhibitory drugs-5-translational modification of European Journal of Medicinal Chemistry,2003,38: 645-659, and Lauffer S A, Augustin J, Dannhardt, et al. (6, 7-Diaryldihydrochrysin-5-yl) acetic acids, a novel class of tertiary linkages of cycloxygenase 5-11894). The NSAIDs used for a long time can cause gastrointestinal ulcer, liver and kidney function damage and other adverse reactions, so that research and development of safer anti-inflammatory drugs with less adverse reactions are necessary, and 2-aminomethyl pyrimidine is an important research direction.
The inventor realizes that coumarin and 2-aminomethyl pyrimidine are natural products with various activities, amino acid not only has structural diversity of branched chains but also can improve pharmacokinetics of the compound, and the introduction of the amino acid can increase water solubility. Natural amino acids are widely used to improve absorption and metabolism of drugs. 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine modified by phenylalanine is taken as a mother nucleus, amino acid is taken as a connecting arm, and the coumarin is coupled with COX-2 inhibitor 2-aminomethyl pyrimidine with stronger anti-inflammatory activity to modify the structure of the coumarin and try to find out a new derivative of a natural product with better activity. The correlation from structure should be extendable to correlation of biological activity.
Disclosure of Invention
In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein: AA is amino acid; n is 0 or 1; r1、R3、R4、R5、R6、R7Each independently selected from hydrogen, benzyl, benzoyl, C1-10Alkanoyl radical, C1-10Alkyl radical, C1-10Alkoxy radical, C6-14Aryl or C5-14Heterocyclyl, wherein the alkyl is optionally substituted by C6-14Aryl or C5-14Heteroaryl substitution; and R2Selected from hydroxyl groups.
In particular, the present invention provides a compound of general formula (II) or a pharmaceutically acceptable salt thereof:
wherein AA is an amino acid; n is 0 or 1.
In the compound of the present invention or a pharmaceutically acceptable salt thereof, AA is preferably glycine, alanine, valine, leucine, isoleucine, phenylalanine, threonine, tyrosine, serine, tryptophan, aspartic acid, glutamic acid, methionine, arginine or lysine.
Typical compounds of the invention or pharmaceutically acceptable salts thereof are shown below:
in another aspect, the present invention provides a process for the preparation of a compound of formula (I) comprising the steps of:
1) condensing 2, 4-dihydroxy benzaldehyde with diethyl malonate under the catalysis of piperidine to generate 7-hydroxycoumarin-3-ethyl carboxylate;
2) in the presence of HCl, heating and refluxing 7-hydroxycoumarin-3-carboxylic acid ethyl ester in water to generate 7-hydroxycoumarin-3-carboxylic acid;
3) coupling 7-hydroxycoumarin-3-carboxylic acid with phenylalanyl phenylalanine-OBzl to obtain 7-hydroxycoumarin-3-formylphenylalanyl phenylalanyl amino acid benzyl ester;
4) carrying out hydrogenolysis on 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine benzyl ester under the catalysis of palladium carbon to generate 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine;
5) coupling tert-butoxy acylamino acid and 2-aminomethyl pyrimidine to obtain tert-butoxy acylamino acyl-2-aminomethyl pyrimidine;
6) adding tert-butoxycarbonyl-2-aminomethyl pyrimidine into hydrogen chloride/ethyl acetate solution to remove tert-butoxycarbonyl group to obtain N-aminoacyl-2-aminomethyl pyrimidine of general formula (III);
7) coupling N-aminoacyl-2-aminomethyl pyrimidine of general formula (III) with 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine of general formula (IV) to obtain 7-hydroxycoumarin-3-formylphenylalanyl phenylalanyl aminoacyl-2-aminomethyl pyrimidine of general formula (I);
8) coupling 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine with L-amino acid benzyl ester to obtain 7-hydroxycoumarin-3-formylphenylalanyl phenylalanyl amino acid benzyl ester;
9) carrying out hydrogenolysis on 7-hydroxycoumarin-3-formylphenylalanyl phenylalanyl amino acid benzyl ester under the catalysis of palladium carbon to generate 7-hydroxycoumarin-3-formylphenylalanyl phenylalanyl amino acid with a general formula (V);
10) coupling the 7-hydroxycoumarin-3-formylphenylalanyl phenylalanyl aminoacid of the general formula (V) with the 2-aminomethyl pyrimidine of the general formula (VI) to obtain the 7-hydroxycoumarin-3-formylphenylalanyl phenylalanyl aminoacyl-2-aminomethyl pyrimidine of the general formula (I);
wherein AA, n, R1、R2、R3、R4、R5、R6、R7As above toAs defined in formula (I).
Preferably, AA in the preparation process is glycine, alanine, valine, leucine, isoleucine, phenylalanine, threonine, tyrosine, serine, tryptophan, aspartic acid, glutamic acid, methionine, arginine or lysine; r1、R3、R4、R6、R7Each independently selected from hydrogen; r2Selected from hydroxyl; and n is 0 or 1.
In yet another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or adjuvant.
In another aspect, the invention provides a use of the compound of the general formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same in the preparation of an anti-inflammatory medicament. The anti-inflammatory effects of the compounds 10a-n,13a-c of the invention were evaluated by a xylene-induced ear swelling model in mice.
The compound of the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be administered to humans or other mammals by various routes, such as oral administration, intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, and the like.
The compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof may be formulated with suitable pharmaceutically acceptable excipients or carriers into various dosage forms known to those skilled in the art, such as tablets, capsules, emulsions, suspensions, etc.
A preferred mode of administration of the compounds of the invention is oral. Preferably, the pharmaceutical product is in the form of a discrete dosage unit. In such a form, the preparation is divided into suitably sized dosage units containing the active compound in the desired dosage, e.g., in an amount effective for its purpose.
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
"alkyl" refers to a saturated aliphatic hydrocarbon group, preferably containing 1 to 10 carbon atoms, more preferably containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, or 2, 3-dimethylbutyl, and the like.
"aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings which carry adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
"heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur, and nitrogen. Preferably 5 to 10 membered. Heteroaryl is preferably 5-or 6-membered, for example furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
the preparation of the compound of the invention, 7-hydroxycoumarin-3-formylphenylalanyl phenylalanyl aminoacyl-2-aminomethyl pyrimidine 10a-n, which can be prepared according to scheme 2, is exemplified by the preparation of the compound of the invention, which comprises the following steps: coupling tert-butoxy acylamino acid and 2-aminomethyl pyrimidine in anhydrous tetrahydrofuran in the presence of 1-ethyl- (dimethylaminopropyl) carbodiimide, N-hydroxybenzotriazole and N-methylmorpholine to obtain tert-butoxy acylamino-2-aminomethyl pyrimidine; removing tert-butyloxycarbonyl group in HCl/EA (4N) solution to obtain N-aminoacyl-2-aminomethyl pyrimidine; coupling 7-hydroxycoumarin-3-carboxylic acid with phenylalanyl phenylalanine benzyl ester to obtain 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine benzyl ester; carrying out catalytic hydrogenolysis on palladium carbon to remove benzyl ester to obtain 7-hydroxycoumarin-3-formyl phenylalanyl phenylalanine; coupling N-aminoacyl-2-aminomethyl pyrimidine and 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine to obtain 7-hydroxycoumarin-3-formylphenylalanyl phenylalanyl aminoacyl-2-aminomethyl pyrimidine 10 a-N.
Scheme 1. synthetic route to aminoacyl-2-aminomethylpyrimidines
Scheme 2.7 Synthesis route of Hydroxycoumarin-3-formylphenylalanyl phenylalanyl aminoacyl-2-aminomethyl pyrimidine 10a-n
The preparation of the compound of the invention, 7-hydroxycoumarin-3-formylphenylalanyl phenylalanyl aminoacyl-2-aminomethyl pyrimidine 13a-b, illustrated as an example, is a process for the preparation of the compound of the invention, which can be prepared by scheme 3, comprising the steps of: coupling 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine with L-amino acid benzyl ester to obtain 7-hydroxycoumarin-3-formylphenylalanyl phenylalanyl amino acid benzyl ester; removing benzyl ester to obtain 7-hydroxycoumarin-3-formyl phenylalanyl amino acid; condensing the derivative with 2-aminomethyl pyrimidine to obtain 7-hydroxycoumarin-3-formyl phenylalanyl aminoacyl-2-aminomethyl pyrimidine 13 a-b.
Scheme 3.7 Synthesis route of Hydroxycoumarin-3-formylphenylalanyl phenylalanyl aminoacyl-2-aminomethyl pyrimidine 13a-b
Detailed Description
The present invention is illustrated by the following specific examples. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.
