CN105461728A - 4-substituted amino-6-methoxycarbonyl group benzofuran and [2,3-d] pyrimidine compound and preparing method - Google Patents
4-substituted amino-6-methoxycarbonyl group benzofuran and [2,3-d] pyrimidine compound and preparing method Download PDFInfo
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- CN105461728A CN105461728A CN201511021894.3A CN201511021894A CN105461728A CN 105461728 A CN105461728 A CN 105461728A CN 201511021894 A CN201511021894 A CN 201511021894A CN 105461728 A CN105461728 A CN 105461728A
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- pyrimidines
- methoxycarbonyl benzo
- cumarone
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- 238000000034 method Methods 0.000 title claims abstract description 13
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 title abstract description 13
- -1 pyrimidine compound Chemical class 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 97
- 238000002360 preparation method Methods 0.000 claims abstract description 57
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims abstract description 11
- 230000035484 reaction time Effects 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 238000007171 acid catalysis Methods 0.000 claims abstract description 3
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 3
- 238000010438 heat treatment Methods 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 152
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 111
- 229960000583 acetic acid Drugs 0.000 claims description 72
- 239000012362 glacial acetic acid Substances 0.000 claims description 72
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 45
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 45
- 238000001953 recrystallisation Methods 0.000 claims description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 38
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical group CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 35
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 150000003230 pyrimidines Chemical class 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 4
- BQFCCCIRTOLPEF-UHFFFAOYSA-N chembl1976978 Chemical compound CC1=CC=CC=C1N=NC1=C(O)C=CC2=CC=CC=C12 BQFCCCIRTOLPEF-UHFFFAOYSA-N 0.000 claims description 4
- 239000003377 acid catalyst Substances 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 150000002790 naphthalenes Chemical class 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 2
- MEJYDZQQVZJMPP-ULAWRXDQSA-N (3s,3ar,6r,6ar)-3,6-dimethoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan Chemical compound CO[C@H]1CO[C@@H]2[C@H](OC)CO[C@@H]21 MEJYDZQQVZJMPP-ULAWRXDQSA-N 0.000 claims 1
- 230000004071 biological effect Effects 0.000 abstract description 3
- PUUNSXIOEYECST-UHFFFAOYSA-N methyl 2-amino-3-cyano-1-benzofuran-5-carboxylate Chemical compound NC=1OC2=C(C=1C#N)C=C(C=C2)C(=O)OC PUUNSXIOEYECST-UHFFFAOYSA-N 0.000 abstract 1
- 239000000047 product Substances 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- 238000010992 reflux Methods 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 111
- 239000007787 solid Substances 0.000 description 100
- 230000003197 catalytic effect Effects 0.000 description 36
- 238000003756 stirring Methods 0.000 description 36
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 34
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- 238000012916 structural analysis Methods 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
- 239000013078 crystal Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 239000002994 raw material Substances 0.000 description 3
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 229960005081 diclofenamide Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229910052755 nonmetal Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- JXOHGGNKMLTUBP-HSUXUTPPSA-N shikimic acid Chemical compound O[C@@H]1CC(C(O)=O)=C[C@@H](O)[C@H]1O JXOHGGNKMLTUBP-HSUXUTPPSA-N 0.000 description 2
- JXOHGGNKMLTUBP-JKUQZMGJSA-N shikimic acid Natural products O[C@@H]1CC(C(O)=O)=C[C@H](O)[C@@H]1O JXOHGGNKMLTUBP-JKUQZMGJSA-N 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- VVSASNKOFCZVES-UHFFFAOYSA-N 1,3-dimethyl-1,3-diazinane-2,4,6-trione Chemical compound CN1C(=O)CC(=O)N(C)C1=O VVSASNKOFCZVES-UHFFFAOYSA-N 0.000 description 1
- RUFPHBVGCFYCNW-UHFFFAOYSA-N 1-naphthylamine Chemical compound C1=CC=C2C(N)=CC=CC2=C1 RUFPHBVGCFYCNW-UHFFFAOYSA-N 0.000 description 1
- CHZCERSEMVWNHL-UHFFFAOYSA-N 2-hydroxybenzonitrile Chemical group OC1=CC=CC=C1C#N CHZCERSEMVWNHL-UHFFFAOYSA-N 0.000 description 1
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 1
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 1
- BLNVISNJTIRAHF-UHFFFAOYSA-N 4-chlorobenzamide Chemical compound NC(=O)C1=CC=C(Cl)C=C1 BLNVISNJTIRAHF-UHFFFAOYSA-N 0.000 description 1
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 1
- 239000002028 Biomass Substances 0.000 description 1
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 238000005815 base catalysis Methods 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 150000001907 coumarones Chemical class 0.000 description 1
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 1
- 239000007772 electrode material Substances 0.000 description 1
- 238000006056 electrooxidation reaction Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- QEZIFBAXJMHDJP-UHFFFAOYSA-N n-chloro-4-fluoroaniline Chemical compound FC1=CC=C(NCl)C=C1 QEZIFBAXJMHDJP-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229940030010 trimethoxybenzene Drugs 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a 4-substituted mino-6-methoxycarbonyl group benzofuran and [2,3-d] pyrimidine compound and a preparing method thereof. 2-amino-3-cyano benzofuran-5-carboxylic acid methyl ester and ortho-formate are dissolved into a solvent A, a reaction is conducted under the acid catalysis and heating conditions, and concentration is carried out after the reaction is finished to obtain an intermediate; then, the intermediate and an amine compound are subjected to a reflux reaction in a solvent B, a reaction product is subjected to separation and purification treatment, and a product is obtained. The compound has potential biological activity, important research value and good application prospects. The preparing method is mild in reaction condition, easy to implement, short in reaction time, high in yield and low in cost, and mass preparation can be easily achieved.
