4-substituted amino-6-methoxycarbonyl benzofuran[2,3-d] pyrimidine compound, and preparation method and application thereof

A technology of methoxycarbonylbenzene and pyrimidines, applied in the field of medicine and chemical industry, can solve the problems of no literature report on the synthesis method, harsh reaction conditions, long reaction time, etc., and achieves easy large-scale preparation, mild reaction conditions, and short reaction time. Effect

Active Publication Date: 2017-07-07
SUN YAT SEN UNIV +1
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Problems solved by technology

[0004] At present, the reported synthesis methods of benzofuropyrimidines mainly include the following: (1) Electrochemical oxidation of 3,4-dihydroxybenzoic acid and coupling of 1,3-dimethylbarbituric acid Decarboxylation reaction (J.Org.Chem., 2002, 67, 5036-5039), but this type of method requires special electrode materials, long reaction time, and narrow substrate applicability; (2) o-methoxyarylboronic acid compounds Suzuki coupling reaction with aminopyrimidines (WO2007 / 090852A1, [P] 2007-08-16), but this method requires expensive Pd metal complexes to catalyze, the reaction conditions are harsh, and the production cost is high; (3) base Catalyzes the coupling ring closure series reaction of o-cyanophenol and α-bromocarbonyl compound (Bioorg.Med.Chem.Lett., 2013,23,2775-2780), but the reaction reagents of this method are highly toxic and cause serious environmental pollution , and the synthetic route is longer
At present, compared with benzofuro[3,2-d]pyrimidines, there is no literature report on the synthesis method of benzofuro[2,3-d]pyrimidines, and there is no use of renewable resources for Starting materials, related reports on the preparation of 4-substituted amino-6-methoxycarbonylbenzofuro[2,3-d]pyrimidines by metal-free catalysis

Method used

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  • 4-substituted amino-6-methoxycarbonyl benzofuran[2,3-d] pyrimidine compound, and preparation method and application thereof
  • 4-substituted amino-6-methoxycarbonyl benzofuran[2,3-d] pyrimidine compound, and preparation method and application thereof
  • 4-substituted amino-6-methoxycarbonyl benzofuran[2,3-d] pyrimidine compound, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1: Preparation of 4-(p-toluidyl)-6-methoxycarbonylbenzofuro[2,3-d]pyrimidine

[0037]Add methyl 2-amino-3-cyanobenzofuran-5-carboxylate (0.22g, 1.0mmol), triethyl orthoformate (0.17ml, 1.0mmol), 8ml of toluene and a catalytic amount of glacial acetic acid into the flask , reflux at 60°C for 1 hour, concentrate and remove the solvent after the reaction is complete, add p-toluidine (0.16 g, 1.5 mmol) and 8 ml of glacial acetic acid to the solid obtained above, reflux at 120°C for 6 hours, and add 40 ml of In water, fully stirred and then filtered, the resulting solid was recrystallized from ethyl acetate and petroleum ether to obtain 0.193 g of a white solid, with a yield of 58.0%.

[0038] 1 H NMR (400MHz, DMSO‐d 6 )δ: 9.70(s,1H), 8.82(s,1H), 8.51(s,1H), 8.12(dd,J 1 =8.40Hz,J 2 =1.60Hz,1H),7.85(d,J=8.40Hz,1H),7.47(d,J=8.00Hz,2H),7.23(d,J=8.40Hz,2H),3.91(s,3H), 2.34(s,3H); 13 C NMR (100MHz, DMSO‐d 6 )δ: 169.1, 166.1, 156.3, 156.2, 154.2, 135.9, 134.0, 129.0...

Embodiment 2

[0039] Example 2: Preparation of 4-(p-toluidyl)-6-methoxycarbonylbenzofuro[2,3-d]pyrimidine

[0040] Add methyl 2-amino-3-cyanobenzofuran-5-carboxylate (0.22g, 1.0mmol), triethyl orthoformate (0.50ml, 3.0mmol), 8ml of toluene and a catalytic amount of glacial acetic acid into the flask , reflux at 60°C for 1 hour, concentrate and remove the solvent after the reaction is complete, add p-toluidine (0.16 g, 1.5 mmol) and 8 ml of glacial acetic acid to the solid obtained above, reflux at 120°C for 6 hours, and add 40 ml of In water, fully stirred and then filtered, the obtained solid was recrystallized with ethyl acetate and petroleum ether to obtain 0.216 g of white solid, with a yield of 65.0%.

[0041] The structural analysis data are the same as in Example 1.

Embodiment 3

[0042] Example 3: Preparation of 4-(p-toluidyl)-6-methoxycarbonylbenzofuro[2,3-d]pyrimidine

[0043] Add methyl 2-amino-3-cyanobenzofuran-5-carboxylate (0.22g, 1.0mmol), triethyl orthoformate (0.50ml, 3.0mmol), 8ml of toluene and a catalytic amount of glacial acetic acid into the flask , reflux at 110°C for 1 hour, concentrate and remove the solvent after the reaction is complete, add p-toluidine (0.16g, 1.5mmol) and 8ml of glacial acetic acid to the solid obtained above, reflux at 120°C for 6h, and add 40ml of In water, fully stirred and then filtered, the obtained solid was recrystallized with ethyl acetate and petroleum ether to obtain 0.247 g of white solid, with a yield of 74.1%.

[0044] The structural analysis data are the same as in Example 1.

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Abstract

The invention discloses a 4-substituted amino-6-methoxycarbonyl benzofuran[2,3-d] pyrimidine compound, and a preparation method and the application thereof. The method comprises the following steps: dissolving 2-amino-3-phenyl cyano benzofuran and ortho-formate in a solvent A; reacting in acid catalysis and heating conditions; concentrating to obtain an intermediate after reaction; performing backflow reaction on the intermediate and an amine compound in a solvent B to obtain a reaction product, and performing separation and purification on the reaction product to obtain a product. The compound provided by the invention can be used for preparing antikinase and anti-tumour and anti-vascular medicines. The compound has remarkable EGFR tyrosine kinase inhibitory activity, significant study value and good application prospect; the preparation method is wild in reaction condition, easy to operate, short in reaction time, high in yield, and low in cost and facilitates large-scale preparation.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a 4-substituted amino-6-methoxycarbonylbenzofuro[2,3-d]pyrimidine compound and its preparation and application. Background technique [0002] Benzofuropyrimidine derivatives are a class of fused heterocyclic compounds with good biological activity, for example: N-(3-bromophenyl)-benzofuro[3,2-d]pyrimidine (structural formula A) has Inhibitory activity of epidermal growth factor receptor tyrosine kinase (J.Med.Chem.1999, 42, 5464-5474); 4-Alkylamino-8-methylsulfonylbenzofuro[3,2-d]pyrimidine -2-amine (structural formula B) is a histamine H 4 Receptor modulator with antihistamine H 4 Mediated various immune and inflammatory reactions and other activities (EP2020412A1, [P] 2009-02-04); derivatives of benzofuro[3,2-d]pyrimidin-2-one (structural formula C) can inhibit HIV The expression of -1 reverse transcriptase has better anti-HIV-1 virus activity (Bioorg. Med. Chem...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/048A61K31/519A61P35/00
CPCC07D491/048
Inventor 邹永盛剑飞王德建位文涛张湘东潘文杰
Owner SUN YAT SEN UNIV
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