Nuclear magnetic resonance apparatus: avance II 300MHz NMR, Bruker; avance II 500MHz NMR, Bruker Corp.
Mass spectrometry: micromass Quattro micro TM API, Waters corporation; trace MS System Mass spectrometer, Thermo Finnigan.
An infrared spectrometer: nicolet iS5, ThermoFisher corporation.
Polarimeters: autopol IV Automatic Polarimeter, Rudolph Research Analytical, Inc.
Thin layer chromatography silica gel: GF254, Qingdao ocean chemical Co.
Column chromatography silica gel: ZCX-11,200-300 mesh, Qingdao ocean chemical Co., Ltd.
The experimental method of the present invention, in which the specific conditions are not specified, is generally carried out under the conventional conditions or under the conditions recommended by the manufacturers of the raw materials or the commercial products. Reagents of specific sources are not indicated, and conventional reagents are purchased in the market.
Preparation example 17 preparation of Ethyl-hydroxycoumarin-3-carboxylate 6
2, 4-dihydroxybenzaldehyde (5g, 36.2mmol) and diethyl malonate (0.70mL, 4.00mmol) were dissolved in 95% ethanol (200mL) at 90 ℃ and piperidine (0.4mL, 4mmol) was added and the reaction turned brown and refluxed for 8 h. Cool and filter the reaction mixture and wash with a small amount of cold ethanol to afford title compound 6(7.66g, 32.7mmol) as a pale yellow solid in 91% yield. ESI-MS M/z 233 (M-1).
Preparation example 27 preparation of hydroxycoumarin-3-carboxylic acid 7
7-Hydroxycoumarin-3-carboxylic acid ethyl ester (2.00g, 8.55mmol) was placed in a 250ml eggplant flask, water (20ml) was used as a solvent, and concentrated hydrochloric acid (6ml) was added, stirred under an oil bath at 90 ℃ and refluxed for 8 hours. Cooling, filtration and rinsing with appropriate amount of water gave compound 3(1.32g, 6.41mmol) as a red-brown solid in 75% yield and ESI-MS M/z 205 (M-1).
Preparation example 3 preparation of t-Butoxyacylglycyl-2-aminomethylpyrimidine 3a
Boc-G-OH (900mg, 5.14mmol) was dissolved in tetrahydrofuran 50ml, N-hydroxybenzotriazole (HOBt) (763.7mg, 5.66mmol),1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC. HCl) (1090mg, 5.68mmol) were added sequentially under ice bath, pH was adjusted to 8-9 with N-methylmorpholine (NMM), reaction was carried out for 30min, 2-aminomethylpyrimidine hydrochloride (824mg, 5.66mmol) was weighed, placed in a 50ml beaker, dissolved by addition of a small amount of N, N-Dimethylformamide (DMF), and the solution was added to a reaction flask, pH was adjusted to 8 with NMM, and reacted at room temperature for 8 hours. Filtering, and concentrating under reduced pressure to dryness. The obtained residue was dissolved in an appropriate amount of methylene chloride, placed in a 250mL separatory funnel, and washed with a saturated aqueous sodium bicarbonate solution (30mL × 3), a saturated aqueous sodium chloride solution (30mL × 3), a 5% aqueous potassium hydrogensulfate solution (30mL × 3), a saturated aqueous sodium chloride solution (30mL × 3), a saturated aqueous sodium bicarbonate solution (30mL × 3), and a saturated aqueous sodium chloride solution (30mL × 3) in this order; the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Column chromatography (dichloromethane: methanol ═ 70: 1) afforded title compound 3a (889mg, 3.34mmol) as a pale yellow oil in 65% yield. ESI-MS M/z 267(M + 1).
Preparation example 4 preparation of t-Butoxyacylvalyl-2-aminomethylpyrimidine 3b
The procedure of preparation 3 was followed from Boc-V-OH (800mg, 3.69mmol) and 2-aminomethylpyrimidine hydrochloride (488mg, 3.35mmol) to give the title compound 3b (784mg, 2.55mmol) as a pale yellow oil in 76% yield and ESI-MS M/z 309(M + 1).
Preparation example 5 preparation of t-Butyloxyleucyl-2-aminomethylpyrimidine 3c
Following the procedure of preparation 3, starting from Boc-L-OH (500mg, 2.16mmol) and 2-aminomethylpyrimidine hydrochloride (287mg, 1.97mmol), the title compound 3c (460mg, 1.43mmol) was obtained as a light yellow oil in 70% yield and ESI-MS M/z 323(M + 1).
Preparation example 6 preparation of t-Butoxylsoleucyl-2-aminomethylpyrimidine 3d
From Boc-I-OH (500mg, 2.16mmol) and 2-aminomethylpyrimidine hydrochloride (287mg, 1.97mmol), according to the procedure of preparation 3, the title compound 3d (431.6mg, 1.34mmol) was obtained as a pale yellow oil in 68% yield, ESI-MS M/z 323(M + 1).
Preparation example 7 preparation of tert-Butyloxyseryl-2-aminomethylpyrimidine 3e
The procedure of preparation 3 was followed from Boc-S-OH (500mg, 2.44mmol) and 2-aminomethylpyrimidine hydrochloride (427mg, 2.93mmol) to give the title compound 3e (382.6mg, 1.29mmol) as a clear oil in 53% yield and ESI-MS M/z 297(M + 1).
PREPARATION EXAMPLE 8 preparation of Butoxybenzyl ester aspartyl-2-aminomethyl pyrimidine 3f
The title compound 3f (717.8mg, 1.73mmol) was obtained as a colorless oil in 56% yield by the procedure of preparation example 3 from Boc-D (OBzl) -OH (1000mg, 3.10mmol) and 2-aminomethyl pyrimidine hydrochloride (542mg, 3.72 mmol).
Preparation example 9 preparation of tert-Butyloxybenzyl ester glutamyl-2-aminomethyl pyrimidine 3g
From Boc-E (OBzl) -OH (500mg, 1.48mmol) and 2-aminomethyl pyrimidine hydrochloride (237.6mg, 1.63mmol), 3g (374.6mg, 0.88mmol) of the title compound was obtained as a colorless oil in 59% yield and ESI-MS M/z 451(M +23) according to the procedure of preparation 3.
Preparation example 10 preparation of t-Butoxyacyl methionyl-2-aminomethyl pyrimidine
From Boc-M-OH (500mg, 2.01mmol) and 2-aminomethylpyrimidine hydrochloride (266mg, 1.83mmol) according to the procedure of preparation 3, the title compound was obtained for 3h (428.6mg, 1.26mmol) as a colorless oil in 69% yield and ESI-MS M/z 341(M + 1).
Preparation example 11 preparation of t-Butoxysuccinyl-2-aminomethylpyrimidine 3i
The procedure of preparation 3 was followed from Boc-T-OH (700mg, 3.20mmol) and 2-aminomethylpyrimidine hydrochloride (512mg, 3.52mmol) to give the title compound 3i (713mg, 2.30mmol) as a colorless oil in 72% yield and ESI-MSm/z 311(M + 1).
Preparation example 12 preparation of t-butoxytryptophanyl-2-aminomethyl pyrimidine 3j
The procedure of preparation 3 was followed to give the title compound 3j (461mg, 1.17mmol) as a yellow solid in 78% yield and ESI-MS M/z 396(M +1) from Boc-W-OH (500mg, 1.64mmol) and 2-aminomethyl pyrimidine hydrochloride (217.7mg, 1.50 mmol).
Preparation example 13 preparation of t-Butoxyalanyl-2-aminomethylpyrimidine 3k
The title compound 3k (860.6mg, 3.07mmol) was obtained as a pale yellow oil in 71% yield and ESI-MS M/z 281(M +1) from Boc-A-OH (900mg, 4.76mmol) and 2-aminomethylpyrimidine hydrochloride (630.3mg, 4.33mmol) according to the procedure of preparation 3.
Preparation example 14 preparation of t-Butyloxyphenylalanyl-2-aminomethylpyrimidine 3l
From Boc-F-OH (800mg, 3.02mmol) and 2-aminomethylpyrimidine hydrochloride (483.3mg, 3.32mmol) according to the procedure of preparation 3, the title compound 3l (580.1mg, 1.63mmol) was obtained as a pale yellow oil in 54% yield and ESI-MS M/z 357(M + 1).