Description
Technical field
The present invention relates to field of medicine and chemical technology, particularly a kind of 4-substituted amido-6-methoxycarbonyl benzo furo [2,3-d] pyrimidines and preparation method.
Background technology
Cumarone miazines derivative is the fused heterocyclic compound that a class has good biological activity, such as: N-(3-bromophenyl)-cumarone also [3,2-d] pyrimidine (structural formula A) has the inhibit activities (J.Med.Chem.1999 of epidermal growth factor recipient tyrosine kinase, 42,5464-5474); 4-alkylamino-8-methylsulfonyl cumarone also [3,2-d] pyrimidine-2-amine (structural formula B) is a kind of histamine H
4receptor modulators, has antihistamine H
4the panimmunity of mediation and inflammatory reaction isoreactivity (EP2020412A1, [P] 2009-02-04); Cumarone also [3,2-d] derivative (structural formula C) of pyrimid-2-one can suppress the expression of HIV1-RT, there is the activity (Bioorg.Med.Chem.Lett.2013,23,2775-2780) of good anti-HIV-1 virus.In addition, containing cumarone and the compound of pyrimidine structure parent nucleus also have anti-inflammatory, sterilization, antiplatelet condensation, hypoglycemic isoreactivity.Because itself and quinazoline compounds structural similitude, and to human body small molecular protein kinases, there is certain restraining effect, there is potential antitumour activity, so cumarone miazines compound now one of study hotspot having become antineoplastic target medicine.Because polysubstituted benzofurans miazines compound has potential application prospect, the cumarone miazines derivative therefore synthesizing various functionalization is the valuable problem of tool.
At present, the synthetic method of the cumarone miazines compound reported mainly contains following several: (1) electrochemical oxidation 3,4-resorcylic acid and 1,3-dimethyl barbituric acid generation coupling decarboxylic reaction (J.Org.Chem., 2002,67,5036-5039), but these class methods need special electrode materials, long reaction time, substrate applicability narrow; (2) the Suzuki linked reaction (WO2007/090852A1 of O-methoxy arylboronic acid compound and amino-metadiazine compound, [P] 2007-08-16), but the method needs expensive Pd metal complex catalyzed, severe reaction conditions, and production cost is high; (3) the adjacent cyanophenol of base catalysis and alpha-brominated carbonyl compound generation coupling cyclization cascade reaction (Bioorg.Med.Chem.Lett., 2013,23,2775-2780), but the reaction reagent toxicity of the method is large, environmental pollution is serious, and synthetic route is longer.At present, relative to cumarone also [3,2-d] pyrimidines, relevant cumarone also [2,3-d] synthetic method of pyrimidines has no bibliographical information, also the relevant report utilizing renewable resources to be starting raw material, adopt nonmetal catalyzed preparation 4-substituted amido-6-methoxycarbonyl benzo furo [2,3-d] pyrimidines is had no.
Summary of the invention
The object of the invention is to overcome the shortcoming existed in prior art, 4-substituted amido-6-methoxycarbonyl benzo furo [2, the 3-d] pyrimidines providing a kind of environmental friendliness, cost low, easy to operate.
Another object of the present invention is to the preparation method that a kind of above-mentioned 4-substituted amido-6-methoxycarbonyl benzo furo [2,3-d] pyrimidines is provided.