Preparation example 15 preparation of t-Butyloxyphenylalanyl-2-aminomethylpyrimidine 3m
From Boc-Y-OH (800mg, 2.85mmol) and 2-aminomethylpyrimidine hydrochloride (455.8mg, 3.13mmol) according to the procedure of preparation 3, the title compound 3M (529.3mg, 1.42mmol) was obtained as a pale yellow oil in 50% yield and ESI-MS M/z 373(M + 1).
PREPARATION EXAMPLE 167 preparation of Hydroxycoumarin-3-formylphenylalanyl phenylalanine benzyl ester 8
Boc-phenylalanyl-benzyl-phenylalaninate (5.00g, 9.96mmol) was dissolved in 4N HCl/EtOAc (50ml) under ice-bath cooling, reacted for 3 hours and drained to give phenylalanyl-benzyl-phenylalanyl-phenylalaninate (3.92g, 9.76mmol) in 98% yield. 7-Hydroxycoumarin-3-carboxylic acid (1.60g, 7.77mmol) was dissolved in 50ml of tetrahydrofuran, N-hydroxybenzotriazole (HOBt) (1.15g, 8.52mmol), 1-ethyl- (dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl) (1.64g, 8.54mmol) were added in succession under ice-bath, the reaction was carried out with N-methylmorpholine (NMM) at pH 8 for 0.5h, the compound phenylalanyl phenylalanine benzyl ester (3.44g, 8.55mmol) was added, NMM was added dropwise at pH 8. The reaction was carried out at room temperature for 9 hours. Filtering, and concentrating under reduced pressure to dryness. The obtained residue was dissolved in an appropriate amount of ethyl acetate, placed in a 250mL separatory funnel, and washed with a saturated aqueous sodium bicarbonate solution (30mL × 3), a saturated aqueous sodium chloride solution (30mL × 3), a 5% aqueous potassium hydrogensulfate solution (30mL × 3), a saturated aqueous sodium chloride solution (30mL × 3), a saturated aqueous sodium bicarbonate solution (30mL × 3), and a saturated aqueous sodium chloride solution (30mL × 3) in this order; the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. Column chromatography (dichloromethane: methanol ═ 80: 1) afforded title compound 8(3.68g, 6.21mmol) as a pale yellow solid in 80% yield, ESI-MS M/z 589 (M-1).
Preparation example 177 preparation of Hydroxycoumarin-3-formylphenylalanyl phenylalanine 9
Adding 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine benzyl ester 8(1.80g, 3.05mmol) into a 100mL eggplant bottle, adding 30mL methanol to dissolve, adding palladium carbon (Pd/C) (0.18g), vacuumizing, and introducing H2TLC to monitor completion of the reaction mixture was filtered and the filtrate was concentrated to dryness under reduced pressure to give the title compound 9(1.37g, 2.74mmol) as a pale yellow solid in calculated yield 90%. Mp:147.6-148.1 ℃ [ α ]]25 D＝+13.8(c＝0.1mg/100ml,DMF)；IR:3278.87,1702.88,1613.80,1530.88,1452.54,1217.85；
1HNMR(300MHz,DMSO-d6):8.88(1H,d,J＝8.1Hz,N-H),8.74(1H,s,CH),8.58(1H,d,J＝8.1Hz,N-H),7.80(1H,d,J＝8.7Hz,Ar-H),7.10-7.30(10H,m,Ar-H),6.90(1H,dd,J＝8.7,2.4Hz,Ar-H),6.81(1H,d,J＝2.1Hz,Ar-H),4.81(1H,m,CH),4.48(1H,m,CH),3.10(2H,m,CH2),2.90(2H,m,CH2)；
13CNMR(75MHz,DMSO-d6)173.2,170.6,161.3,156.8,148.9,137.8,137.3,132.6,129.8,129.6,128.7,128.5,126.9,114.9,113.3,111.5,102.2,53.9,53.8,38.5,37.1；ESIMS m/z 499(M-1)；
HRMS calculated value (C)28H24N2O7-1), m/z (499.1500); found, m/z (499.118).
Preparation example 187 preparation of Hydroxycoumarin-3-formylphenylalanyl-phenylalanyl-arginine benzyl ester 11a
Dissolving 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine (1000mg, 2.00mmol) in 50ml tetrahydrofuran, sequentially adding N-hydroxybenzotriazole (HOBt) (300mg, 2.22mmol),1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC. HCl) (420mg, 2.19mmol) under ice bath, adjusting pH to 8-9 with N-methylmorpholine (NMM), reacting for 30mins, adding R (NO)2) OBzl Tos (1030mg, 2.20mmol), pH adjusted to 8 with NMM, reaction at room temperature for 8 hours, filtration, and concentration under reduced pressure to dryness, the obtained residue was dissolved with an appropriate amount of ethyl acetate, placed in a 250mL separatory funnel, washed successively with a saturated aqueous sodium bicarbonate solution (30mL × 3), a saturated aqueous sodium chloride solution (30mL × 3), a 5% aqueous potassium hydrogen sulfate solution (30mL × 3), a saturated aqueous sodium chloride solution (30mL × 3), a saturated aqueous sodium hydrogen carbonate solution (30mL × 3), a saturated aqueous sodium chloride solution (30mL × 3), an organic layer was dried over anhydrous sodium sulfate, filtration, and the filtrate was concentrated under reduced pressure to dryness, column chromatography (dichloromethane: methanol: 70: 1) gave title compound 11a (1010mg, 1.30mmol) as a pale yellow solid with a yield of 65%. ESI-MS M/z (M-776 (M-1).
Preparation example 197 preparation of hydroxy coumarin-3-formyl phenylalanyl arginine benzyl ester 11b
From 7-hydroxycoumarin-3-formylphenylalanylphenylalanine (220mg, 0.44mmol) and K (Boc) -OBzL (178mg, 0.53mmol), the title compound 11b (360mg, 0.44mmol) was obtained as a white solid in a yield of 63% according to the procedure of preparation 18. ESI-MS M/z 820(M + 1).
Preparation example 207 preparation of dibenzyl 11 c-hydroxycoumarin-3-formylphenylalanyl phenylalanyl aspartic acid
By following the procedure of preparation 18, starting from 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine (500mg, 1.00mmol) and D (OBzL)2Tos (533.5mg, 1.10mmol), to give the title compound 11c (572.4mg, 0.72mmol) as a pale yellow solidSolid, 72% yield ESI-MS M/z 796(M + 1).
EXAMPLE 17 preparation of Hydroxycoumarin-3-formylphenylalanyl phenylalanyl-2-aminomethyl pyrimidine 10a
Under ice-bath cooling, tert-butoxyacylaglycosyl-2-aminomethylpyrimidine (125mg, 0.47mmol) was dissolved in 4N HCl/EtOAc (10ml), the reaction was completed and dried by suction to give aglycosyl-2-aminomethylpyrimidine (70mg, 0.26 mmol). 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine (120mg, 0.24mmol) was dissolved in DMF, and N-hydroxybenzotriazole (HOBt) (35.1mg, 0.26mmol), 1-ethyl- (dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl) (49.9mg, 0.26mmol) were added in sequence under ice-bath, N-methylmorpholine (NMM) was used to adjust pH to 8 for 0.5h, the compound aglycosyl-2-aminomethylpyrimidine (70mg, 0.26mmol) was added dropwise, the pH was adjusted to 8, the reaction was carried out for 9 h at room temperature, the filtration was carried out, and the column chromatography (dichloromethane: 30: 1) was concentrated to give the title compound as pale yellow solid (10.3 a, 31 mg, 0.54.54 mmol, 31: 355 mmol), the yield was increased to 35.242%]25 D＝-22.2(c＝0.1mg/100ml,DMF)；IR:3270.28,1696.71,1639.40,1563.33,1525.78,1215.99；
1HNMR(300MHz,DMSO-d6):11.15(1H,s,O-H),8.87(1H,d,J＝7.8Hz,N-H),8.75(3H,m,CH),8.51(1H,d,J＝8.1Hz,N-H),8.35(2H,m,N-H),7.79(1H,d,J＝8.7Hz,Ar-H),7.39(1H,t,J＝5.1Hz,CH),7.10-7.28(10H,m,Ar-H),6.88(1H,dd,J＝8.7,2.1Hz,Ar-H),6.80(1H,d,J＝2.1Hz,Ar-H),4.75(1H,m,CH),4.60(1H,m,CH),4.48(2H,s,CH2),3.84(2H,d,J＝2.4Hz,CH2),3.08(2H,m,CH2),2.84(2H,m,CH2)；
13CNMR(75MHz,DMSO-d6)171.6,170.6,169.1,167.0,164.0,161.4,161.3,157.8,156.8,148.9,138.2,137.3,132.6,129.8,129.6,128.5,126.8,126.7,120.3,114.8,113.4,111.5,102.2,54.4,54.2,45.2,42.4,38.3,37.8；
ESIMS M/z 647 (M-1); HRMS calculated value (C)35H32N6O7-1), m/z (647.2249); found, m/z (647.1824).