Object of the present invention is achieved through the following technical solutions:
A kind of 4-substituted amido-6-methoxycarbonyl benzo furo [2,3-d] pyrimidines, has following general structure:
Wherein, substituent R is aryl or alkyl; Aryl includes but not limited to: single or polysubstituted phenyl ring, naphthalene nucleus and aromatic heterocycle; Alkyl includes but not limited to straight chained alkyl, branched-chain alkyl and substituted alkyl.
The preparation method of above-mentioned 4-substituted amido-6-methoxycarbonyl benzo furo [2,3-d] pyrimidines, comprises the steps:
(1) 2-Amino 3 cyano cumarone-5-carboxylate methyl ester and ortho-formiate are dissolved in solvent orange 2 A, react under acid catalysis and heating condition, after completion of the reaction, concentrate to obtain intermediate; Above-mentioned ortho-formiate is triethyl orthoformate or trimethyl orthoformate;
(2) described intermediate and aminated compounds are carried out back flow reaction in solvent B, reaction product, through separating-purifying process, obtains 4-substituted amido-6-methoxycarbonyl benzo furo [2,3-d] pyrimidines.
Described 2-Amino 3 cyano cumarone-5-carboxylate methyl ester is for raw material prepares (concrete preparation method see: SCI, 2015,36 (2), 267-273) with renewable biomass resource shikimic acid.
Described solvent orange 2 A and solvent B are: C
2h
5oH, CH
3cN, CHCl
3, CH
2cl
2, toluene, glacial acetic acid (AcOH)), tetrahydrofuran (THF) (THF), dimethyl sulfoxide (DMSO) (DMSO), dimethyl formamide (DMF) or Isosorbide-5-Nitrae-dioxane; Preferred solvent A is toluene, and solvent B is glacial acetic acid.
In step (1), described acid catalyst is HCl, H
2sO
4, AcOH or H
3pO
4; Preferred AcOH.
Reaction described in step (1), temperature of reaction is 60 ~ 140 DEG C, and the reaction times is 1 ~ 10 hour; Preferable reaction temperature is 110 DEG C, and the preferred reaction time is 5 hours.
Reaction described in step (2), temperature of reaction is 60 ~ 140 DEG C, and the reaction times is 1 ~ 10 hour; Preferable reaction temperature 120 DEG C, selects the reaction times to be 6 hours.
The mol ratio of described 2-Amino 3 cyano cumarone-5-carboxylate methyl ester and ortho-formiate is 1:(1.0 ~ 6.0); Preferred molar ratio is 1:3; The mol ratio of 2-Amino 3 cyano cumarone-5-carboxylate methyl ester and aminated compounds is 1:(1.0 ~ 3.0), preferred molar ratio is 1:1.5.
In step (2), described separating-purifying process is after the completion of reaction, is added to the water by reaction mixture, successively after filtration, dry and recrystallization process.
The preparation process of the compounds of this invention is: under acid catalysed conditions, 2-Amino 3 cyano cumarone-5-carboxylate methyl ester and ortho-formiate are obtained by reacting intermediate in a solvent, there is ring-closure reaction in organic solvent in this intermediate and aminated compounds, thus obtain 4-substituted amido-6-methoxycarbonyl benzo furo [2,3-d] pyrimidines, synthetic route is as follows:
The present invention compared with prior art tool has the following advantages and effect:
(1) 4-substituted amido-6-methoxycarbonyl benzo furo [2,3-d] pyrimidines is the cumarone miazines compound that a class is novel, there is not been reported, has potential biological activity and important researching value and good application prospect;
(2) preparation method of the present invention provide a kind of completely newly, the method for nonmetal catalyzed preparation 4-substituted amido-6-methoxycarbonyl benzo furo [2,3-d] pyrimidines;
(3) the compounds of this invention prepares critical materials 2-Amino 3 cyano cumarone-5-carboxylate methyl ester used is be that raw material prepares by renewable natural resource shikimic acid, therefore the Sustainable Exploitation of 4-aryl amine-6-methoxycarbonyl benzo furo [2,3-d] pyrimidines can be realized;
(4) preparation method's reaction conditions of the present invention is gentle, simple to operate, the reaction times is short, yield is high, cost is low, is easy to realize mass-producing preparation.
Embodiment
Below in conjunction with embodiment, further detailed description is done to the present invention, but embodiments of the present invention are not limited thereto.
The preparation of embodiment 1:4-(para-totuidine base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.17ml, 1.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 1h under 60 DEG C of conditions, react complete concentrated except desolventizing, para-totuidine (0.16g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and sherwood oil recrystallization, obtain white solid 0.193g, yield 58.0%.