EXAMPLE 27 preparation of Hydroxycoumarin-3-formylphenylalanyl phenylalanyl valyl-2-aminomethylpyrimidine 10b
Following the procedure of example 1, t-butoxyacylvalyl-2-aminomethylpyrimidine (611mg, 1.98mmol) was stripped of Boc protecting group in 4NHCl/EA (20ml) to give valyl-2-aminomethylpyrimidine (371mg, 1.78 mmol.) the condensation of 7-hydroxycoumarin-3-formylphenylalanyl-phenylalanine (810mg, 1.62mmol) and valyl-2-aminomethylpyrimidine gave the title compound 10b (524.6mg, 0.76mmol) as a pale yellow solid in 47% yield, Mp:217.7-218.4 ℃ [ α ] m]25 D＝+20.4(c＝0.1mg/100ml,DMF)；IR:3275.31,1702.81,1667.45,1563.14,1526.19,1218.47；
1HNMR(300MHz,DMSO-d6):11.11(1H,brs,O-H),8.85(1H,d,J＝7.8Hz,N-H),8.74(3H,m,CH),8.43(2H,m,N-H),8.04(1H,d,J＝8.7Hz,N-H),7.80(1H,d,J＝8.7Hz,Ar-H),7.39(1H,t,J＝4.8Hz,CH),7.10-7.32(10H,m,Ar-H),6.87(1H,dd,J＝8.4,2.1Hz,Ar-H),6.78(1H,d,J＝1.8Hz,Ar-H),4.73(2H,m,CH),4.49(2H,m,CH2),4.33(1H,m,CH),3.07(2H,m,CH2),2.87(2H,m,CH2),2.06(1H,m,CH),0.89(6H,t,J＝15Hz,CH3)；
13CNMR(75MHz,DMSO-d6)171.4,171.3,170.4,167.2,164.3,161.3,157.7,156.8,148.9,138.2,137.3,132.6,129.9,129.7,128.4,126.8,126.6,120.3,114.9,113.4,111.5,102.3,58.2,54.2,54.1,45.4,38.4,38.0,31.2,19.7,18.5；
ESIMS M/z 689 (M-1); HRMS calculated value (C)38H38N6O7-1), m/z (689.2718); found, m/z (689.2266).
EXAMPLE 37 preparation of Hydroxycoumarin-3-formylphenylalanyl phenylalanyl-leucyl-2-aminomethyl pyrimidine 10c
Following the procedure of example 1, tert-butoxyacylleucyl-2-aminomethylpyrimidine (708mg, 2.20mmol) was stripped of the Boc protecting group in 4N Cl/EA (20ml) to give leucyl-2-aminomethylpyrimidine (439mg, 1.98 mmol). From 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine (900mg, 1.80mmol) and leucyl-2-aminomethylpyrimidine, condensation was carried out to give the title compound 10c (544mg, 0.77mmol) as a pale yellow solid in 43% yield. Mp is 235.4-236.9 ℃;[α]25 D＝+2.57(c＝0.1mg/100ml,DMF)；IR:3266.18,1694.82,1634.88,1562.98,1529.23,1215.25；
1HNMR(300MHz,DMSO-d6):11.09(1H,brs,O-H),8.85(1H,d,J＝8.1Hz,N-H),8.74(3H,m,CH),8.44(1H,d,J＝8.4Hz,N-H),8.30(1H,t,J＝5.4Hz,N-H),8.18(1H,d,J＝8.1Hz,N-H),7.79(1H,d,J＝8.4Hz,Ar-H),7.39(1H,t,J＝5.1Hz,CH),7.09-7.28(10H,m,Ar-H),6.87(1H,dd,J＝8.7,2.1Hz,Ar-H),6.79(1H,d,J＝2.1Hz,Ar-H),4.75(1H,m,CH),4.62(1H,m,CH),4.45(3H,m,CH,CH2),3.09(2H,m,CH2),2.84(2H,m,CH2),1.67(1H,m,CH),1.53(2H,m,CH2),0.90(6H,t,J＝6.9Hz,CH3)；
13CNMR(75MHz,DMSO-d6)172.3,171.2,170.5,167.1,164.3,161.4,161.3,157.8,156.8,148.8,138.2,137.4,132.5,129.8,129.6,128.4,126.8,126.6,120.3,114.9,113.4,111.5,102.3,54.2,54.1,51.6,45.4,38.4,38.0,24.6,23.5,22.2；
ESIMS M/z 703 (M-1); HRMS calculated value (C)39H40N6O7-1), m/z (703.2875); found, m/z (703.2429).
EXAMPLE 47 preparation of hydroxycoumarin-3-formylphenylalanyl-phenylalanyl-isoleucyl-2-aminomethylpyrimidine 10d
Following the procedure of example 1, tert-butoxyisoleucyl-2-aminomethylpyrimidine (250mg, 0.78mmol) was stripped of Boc protecting group in 4NHCl/EA (20ml) to give isoleucyl-2-aminomethylpyrimidine (155mg, 0.70 mmol). condensation of 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine (320mg, 0.64mmol) and isoleucyl-2-aminomethylpyrimidine gave the title compound 10d (184.5mg, 0.26mmol) as a pale yellow solid in 41% yield, Mp:236.5-236.9 ℃ [ α mmol ], []25 D＝+9.59(c＝0.1mg/100ml,DMF)；IR:3268.98,1688.06,1669.67,1562.48,1525.92,1215.48；
1HNMR(300MHz,DMSO-d6):11.09(1H,brs,O-H),8.86(1H,d,J＝7.8Hz,N-H),8.74(3H,m,CH,CH,CH),8.46(2H,m,N-H),8.04(1H,d,J＝9.0Hz,N-H),7.80(1H,d,J＝8.4,Hz,Ar-H),7.39(1H,t,J＝2.4Hz,CH),7.10-7.31(10H,m,Ar-H),6.87(1H,dd,J＝8.4,2.4Hz,Ar-H),6.79(1H,d,J＝2.1Hz,Ar-H),4.73(2H,m,CH),4.46(3H,m,CH,CH2),3.08(2H,m,CH2),2.88(2H,m,CH2),1.82(1H,m,CH),1.50(1H,m,CH2),1.13(1H,m,CH2),0.90(3H,d,J＝6.6Hz,CH3),0.84(3H,t,J＝7.2Hz,CH3)；
13CNMR(75MHz,DMSO-d6)171.4,171.3,170.4,167.2,164.3,161.3,161.2,157.7,156.8,148.9,138.2,137.3,132.6,129.9,129.7,128.4,126.8,126.6,120.3,114.9,113.3,111.5,102.2,57.4,54.1,54.0,45.3,38.4,38.0,37.4,24.6,15.9,11.7；
ESIMS M/z 703 (M-1); HRMS calculated value (C)39H40N6O7-1), m/z (703.2875); found, m/z (703.2457).
Example preparation of 57-Hydroxycoumarin-3-formylphenylalanyl phenylalanyl seryl-2-aminomethyl pyrimidine 10e
Following the procedure of example 1, tert-butoxyserinyl-2-aminomethylpyrimidine (300mg, 1.01mmol) was deprotected from Boc in 4NHCl/EA (20ml) to give seryl-2-aminomethylpyrimidine (174.8mg, 0.89 mmol). condensation of 7-hydroxycoumarin-3-formylphenylalanyl-phenylalanine (405mg, 0.81mmol) and seryl-2-aminomethylpyrimidine gave the title compound 10e (202mg, 0.30mmol) as a pale yellow solid in 37% yield, Mp:239.5-240.1 ℃ [ α ℃ ], []25 D＝+8.29(c＝0.1mg/100ml,DMF)；IR:3270.66,1700.84,1661.14,1563.96,1526.81,1217.81；
1HNMR(300MHz,DMSO-d6):8.86(1H,d,J＝8.1Hz,N-H),8.71(3H,m,CH,CH,CH),8.46(2H,d,J＝8.4Hz,N-H),8.30(1H,t,J＝5.7Hz,N-H),8.25(1H,d,J＝8.1Hz,N-H),7.79(1H,d,J＝8.7Hz,Ar-H),7.41(1H,t,J＝5.1Hz,Ar-H),7.09-7.32(10H,m,Ar-H),6.86(1H,dd,J＝8.4,2.1Hz,Ar-H),6.77(1H,d,J＝2.1Hz,Ar-H),5.04(1H,brs,O-H),4.72(2H,m,CH),4.47(3H,m,CH,CH2),3.65(2H,m,CH2),3.11(2H,m,CH2),2.84(2H,m,CH2)；
13CNMR(75MHz,DMSO-d6)171.6,170.5,166.8,164.6,161.4,157.8,156.8,148.8,138.3,137.4,132.6,129.8,129.7,128.4,126.8,126.6,120.4,115.0,113.1,111.4,102.3,62.3,55.7,54.1,45.4,38.4,38.0；ESIMS m/z 677(M-1)；
HRMS calculated value (C)36H34N6O8-1), m/z (677.2354); found, m/z (677.1905).