1HNMR(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)；
13CNMR(100MHz,DMSO‐d
6)δ:169.1,166.1,156.3,156.2,154.2,135.9,134.0,129.0,128.3,125.7,124.4,124.3,120.8,111.5,97.0.52.2,20.6；HRMS(ESI‐TOF)m/zcalcdforC
19H
15N
3NaO
3[M+Na]
+356.1006,found356.1007.
The preparation of embodiment 2:4-(para-totuidine base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.50ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 1h under 60 DEG C of conditions, react complete concentrated except desolventizing, para-totuidine (0.16g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and sherwood oil recrystallization, obtain white solid 0.216g, yield 65.0%.
Structural analysis data consistent with Example 1.
The preparation of embodiment 3:4-(para-totuidine base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.50ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 1h under 110 DEG C of conditions, react complete concentrated except desolventizing, para-totuidine (0.16g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and sherwood oil recrystallization, obtain white solid 0.247g, yield 74.1%.
Structural analysis data consistent with Example 1.
The preparation of embodiment 4:4-(para-totuidine base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.50ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, para-totuidine (0.16g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and sherwood oil recrystallization, obtain white solid 0.291g, yield 87.3%.
Structural analysis data consistent with Example 1.
The preparation of embodiment 5:4-(para-totuidine base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.50ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 140 DEG C of conditions, react complete concentrated except desolventizing, para-totuidine (0.16g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and sherwood oil recrystallization, obtain white solid 0.286g, yield 86.0%.
Structural analysis data consistent with Example 1.
The preparation of embodiment 6:4-(para-totuidine base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (1.0ml, 6.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, para-totuidine (0.16g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and sherwood oil recrystallization, obtain white solid 0.285g, yield 85.7%.
Structural analysis data consistent with Example 1.
The preparation of embodiment 7:4-(para-totuidine base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), trimethyl orthoformate (0.33ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 10h under 110 DEG C of conditions, react complete concentrated except desolventizing, para-totuidine (0.16g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and sherwood oil recrystallization, obtain white solid 0.283g, yield 84.9%.
Structural analysis data consistent with Example 1.
The preparation of embodiment 8:4-(para-totuidine base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.50ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, para-totuidine (0.32g is added in above-mentioned gained solid, 3.0mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and sherwood oil recrystallization, obtain white solid 0.276g, yield 83.0%.
Structural analysis data consistent with Example 1.
The preparation of embodiment 9:4-(para-totuidine base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.50ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, para-totuidine (0.11g is added in above-mentioned gained solid, 1.0mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and sherwood oil recrystallization, obtain white solid 0.254g, yield 76.3%.
Structural analysis data consistent with Example 1.
The preparation of embodiment 10:4-(para-totuidine base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.50ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, para-totuidine (0.16g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 60 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and sherwood oil recrystallization, obtain white solid 0.220g, yield 66.0%.
Structural analysis data consistent with Example 1.
The preparation of embodiment 11:4-(para-totuidine base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.50ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, para-totuidine (0.16g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 140 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and sherwood oil recrystallization, obtain white solid 0.286g, yield 85.8%.
Structural analysis data consistent with Example 1.
The preparation of embodiment 12:4-(para-totuidine base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.50ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, para-totuidine (0.16g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 1h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and sherwood oil recrystallization, obtain white solid 0.175g, yield 52.6%.
Structural analysis data consistent with Example 1.
The preparation of embodiment 13:4-(para-totuidine base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.50ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, para-totuidine (0.16g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 10h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and sherwood oil recrystallization, obtain white solid 0.275g, yield 82.7%.
Structural analysis data consistent with Example 1.
The preparation of embodiment 14:4-(para-totuidine base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), trimethyl orthoformate (0.33ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, para-totuidine (0.16g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and sherwood oil recrystallization, obtain white solid 0.259g, yield 77.7%.
Structural analysis data consistent with Example 1.
The preparation of embodiment 15:4-(P-nethoxyaniline base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.5ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, P-nethoxyaniline (0.18g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and sherwood oil (or ethyl acetate and normal hexane) recrystallization, obtain white crystal 0.308g, yield 88.3%.