EXAMPLE 67 preparation of hydroxy coumarin-3-formyl phenylalanyl aspartyl benzyl ester-2-aminomethyl pyrimidine 10f
Following the procedure of example 1, tert-butoxyaspartyl benzyl ester-2-aminomethyl pyrimidine (650mg, 1.57mmol) was deprotected from Boc-protecting group in 4N HCl/EA (20ml) to give aspartyl benzyl ester-2-aminomethyl pyrimidine (429mg, 1.36 mmol). condensation of 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine (618mg, 1.24mmol) and aspartyl benzyl ester-2-aminomethyl pyrimidine gave 10f (403mg, 0.51mmol) as a pale yellow solid in 41% yield, Mp: 222.7-224.2 ℃ [ α ]]25 D＝-17.6(c＝0.1mg/100ml,DMF)；IR:3270.08,1703.29,1671.74,1615.14,1602.71,1215.83；
1HNMR(300MHz,DMSO-d6):8.86(1H,d,J＝7.8Hz,N-H),8.73(3H,m,CH,CH,CH),8.50(2H,m,N-H),8.21(1H,t,J＝5.4Hz,N-H),7.78(1H,d,J＝8.7Hz,Ar-H),7.09-7.40(17H,m,CH,Ar-H),6.87(1H,dd,J＝8.4,2.1Hz,Ar-H),6.79(1H,d,J＝2.1Hz,Ar-H),5.10(2H,s,CH2),4.80(2H,m,CH),4.55(3H,m,CH,CH2),3.08(2H,m,CH2),2.89(3H,m,CH2),2.67(1H,m,CH2)；
13CNMR(75MHz,DMSO-d6)171.5,170.6,170.4,166.7,164.0,161.4,157.8,156.8,148.9,138.1,137.4,136.4,132.6,129.8,129.6,128.8,128.5,128.4,128.3,126.8,126.7,120.4,114.8,113.4,111.5,102.2,66.2,54.3,54.1,49.7,45.3,38.4,37.8,36.6；
ESIMS M/z 795 (M-1); HRMS calculated value (C)44H40N6O9-1), m/z (795.2773); found, m/z (795.2308).
EXAMPLE 77 preparation of 10g of Hydroxycoumarin-3-formylphenylalanyl-phenylalanyl-glutamyl-benzyl ester-2-aminomethyl pyrimidine
Following the procedure of example 1, tert-butoxyglutamyl benzyl ester-2-aminomethyl pyrimidine (5)90mg, 1.38mmol) of Boc protecting group was removed in 4N HCl/EA (20ml) to give glutamylbenzyl ester-2-aminomethylpyrimidine (398mg, 1.21 mmol). The condensation of 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine (550mg, 1.10mmol) and glutamylbenzyl ester-2-aminomethylpyrimidine gave the title compound 10g (329mg, 0.41mmol) as a pale yellow solid in 37% yield, Mp:240.7-242.2 ℃ [ α ]]25 D＝-9.82(c＝0.1mg/100ml,DMF)；IR:3266.08,1695.83,1635.69,1562.86,1527.10,1214.67；
1HNMR(300MHz,DMSO-d6):11.11(1H,brs,O-H),8.87(1H,d,J＝7.8Hz,N-H),8.71(3H,m,CH,CH,CH),8.48(1H,d,J＝8.4Hz,N-H),8.41(1H,t,J＝5.7Hz,N-H),8.23(1H,d,J＝7.8Hz,N-H),7.79(1H,d,J＝8.7Hz,Ar-H),7.08-7.40(16H,m,CH,Ar-H),6.87(1H,dd,J＝8.4,2.1Hz,Ar-H),6.79(1H,d,J＝2.1Hz,Ar-H),5.09(2H,s,CH2),4.75(1H,m,CH),4.62(2H,m,CH),4.45(2H,m,CH2),3.07(2H,m,CH2),3.05(2H,m,CH2) 2.50(2H, overlap, CH)2),1.98(2H,m,CH2)；
13CNMR(75MHz,DMSO-d6)172.8,171.4,171.3,170.6,167.0,164.3,161.4,161.3,157.8,156.8,148.9,138.2,137.3,136.6,132.6,129.8,129.6,128.9,128.4,126.8,126.7,120.3,114.9,113.3,111.5,102.2,66.0,54.2,54.1,52.3,45.2,38.4,37.8,30.4,28.0；
ESI-MS M/z 809 (M-1); HRMS calculated value (C)45H42N6O9-1), m/z (809.2929); found, m/z (809.2427).
EXAMPLE 87 preparation of Hydroxycoumarin-3-formylphenylalanyl-phenylalanyl-methionyl-2-aminomethylpyrimidine
Following the procedure of example 1, tert-butoxyacylmethionyl-2-aminomethylpyrimidine (560mg, 1.65mmol) was deprotected from Boc-protecting group in 4NHCl/EA (20ml) to give methionyl-2-aminomethylpyrimidine (352mg, 1.46 mmol). condensation of 7-hydroxycoumarin-3-formylphenylalanyl-phenylalanine (663.6mg, 1.33mmol) and methionyl-2-aminomethylpyrimidine gave the title compound 10h (368mg, 0.51mmol) as a pale yellow solid in 40% yield at 238.1-239.3 ℃ [ α ] Mp:238.1-239.3 ℃ [ α ] yield]25 D＝+0.36(c＝0.1mg/100ml,DMF)；IR:3266.19,1634.48,1614.87,1601.27,1563.17,1525.88,1215.68；
1HNMR(300MHz,DMSO-d6):11.09(1H,s,O-H),8.87(1H,d,J＝7.8Hz,N-H),8.76(3H,m,CH,CH,CH),8.48(1H,d,J＝8.1Hz,N-H),8.36(1H,t,J＝5.7Hz,N-H),8.24(1H,d,J＝7.8Hz,N-H),7.80(1H,d,J＝8.7Hz,CH),7.40(1H,t,J＝5.1Hz,Ar-H),7.10-7.29(10H,m,Ar-H),6.88(1H,dd,J＝8.7,2.4Hz,Ar-H),6.79(1H,d,J＝2.1Hz,Ar-H),4.74(1H,m,CH),4.52(4H,m,CH,CH2),3.08(2H,m,CH2),2.85(2H,m,CH2),2.54(2H,m,CH2),2.05(3H,s,CH3),1.88(2H,m,CH2)；
13CNMR(75MHz,DMSO-d6)171.4,171.0,170.6,167.0,166.9,164.3,161.4,161.3,157.8,157.7,156.8,148.8,138.2,138.1,137.3,132.6,129.8,129.6,128.5,126.8,126.7,120.4,114.9,113.4,111.5,102.3,54.3,54.2,52.2,45.3,38.5,37.6,32.5,30.0,5.1；
ESIMS M/z 721 (M-1); HRMS calculated value (C)38H38N6O7S-1), m/z (721.2440); found, m/z (724.2076).
EXAMPLE 97 preparation of Hydroxycoumarin-3-formylphenylalanyl phenylalanyl threonyl-2-aminomethyl pyrimidine 10i
Following the procedure of example 1, tert-Butyloxythreonyl-2-aminomethylpyrimidine (450mg, 1.45mmol) was stripped of Boc protecting group in 4NHCl/EA (20ml) to give threonyl-2-aminomethylpyrimidine (274mg, 1.31 mmol). condensation of 7-hydroxycoumarin-3-formylphenylalanyl-phenylalanine (595mg, 1.19mmol) and threonyl-2-aminomethylpyrimidine gave the title compound 10i (263.1mg, 0.38mmol) as a pale yellow solid in 32% yield, Mp:221.9-223.5 ℃ [ α ] m]25 D＝+13.1(c＝0.1mg/100ml,DMF)；IR:3273.58,1635.66,1614.79,1601.20,1563.61,1524.80,1215.60；
1HNMR(300MHz,DMSO-d6):11.11(1H,brs,O-H),8.88(1H,d,J＝7.8Hz,N-H),8.75(3H,m,CH,CH,CH),8.50(1H,d,J＝8.4Hz,N-H),8.49(1H,t,J＝5.4Hz,N-H),8.30(1H,d,J＝7.2Hz,N-H),7.81(1H,d,J＝8.7Hz,Ar-H),7.40(1H,t,J＝4.8Hz,CH),7.11-7.29(10H,m,Ar-H),6.87(1H,dd,J＝8.7,2.4Hz,Ar-H),6.79(1H,d,J＝2.1Hz,Ar-H),4.75(1H,m,CH),4.61(1H,m,CH),4.48(3H,m,CH,CH2),3.08(2H,m,CH2),2.84(2H,m,CH2),1.31(3H,d,J＝6.9Hz,CH3)；
13CNMR(75MHz,DMSO-d6)171.9,170.6,170.5,166.8,164.3,161.3,157.8,156.8,148.9,138.4,137.3,132.6,129.9,129.7,128.4,126.8,126.6,120.4,114.9,113.3,111.5,102.2,67.1,58.7,54.3,54.0,45.3,38.4,37.9,20.1；
ESIMS M/z 691 (M-1); HRMS calculated value (C)37H36N6O8-1), m/z (691.2511); found, m/z (691.2072).
EXAMPLE 107 preparation of Hydroxycoumarin-3-formylphenylalanyl phenylalanyl-tryptophyl-2-aminomethyl pyrimidine 10j
Following the procedure of example 1, t-butoxyacyltryptophanyl-2-aminomethylpyrimidine (420mg, 1.06mmol) was deprotected from Boc-protecting group in 4NHCl/EA (20ml) to give tryptophanyl-2-aminomethylpyrimidine (282mg, 0.96 mmol). condensation of 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine (435mg, 0.87mmol) and tryptophanyl-2-aminomethylpyrimidine gave the title compound 10j (216mg, 0.28mmol) as a pale yellow solid in 32% yield, Mp:227.1-228.3 ℃ [ α mmol ℃ ], []25 D＝-0.67(c＝0.1mg/100ml,DMF)；IR:3265.76,1692.94,1635.84,1563.23,1215.55；
1HNMR(300MHz,DMSO-d6):11.09(1H,brs,O-H),10.82(1H,s,N-H),8.84(1H,d,J＝8.1Hz,N-H),8.74(3H,m,CH,CH,CH),8.40(2H,m,N-H),8.25(1H,d,J＝7.8Hz,N-H),7.77(1H,d,J＝8.4Hz,Ar-H),7.61(1H,d,J＝7.8Hz,Ar-H),7.40(1H,t,J＝4.8Hz,CH),7.32(1H,d,J＝7.8Hz,Ar-H),6.94-7.24(14H,m,Ar-H),6.87(1H,dd,J＝8.7,2.1Hz,Ar-H),6.79(1H,d,J＝1.8Hz,Ar-H),4.75(2H,m,CH),4.62(1H,m,CH),4.46(2H,d,J＝6.6Hz,CH2),3.20(1H,m,CH2),3.06(3H,m,CH2),2.83(2H,m,CH2)；
13CNMR(75MHz,DMSO-d6)171.7,171.3,170.5,167.0,164.3,161.4,161.3,157.8,156.8,148.9,138.2,137.4,136.5,132.6,129.8,129.7,128.4,127.9,126.8,126.6,124.1,121.2,120.3,118.8,118.6,114.9,113.4,111.7,111.5,110.3,102.3,54.3,54.2,53.9,45.4,38.3,38.1,28.4；
ESIMS M/z 776 (M-1); HRMS calculated value (C)44H39N7O7-1), found m/z, m/z (776.2317).
EXAMPLE 117 preparation of Hydroxycoumarin-3-formylphenylalanyl-phenylalanyl-alanyl-2-aminomethyl pyrimidine 10k
Following the procedure of example 1, tert-butoxyalanyl-2-aminomethylpyrimidine (380mg, 1.36mmol) was stripped of Boc protecting group in 4NHCl/EA (20ml) to give alanyl-2-aminomethylpyrimidine (220mg, 1.22 mmol.) the condensation of 7-hydroxycoumarin-3-formylphenylalanyl-phenylalanine (555mg, 1.11mmol) and alanyl-2-aminomethylpyrimidine gave the title compound 10k (293.5mg, 0.44mmol) as a pale yellow solid in 40% yield, Mp: 223.8-224.7 ℃ [ α ]]25 D＝+6.78(c＝0.1mg/100ml,DMF)；IR:3265.93,1694.58,1635.36,1563.05,1525.92,1215.18；
1HNMR(300MHz,DMSO-d6):11.13(1H,brs,O-H),8.88(1H,d,J＝7.8Hz,N-H),8.75(3H,m,CH,CH,CH),8.51(1H,d,J＝8.4Hz,N-H),8.35(1H,t,J＝6.3Hz,N-H),8.30(1H,d,J＝7.5Hz,N-H),7.81(1H,d,J＝8.7Hz,Ar-H),7.40(1H,t,J＝5.1Hz,CH),7.11-7.29(10H,m,Ar-H),6.87(1H,dd,J＝8.4,2.1Hz,Ar-H),6.79(1H,d,J＝1.8Hz,Ar-H),4.75(1H,m,CH),4.61(1H,m,CH),4.46(3H,m,CH,CH2),3.08(2H,m,CH2),2.85(2H,m,CH2),1.31(3H,d,J＝7.2Hz,CH3)；
13CNMR(75MHz,DMSO-d6)172.6,171.2,170.4,167.1,164.3,161.3,157.8,156.8,148.9,138.2,137.3,132.6,129.9,129.7,128.5,126.8,126.7,120.3,114.9,113.3,111.5,102.2,54.2,54.1,48.7,45.2,38.4,37.9,18.8；
ESI-MS M/z661 (M-1); HRMS calculated value (C)36H34N6O7-1), m/z (661.2405); found, m/z (661.2121).
Example preparation of 127-Hydroxycoumarin-3-formylphenylalanyl phenylalanyl-2-aminomethylpyrimidine 10l
Following the procedure of example 1, tert-butoxyphenylalanyl-2-aminomethylpyrimidine (290mg, 0.81)mmol) removal of the Boc protecting group in 4N HCl/EA (20ml) to give phenylalanyl-2-aminomethylpyrimidine (186mg, 0.72 mmol.) condensation of 7-hydroxycoumarin-3-formylphenylalanyl-phenylalanine (325mg, 0.65mmol) and phenylalanyl-2-aminomethylpyrimidine gave the title compound 10l (191.6mg, 0.26mmol) as a pale yellow solid in 40% yield Mp:246.5-247.1 ℃ [ α ]]25 D＝-1.47(c＝0.1mg/100ml,DMF)；IR:3264.24,1693.67,1636.54,1562.50,1530.72,1215.34；
1HNMR(300MHz,DMSO-d6):11.09(1H,s,O-H),8.84(1H,d,J＝8.1Hz,N-H),8.75(3H,m,CH,CH,CH),8.47(1H,t,J＝5.7Hz,N-H),8.35(1H,d,J＝8.4Hz,N-H),8.26(1H,d,J＝8.1Hz,N-H),7.79(1H,d,J＝8.7Hz,Ar-H),7.40(1H,t,J＝4.8Hz,CH),7.10-7.30(15H,m,Ar-H),6.87(1H,dd,J＝8.4,2.1Hz,Ar-H),6.79(1H,d,J＝1.8Hz,Ar-H),4.68(2H,m,CH),4.55(1H,m,CH,CH2),3.11(3H,m,CH2),2.82(3H,m,CH2)；
13CNMR(75MHz,DMSO-d6)171.4,171.3,170.4,167.0,164.3,161.4,161.3,157.8,156.8,148.9,138.2,138.1,137.4,132.6,129.8,129.7,128.5,128.4,126.8,126.7,126.6,120.4,114.9,113.3,111.5,102.2,54.4,54.2,54.0,45.4,38.4,38.2；
ESIMS M/z 737 (M-1); HRMS calculated value (C)42H38N6O7-1), m/z (737.2718); found, m/z (737.2253).