1HNMR(400MHz,DMSO-d
6)δ:9.67(s,1H),8.76(s,1H),8.48(s,1H),8.12(dd,J
1＝8.80Hz,J
2＝1.20Hz,1H),7.85(d,J＝8.80Hz,1H),7.46(d,J＝8.80Hz,2H),7.00(d,J＝8.80Hz,2H),3.91(s,3H),3.80(s,3H)；
13CNMR(100MHz,DMSO-d
6)δ:169.0,166.0,156.7,156.5,156.1,154.1,131.1,128.1,126.2,125.6,124.3,120.8,113.7,111.5,96.6,55.2,52.1；HRMS(ESI-TOF)m/zcalcdforC
19H
15N
3NaO
4[M+Na]
+372.0955,found372.0956。
The preparation of embodiment 16:4-(P-nethoxyaniline base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), trimethyl orthoformate (0.33ml, 3.0mmol), 8mlN, the glacial acetic acid of dinethylformamide (DMF) and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, P-nethoxyaniline (0.18g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and sherwood oil recrystallization, obtain white crystal 0.256g, yield 73.4%.
Structural analysis data consistent with Example 15.
The preparation of embodiment 17:4-(P-nethoxyaniline base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.5ml, 3.0mmol), 8ml1, the glacial acetic acid of 4-epoxy six alkane and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, P-nethoxyaniline (0.18g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and sherwood oil recrystallization, obtain white crystal 0.269g, yield 77.1%.
Structural analysis data consistent with Example 15.
The preparation of embodiment 18:4-(P-nethoxyaniline base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.5ml, 3.0mmol), the hydrochloric acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, P-nethoxyaniline (0.18g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and sherwood oil recrystallization, obtain white crystal 0.201g, yield 57.6%.
Structural analysis data consistent with Example 15.
The preparation of embodiment 19:4-(P-nethoxyaniline base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.5ml, 3.0mmol), the hydrochloric acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, P-nethoxyaniline (0.18g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and sherwood oil recrystallization, obtain white crystal 0.200g, yield 57.4%.
Structural analysis data consistent with Example 15.
The preparation of embodiment 20:4-(P-nethoxyaniline base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.5ml, 3.0mmol), the sulfuric acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, P-nethoxyaniline (0.18g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and sherwood oil recrystallization, obtain white crystal 0.208g, yield 59.6%.
Structural analysis data consistent with Example 15.
The preparation of embodiment 21:4-(p-nitrophenyl amido)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.5ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, p-Nitroaniline (0.21g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and sherwood oil recrystallization, obtain yellow crystals 0.313g, yield 86.0%.
1HNMR(400MHz,DMSO-d
6)δ:10.22(s,1H),9.03(d,J＝1.20Hz,1H),8.73(s,1H),8.30(d,J＝9.20Hz,2H),8.19(dd,J
1＝8.80Hz,J
2＝1.60Hz,1H),8.03(d,J＝9.20Hz,2H),7.92(d,J＝8.40Hz,1H),3.93(s,3H)；
13CNMR(100MHz,DMSO-d
6)δ:169.2,165.9,155.9,154.9,154.6,145.5,142.3,129.0,125.7,124.9,124.4,121.6,120.1,111.9,99.3,52.3；HRMS(ESI-TOF)m/zcalcdforC
18H
12N
4NaO
5[M+Na]
+387.0700,found387.0699。
The preparation of embodiment 22:4-(p-Chlorobenzoic acid amide base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.5ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, p-Chlorobenzoic acid amide (0.19g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and normal hexane recrystallization, obtain white solid 0.231g, yield 65.5%.
1HNMR(400MHz,DMSO-d
6)δ:9.81(s,1H),8.97(s,1H),8.57(s,1H),8.16(dd,J
1＝8.80Hz,J
2＝1.60Hz,1H),7.89(d,J＝8.80Hz,1H),7.68(d,J＝8.80Hz,2H),7.47(t,J＝6.80Hz,2H),3.93(s,3H)；
13CNMR(100MHz,DMSO-d
6)δ:169.1,166.1,156.1,155.8,154.4,137.6,128.5,128.4,128.3,125.8,125.4,124.5,120.6,111.7,97.6,52.3；HRMS(ESI-TOF)m/zcalcdforC
18H
12ClN
3NaO
3[M+Na]
+376.0459,found376.0457。
The preparation of embodiment 23:4-(m-chloro aniline base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.5ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, m-chloro aniline (0.19g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and normal hexane recrystallization, obtain white solid 0.250g, yield 70.8%.
1HNMR(400MHz,CDCl
3)δ8.68(s,1H),8.26(s,1H),8.20(d,J＝8.7Hz,1H),7.80(s,1H),7.67(d,J＝8.6Hz,1H),7.52(d,J＝8.1Hz,1H),7.36(s,1H),7.33(d,J＝8.1Hz,1H),7.19(d,J＝8.0Hz,1H),3.96(s,3H).
13CNMR(100MHz,CDCl
3)δ169.6,166.5,156.5,155.9,155.2,139.0,134.9,130.1,129.1,126.4,125.1,123.0,122.3,120.5,120.2,112.0,98.3,52.5.
The preparation of embodiment 24:4-(Ortho-Chloro aniline base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.5ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, Ortho-Chloro aniline (0.19g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and normal hexane recrystallization, obtain white solid 0.20g, yield 67.9%.
1HNMR(400MHz,DMSO-d6)δ9.86(s,1H),8.88(s,1H),8.47(s,1H),8.15(dd,J＝8.7,1.7Hz,1H),7.89(d,J＝8.7Hz,1H),7.62(ddd,J＝16.5,7.8,1.6Hz,2H),7.43(dtd,J＝22.9,7.5,1.6Hz,2H),3.92(s,3H).
13CNMR(100MHz,DMSO-d6)δ169.6,166.5,157.1,156.8,154.8,136.2,131.9,130.3,129.0,128.7,128.3,126.4,124.6,121.2,112.3,97.4,52.7.
The preparation of embodiment 25:4-(2 ', 5 '-dichlorphenamide bulk powder)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.5ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, 2 are added in above-mentioned gained solid, 5-dichlorphenamide bulk powder (0.24g, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and normal hexane recrystallization, obtain white solid 0.308g, yield 79.5%.
1HNMR(400MHz,DMSO)δ9.89(s,1H),8.93(s,1H),8.52(s,1H),8.17(dd,J＝8.7,1.6Hz,1H),7.90(d,J＝8.7Hz,1H),7.76(d,J＝2.5Hz,1H),7.67(d,J＝8.6Hz,1H),7.48(dd,J＝8.6,2.5Hz,1H),3.93(s,3H).
13CNMR(100MHz,DMSO-d
6)δ169.6,166.4,156.7,156.7,154.9,137.6,132.2,131.5,130.4,129.4,129.1,128.2,126.4,124.5,121.0,112.3,97.8,52.8
The preparation of embodiment 26:4-(para-bromoaniline base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.5ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, para-bromoaniline (0.26g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and normal hexane recrystallization, obtain white crystal 0.319g, yield 80.1%.
1HNMR(400MHz,DMSO-d
6)δ:9.76(s,1H),8.95(s,1H),8.56(s,1H),8.13(dd,J
1＝8.80Hz,J
2＝1.60Hz,1H),7.86(d,J＝8.4Hz,1H),7.61(m,4H),3.93(s,3H)；
13CNMR(100MHz,DMSO-d
6)δ:169.1,166.0,156.0,155.6,154.3,138.0,131.3,128.5,125.7,125.6,124.5,120.5,116.3,111.7,97.7,52.3；HRMS(ESI-TOF)m/zcalcdforC
18H
12BrN
3NaO
3[M+Na]
+419.9954,found419.9951。
The preparation of embodiment 27:4-(paraiodoaniline base)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.5ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, paraiodoaniline (0.33g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and normal hexane recrystallization, obtain light gray solid 0.376g, yield 84.4%.
1HNMR(400MHz,DMSO-d
6)δ:9.69(s,1H),8.90(s,1H),8.53(s,1H),8.09(dd,J
1＝8.80Hz,J
2＝1.60Hz,1H),7.81(d,J＝8.40Hz,1H),7.73(d,J＝8.80Hz,2H),7.48(d,J＝8.80Hz,2H),3.91(s,3H)；
13CNMR(100MHz,DMSO-d
6)δ:169.0,166.0,156.0,155.5,154.3,138.5,137.1,128.5,125.7,125.6,124.4,120.5,111.6,97.7,88.3,52.3；HRMS(ESI-TOF)m/zcalcdforC
18H
12IN
3NaO
3[M+Na]
+467.9816,found467.9816。
The preparation of embodiment 28:4-anilino-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.5ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, in above-mentioned gained solid, add aniline (0.14g, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filters, gained solid with ethyl acetate and normal hexane recrystallization after fully stirring, obtain white solid 0.20g, yield 75.3%.
1HNMR(400MHz,CDCl
3)δ8.67(s,1H),8.21(dd,J＝8.6,1.6Hz,1H),8.04(s,1H),7.68(d,J＝8.7Hz,1H),7.62(d,J＝7.5Hz,2H),7.46(t,J＝7.9Hz,2H),7.29(d,J＝7.4Hz,2H),3.96(s,3H).
13CNMR(100MHz,CDCl
3)δ169.7,166.5,156.6,156.4,155.2,137.6,129.3,128.9,126.2,125.5,123.2,122.9,120.7,111.9,98.0,52.4.
The preparation of embodiment 29:4-(3 '-chloro-4 '-fluoroanilino)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.5ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, the chloro-4-fluoroaniline of 3-(0.22g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and normal hexane recrystallization, obtain white solid 0.303g, yield 81.6%.