EXAMPLE 137 preparation of Hydroxycoumarin-3-formylphenylalanyl phenylalanyl tyrosyl-2-aminomethylpyrimidine 10m
Following the procedure of example 1, t-Butyloxytyrosyl-2-aminomethylpyrimidine (500mg, 1.34mmol) was stripped of Boc protecting group in 4NHCl/EA (20ml) to give tyrosyl-2-aminomethylpyrimidine (333mg, 1.22 mmol.) the condensation of 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine (554.5mg, 1.11mmol) and tyrosyl-2-aminomethylpyrimidine gave the title compound 10m (208.7mg, 0.28mmol) as a pale yellow solid in 25% yield, Mp:250.5-251.1 ℃ [ α ] M]25 D＝-8.93(c＝0.1mg/100ml,DMF)；IR:3265.33,1693.04,1637.10,1613.14,1563.55,1532.15,1513.09,1215.85；
1HNMR(300MHz,DMSO-d6):11.11(1H,brs,O-H),9.16(1H,brs,O-H),8.85(1H,d,J＝7.8Hz,N-H),8.73(3H,m,CH,CH,CH),8.44(1H,t,J＝5.7Hz,N-H),8.38(1H,d,J＝8.4Hz,N-H),8.21(1H,d,J＝8.1Hz,N-H),7.79(1H,d,J＝8.7Hz,Ar-H),7.40(1H,t,J＝4.8Hz,CH),7.05-7.26(13H,m,Ar-H),6.88(1H,dd,J＝8.7,2.1Hz,Ar-H),6.79(1H,d,J＝2.1Hz,Ar-H),6.64(2H,d,J＝8.4Hz,Ar-H),4.77(1H,m,CH),4.58(2H,m,CH),4.46(2H,m,CH2),3.02(3H,m,CH2),2.78(3H,m,CH2)；
13CNMR(75MHz,DMSO-d6)171.4,171.2,170.4,167.0,164.3,157.8,156.8,156.3,148.9,138.1,137.4,132.6,130.6,129.8,129.7,128.5,128.4,128.2,126.8,126.6,120.3,115.4,114.9,113.4,111.5,102.3,54.8,54.2,54.1,45.4,38.4,38.1,37.4；
ESI-MS M/z 753 (M-1); HRMS calculated value (C)42H38N6O8-1), m/z (753.2667); found, m/z (753.2216).
EXAMPLE 147 preparation of Hydroxycoumarin-3-formylphenylalanyl phenylalanyl-2-aminomethyl pyrimidine 10n
From 7-hydroxycoumarin-3-formylphenylalanylphenylalanine (800mg, 1.60mmol) and 2-aminomethylpyrimidine hydrochloride (212mg, 1.46mmol), the title compound 10n (387mg, 0.65mmol) was obtained in the same manner as in example 1 in a 45% yield as a pale yellow solid at 116.8-117.5 ℃ Mp [ α ℃ ], []25 D＝+0.26(c＝0.1mg/100ml,DMF)；IR:3276.69,1701.56,1644.16,1614.44,1562.98,1525.60,1217.56；
1HNMR(300MHz,DMSO-d6):11.13(1H,s,OH),8.89(1H,d,J＝7.8Hz,N-H),8.76(3H,m,CH,CH,CH),8.60(1H,t,J＝5.7Hz,N-H),8.52(1H,d,J＝8.4Hz,N-H),7.80(1H,d,J＝8.4Hz,Ar-H),7.04-7.42(11H,m,CH,Ar-H),6.87(1H,dd,J＝8.4,2.1Hz,Ar-H),6.79(1H,d,J＝2.1,Ar-H),4.85(1H,m,CH),4.67(1H,m,CH),4.52(2H,m,CH2),3.09(2H,m,CH2),2.85(2H,m,CH2)；
13CNMR(75MHz,DMSO-d6)171.4,170.5,167.1,164.3,161.4,161.3,157.8,156.8,148.8,138.2,137.4,132.6,129.9,129.8,129.7,128.5,126.8,126.6,120.3,114.9,113.4,111.5,102.3,54.3,54.2,45.4,38.4,38.1；
ESI-MS M/z 590 (M-1); HRMS calculated value (C)33H29N5O6-1), m/z (590.2034); found, m/z (590.1703).
EXAMPLE 157 preparation of hydroxycoumarin-3-formylphenylalanyl-phenylalanyl-arginyl-2-aminomethyl pyrimidine 13a
Adding 7-hydroxycoumarin-3-formylphenylalanyl-phenylalanyl-arginine benzyl (370mg, 0.48mmol) into 100mL eggplant bottle, adding 1mL small amount of dichloromethane to dissolve, adding 2mL methanol, adding palladium carbon (Pd/C) (40mg), vacuumizing, introducing H2The reaction was monitored by TLC, the reaction mixture was filtered, the filtrate was concentrated to dryness under reduced pressure to give 7-hydroxycoumarin-3-formylphenylalanyl phenylalanyl arginine (262mg, 0.38mmol), N-Dimethylformamide (DMF) (30ml) was added to dissolve it, HOBt (56.4mg, 0.42mmol), EDC-HCl (80.6mg, 0.42mmol) and NMM was added in that order to adjust the pH to 8 for 30 minutes, 2-aminomethylpyrimidine hydrochloride (61.2mg, 0.42mmol) was added under ice bath to react at room temperature for 12 hours, the filtrate was concentrated to dryness under reduced pressure to give the title compound 13a (112mg, 0.14mmol) as a pale yellow solid in 38% yield, Mp:211.7-212.5 ℃, [ α ] as a column chromatography (dichloromethane: methanol ═ 25: 1)]25 D＝+8.60(c＝0.1mg/100ml,DMF)；IR:3267.22,1633.27,1600.79,1563.87,1526.89,1215.29；
1HNMR(300MHz,DMSO-d6)11.10(1H,s,O-H),8.87(1H,d,J＝7.8Hz,N-H),8.75(3H,m,CH,CH,CH),8.58(1H,brs,N-H),8.44(2H,m,N-H),8.25(1H,d,J＝8.1Hz,N-H),7.81(1H,d,J＝8.4Hz,Ar-H),7.39(1H,t,J＝4.8Hz,CH),7.12-7.28(10H,m,Ar-H),6.87(1H,dd,J＝8.4,1.8Hz,Ar-H),6.80(1H,s,Ar-H),4.76(1H,m,CH),4.61(1H,m,CH),4.46(3H,m,CH,CH2),3.18(2H,m,CH2),3.07(2H,m,CH2),2.85(2H,m,CH2),1.78(1H,m,CH2),1.61(3H,m,CH2)；
13CNMR(75MHz,DMSO-d6)171.8,171.4,170.6,167.0,164.3,161.4,161.3,157.8,156.8,148.9,138.2,137.3,132.6,129.8,129.6,128.5,126.8,126.7,120.3,114.9,113.4,111.5,102.3,54.3,54.1,52.7,45.3,38.4,37.9,30.0；
ESI-MS M/z 791 (M-1); HRMS calculated value (C)39H40N10O9-1) m/z (791.2896); found, m/z (791.2415).
EXAMPLE 167 preparation of Hydroxycoumarin-3-formylphenylalanyl phenylalanyl lysyl-2-aminomethyl pyrimidine 13b
Following the procedure of example 14, hydrogenolysis of 7-hydroxycoumarin-3-formylphenylalanyl phenylalanyl lysine benzyl ester (900mg, 1.10mmol) over Pd/C (5%) (90mg) gave 7-hydroxycoumarin-3-formylphenylalanyl phenylalanyl lysine (681mg, 0.94mmol), which was condensed with 2-aminomethylpyrimidine hydrochloride (150mg, 1.03mmol) to give intermediate compound (386mg, 0.47mmol), which was deprotected with 4mol/L HCl/EA (7ml) to give title compound 13b (305mg, 0.42mmol) as a white solid in 41% yield, Mp:218.3-218.8 ℃ [ α mmol ]]25 D＝-12.9(c＝0.1mg/100ml,DMF)；IR:3263.76,1694.08,1636.35,1612.70,1527.83,1215.97；
1HNMR(300MHz,DMSO-d6):11.30(1H,brs,O-H),8.87(1H,d,J＝8.1Hz,N-H),8.76(3H,m,CH,CH,CH),8.54(1H,d,J＝8.1Hz,N-H),8.43(1H,t,J＝5.7Hz,N-H),8.31(1H,d,J＝8.1Hz,N-H),7.95(3H,s,NH3 +),7.80(1H,d,J＝8.7Hz,Ar-H),7.41(1H,t,J＝4.8Hz,Ar-H),7.10-7.30(10H,m,Ar-H),6.90(1H,dd,J＝8.7,1.8Hz,Ar-H),6.84(1H,d,J＝1.5Hz,Ar-H),4.51(5H,m,CH,CH2),3.12(2H,m,CH2),2.82(4H,m,CH2),1.78(1H,m,CH),1.50(3H,m,CH2),1.42(2H,m,CH2)；
13CNMR(75MHz,DMSO-d6)171.9,171.4,170.6,167.0,164.4,161.4,161.3,157.8,156.8,148.5,138.2,137.4,132.5,129.8,129.7,128.5,126.8,126.7,120.4,115.0,113.3,111.4,102.3,54.4,54.2,52.9,45.2,38.4,37.9,31.9,27.1,22.6；
ESI-MS M/z 718 (M-1); HRMS calculated value (C)39H41N7O7-1), m/z (718.2984); found, m/z (718.2503).