1HNMR(400MHz,DMSO-d6)δ9.81(s,1H),8.99(s,1H),8.63(s,1H),8.20(dd,J＝8.6,1.6Hz,1H),7.95(dd,J＝6.8,2.6Hz,1H),7.92(d,J＝8.6Hz,1H),7.71(ddd,J＝8.9,4.3,2.7Hz,1H),7.52(t,J＝9.1Hz,1H),3.98(s,3H).
13CNMR(100MHz,DMSO-d6)δ169.5,166.5,156.5,156.0,154.8,154.5(d,J＝243.9Hz),136.3(d,J＝3.0Hz),129.0,126.2,125.9,124.7(d,J＝7.6Hz),120.9,119.3(d,J＝18.5Hz),117.0(d,J＝21.8Hz),112.1,98.0,52.7.
The preparation of embodiment 30:4-naphthylamine base-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.5ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, naphthalidine (0.21g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and normal hexane recrystallization, obtain white solid 0.353g, yield 95.7%.
1HNMR(400MHz,DMSO-d6)δ10.15(s,1H),8.60(s,1H),8.38(s,1H),8.11(d,J＝8.4Hz,1H),8.06(d,J＝8.0Hz,1H),7.98(d,J＝7.9Hz,2H),7.86(d,J＝8.6Hz,1H),7.65–7.47(m,4H),3.86(s,3H).
13CNMR(100MHz,DMSO-d6)δ169.7,166.5,158.3,156.8,154.7,135.1,134.5,130.8,128.7,127.6,126.8,126.7,126.2,125.3,124.8,124.1,121.4,112.0,97.2,52.6.
The preparation of embodiment 31:4-(3 ', 4 ', 5 ' ,-trimethoxy-benzene amido)-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.5ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, 3 are added in above-mentioned gained solid, 4, 5-trimethoxy-aniline (0.27g, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and normal hexane recrystallization, obtain white solid 0.354g, yield 86.6%.
1HNMR(400MHz,DMSO-d6)δ9.73(s,1H),8.68(s,1H),8.55(s,1H),8.13(dd,J＝8.6,1.7Hz,1H),7.86(dd,J＝8.6,3.8Hz,1H),6.92(s,2H),3.90(s,3H),3.75(s,6H),3.70(s,3H).
13CNMR(100MHz,DMSO-d6)δ169.7,166.5,156.8,156.6,154.7,153.2,135.5,134.8,128.7,126.1,125.0,121.2,112.0,102.9,97.7,60.6,56.5,52.7.
The preparation of embodiment 32:4-ethylamino--6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.5ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, in above-mentioned gained solid, add ethamine (0.07g, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filters, gained solid with ethyl acetate and normal hexane recrystallization after fully stirring, obtain white solid 0.193g, yield 71.1%.
1HNMR(400MHz,DMSO-d6)δ9.02(s,1H),8.47(s,1H),8.10(d,J＝7.4Hz,2H),7.81(d,J＝8.6Hz,1H),3.94(s,3H),3.73–3.60(m,2H),1.26(t,J＝7.1Hz,3H).
13CNMR(100MHz,DMSO-d6)δ169.1,166.6,157.7,157.0,154.4,128.2,126.2,123.6,121.7,111.9,96.1,52.7,36.0,15.3.
The preparation of embodiment 31:4-n-butylamine-based-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.5ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, n-Butyl Amine 99 (0.11g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and normal hexane recrystallization, obtain white solid 0.159g, yield 53.3%.
1HNMR(400MHz,CDCl
3)δ9.04(d,J＝1.5Hz,1H),8.46(s,1H),8.15–8.01(m,2H),7.81(d,J＝8.6Hz,1H),3.94(s,3H),3.63(dd,J＝13.7,6.7Hz,2H),1.73–1.58(m,2H),1.46–1.32(m,2H),0.95(t,J＝7.4Hz,3H).
13CNMR(100MHz,DMSO-d6)δ169.1,166.7,157.9,157.1,154.4,128.3,126.3,123.7,121.8,112.0,96.1,52.8,31.7,20.2,14.3.
The preparation of embodiment 33:4-isobutyl amine-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.5ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, isobutylamine (0.11g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and normal hexane recrystallization, obtain white solid 0.192g, yield 64.3%.
1HNMR(400MHz,DMSO-d6)δ9.07(d,J＝1.3Hz,1H),8.46(s,1H),8.10(dd,J＝8.6,1.4Hz,2H),7.81(d,J＝8.6Hz,1H),3.94(s,3H),3.46(t,J＝6.5Hz,2H),2.10(dp,J＝13.6,6.8Hz,1H),0.95(d,J＝6.7Hz,6H).