EXAMPLE 177 preparation of Hydroxycoumarin-3-formylphenylalanyl phenylalanyl aspartyl bis-2-aminomethyl pyrimidine 13c
Following the procedure of example 14, bis-benzyl 7-hydroxycoumarin-3-formylphenylalanyl phenylalanyl aspartyl (450mg, 0.57mmol) was subjected to hydrogenolysis under the catalysis of Pd/C (5%) (45mg) to give 7-hydroxycoumarin-3-formylphenylalanyl phenylalanyl aspartyl (310mg, 0.50mmol), which was condensed with 2-aminomethylpyrimidine hydrochloride (80.1mg, 0.55mmol) to give the title compound 13C (115mg, 0.14mmol) as a pale yellow solid in 33% yield at 240.7-241.5 ℃ Mp [ α ]]25 D＝-5.97(c＝0.1mg/100ml,DMF)；IR:3269.18,1639.69,1562.77,1527.17,1423.07,1216.56；
1HNMR(300MHz,DMSO-d6):8.86(1H,d,J＝7.8Hz,N-H),8.74(5H,m,CH,CH,CH,CH,CH),8.52(2H,m,N-H),8.44(1H,d,J＝8.1Hz,N-H),7.79(1H,d,J＝8.4Hz,Ar-H),7.38(2H,m,CH,CH),7.10-7.27(10H,m,Ar-H),6.87(1H,dd,J＝8.4,2.1Hz,Ar-H),6.79(1H,d,J＝2.1,Ar-H),4.75(2H,m,CH),4.53(5H,m,CH,CH2),3.09(2H,m,CH2),2.81(3H,m,CH2),2.60(1H,m,CH2)；
13CNMR(75MHz,DMSO-d6)171.3,171.1,170.5,169.9,167.2,166.7,164.0,161.4,161.3,157.8,156.8,148.9,138.2,137.4,132.6,129.8,129.7,128.5,128.4,126.8,126.7,120.3,120.2,114.8,113.4,111.5,102.2,54.2,54.1,50.0,45.4,45.3,39.1,38.4,37.9；
ESI-MS M/z 796 (M-1); HRMS calculated value (C)42H39N9O8-1), m/z (796.2838); found, m/z (796.2346).
Experimental example 1 mouse ear xylene inflammation model experiment
The compounds of the invention are all prepared by distilled water containing 0.5 percent of CMC-Na, the administration dosage is 0.1 mu mol/kg, the administration mode is oral administration, aspirin (Beijing elite Yaobang medicine science and technology Co., Ltd.) is a positive control, the administration dosage is 1.11mmol/kg, and the administration mode is oral administration.
21 +/-3 g of ICR male mice (Beijing Wittidelawa laboratory animal technology Co., Ltd.) were selected and randomly divided into 20 groups, each group containing 12 mice, 20 groups were CMC-Na, aspirin, 9, 10a, 10b, 10c, 10d, 10e, 10f, 10g, 10h, 10i, 10j, 10k, 10l, 10m, 10n, 13a, 13b, and 13 c. After 30 minutes, grab one side of the mouse, expose the left ear, aspirate 30 μ l xylene with a pipette gun, and spread evenly along the inner auricle. After 2 hours, the ear is killed, the left ear and the right ear are cut off, and the two ears are smashed into round pieces with the same size by a smashing instrument. Weighing and calculating the difference value between two ears. Swelling degree (left ear weight-right ear weight), and anti-inflammatory inhibition rate (1-dichotomy/right ear weight)%.
TABLE 1 xylene-induced ear inflammation inhibitory Activity in mice
The tested compound was administered orally at 0.1 μmol/kg, aspirin at 1.1 mmol/kg; n is 12.
aP in comparison with the blank (CMC-Na)<0.01；
bP in comparison with the blank (CMC-Na)<0.05。
Experimental example 2 anti-inflammatory Activity of Compound 10j dose dependence
Animal test methods As in Experimental example 1, test compound 10j was administered at doses of 0.1. mu. mol/kg, 0.01. mu. mol/kg, and 0.001. mu. mol/kg, all in a single administration by gavage. The results are shown in Table 2.
TABLE 2 inhibition of ear swelling in mice at different doses of 10j
aAspirin ═ positive control, CMC-Na ═ blank group, n ═ 12;
bp in comparison with CMC-Na group<0.01; p compared to the 0.01. mu. mol/kg group<0.05；
cP in comparison with CMC-Na group<0.05。
Claims (5)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
AA is an amino acid residue selected from Gly, Val, Leu, Ile, Ser, Asp (OBzl), Glu (OBzl), Met, Thr, Trp, Ala, Phe, Tyr, Arg, and Lys;
n is 0 or 1;
R1、R3、R4、R5、R6、R7each independently selected from hydrogen; and
R2selected from hydroxyl groups.
2. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that it comprises the following steps:
1) condensing 2, 4-dihydroxy benzaldehyde with diethyl malonate under the catalysis of piperidine to generate 7-hydroxycoumarin-3-ethyl carboxylate;
2) in the presence of HCl, heating and refluxing 7-hydroxycoumarin-3-carboxylic acid ethyl ester in water to generate 7-hydroxycoumarin-3-carboxylic acid;
3) coupling 7-hydroxycoumarin-3-carboxylic acid with phenylalanyl phenylalanine-OBzl to obtain 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine benzyl ester;
4) carrying out hydrogenolysis on 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine benzyl ester under the catalysis of palladium carbon to generate 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine;
5) coupling tert-butoxy acyl amino acid and 2-aminomethyl pyrimidine to obtain tert-butoxy acyl-2-aminomethyl pyrimidine;
6) adding tert-butoxy acyl-2-aminomethyl pyrimidine into hydrogen chloride/ethyl acetate solution, removing tert-butoxy carbonyl group to obtain N-amino acyl-2-aminomethyl pyrimidine of general formula (III);
7) coupling N-aminoacyl-2-aminomethyl pyrimidine of general formula (III) with 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine of general formula (IV) to give 7-hydroxycoumarin-3-formylphenylalanyl phenylalanyl aminoacyl-2-aminomethyl pyrimidine of general formula (I);
8) coupling 7-hydroxycoumarin-3-formylphenylalanyl phenylalanine with L-amino acid benzyl ester to obtain 7-hydroxycoumarin-3-formylphenylalanyl phenylalanyl amino acid benzyl ester;
9) carrying out hydrogenolysis on 7-hydroxycoumarin-3-formylphenylalanyl phenylalanyl amino acid benzyl ester under the catalysis of palladium carbon to generate 7-hydroxycoumarin-3-formylphenylalanyl phenylalanyl amino acid with a general formula (V);
10) coupling the 7-hydroxycoumarin-3-formylphenylalanyl phenylalanyl aminoacid of the general formula (V) with the 2-aminomethyl pyrimidine of the general formula (VI) to obtain the 7-hydroxycoumarin-3-formylphenylalanyl phenylalanyl aminoacyl-2-aminomethyl pyrimidine of the general formula (I);
wherein AA is an amino acid residue selected from the group consisting of Gly, Val, Leu, Ile, Ser, Asp (OBzl), Glu (OBzl), Met, Thr, Trp, Ala, Phe, Tyr, Arg, and Lys;
n is 0 or 1;
R1、R3、R4、R5、R6、R7each independently selected from hydrogen;
and R2Selected from hydroxyl groups.
3. Use of a compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of an anti-inflammatory medicament.
4. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or adjuvant.
5. Use of a pharmaceutical composition according to claim 4 in the manufacture of an anti-inflammatory medicament.
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| Synthesis and biological evaluation of a novel class of coumarin derivatives;Hong Li等;《Bioorganic & Medicinal Chemistry Letters》;20140928;第24卷;5274-5278 * |
| 香豆素及其衍生物的合成与生物活性研究进展;包文艳等;《精细化工中间体》;20110228;第41卷(第1期);1-7 * |
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