13CNMR(100MHz,DMSO-d6)δ169.1,166.7,158.0,157.0,154.4,128.2,126.2,123.7,121.7,111.9,96.0,52.7,48.5,28.3,20.6.
The preparation of embodiment 34:4-cyclohexylamino-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.5ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, hexahydroaniline (0.15g is added in above-mentioned gained solid, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filter after abundant stirring, gained solid with ethyl acetate and normal hexane recrystallization, obtain white solid 0.299g, yield 91.9%.
1HNMR(400MHz,DMSO-d6)δ9.06(s,1H),8.46(s,1H),8.09(dd,J＝8.6,0.5Hz,1H),7.80(d,J＝8.6Hz,1H),7.67(d,J＝8.0Hz,1H),4.31(ddd,J＝11.4,9.6,6.0Hz,1H),3.94(s,3H),1.96(d,J＝10.5Hz,2H),1.81(d,J＝13.0Hz,2H),1.68(d,J＝12.5Hz,1H),1.59(qd,J＝12.5,3.1Hz,2H),1.37(q,J＝12.9Hz,2H),1.25–1.13(m,1H).
13CNMR(100MHz,DMSO-d6)δ169.2,166.7,157.2,157.0,154.4,128.3,126.1,124.1,121.7,111.9,96.1,52.8,50.4,32.5,25.8,25.7.
The preparation of embodiment 35:4-Bian amido-6-methoxycarbonyl benzo furo [2,3-d] pyrimidine
By 2-Amino 3 cyano cumarone-5-carboxylate methyl ester (0.22g, 1.0mmol), triethyl orthoformate (0.5ml, 3.0mmol), the glacial acetic acid of 8ml toluene and catalytic amount adds in flask, back flow reaction 5h under 110 DEG C of conditions, react complete concentrated except desolventizing, in above-mentioned gained solid, add benzylamine (0.16g, 1.5mmol) and 8ml glacial acetic acid, back flow reaction 6h at 120 DEG C, reacting complete adds in 40ml water, filters, gained solid with ethyl acetate and normal hexane recrystallization after fully stirring, obtain white solid 0.272g, yield 81.8%.
1HNMR(400MHz,DMSO-d6)δ9.11(s,1H),8.64(t,J＝5.8Hz,1H),8.46(s,1H),8.12(dt,J＝8.6,1.9Hz,1H),7.84(dd,J＝8.6,2.6Hz,1H),7.40(d,J＝7.2Hz,2H),7.33(t,J＝7.5Hz,2H),7.24(t,J＝7.2Hz,1H),4.89(d,J＝6.0Hz,2H),3.93(s,3H).
13CNMR(100MHz,DMSO-d6)δ169.2,166.6,157.8,157.1,154.5,140.1,128.8,128.4,127.5,127.2,126.3,123.8,121.6,112.0,96.3,52.7,44.2.
Claims (10)
1. 4-substituted amido-6-methoxycarbonyl benzo furo [2, a 3-d] pyrimidines, is characterized in that having following general structure:
Wherein, substituent R is aryl or alkyl; Aryl includes but not limited to: single or polysubstituted phenyl ring, naphthalene nucleus and aromatic heterocycle; Alkyl includes but not limited to straight chained alkyl, branched-chain alkyl and substituted alkyl.
2. the preparation method of 4-substituted amido-6-methoxycarbonyl benzo furo [2, a 3-d] pyrimidines according to claim 1, is characterized in that comprising the steps:
(1) 2-Amino 3 cyano cumarone-5-carboxylate methyl ester and ortho-formiate are dissolved in solvent orange 2 A, react under acid catalysis and heating condition, after completion of the reaction, concentrate to obtain intermediate;
(2) described intermediate and aminated compounds are carried out back flow reaction in solvent B, reaction product, through separating-purifying process, obtains 4-substituted amido-6-methoxycarbonyl benzo furo [2,3-d] pyrimidines.
3. the preparation method of 4-substituted amido-6-methoxycarbonyl benzo furo [2,3-d] pyrimidines according to claim 2, is characterized in that: described ortho-formiate is triethyl orthoformate or trimethyl orthoformate.
4. the preparation method of 4-substituted amido-6-methoxycarbonyl benzo furo [2,3-d] pyrimidines according to claim 2, is characterized in that: described solvent orange 2 A and solvent B are: C
2h
5oH, CH
3cN, CHCl
3, CH
2cl
2, toluene, glacial acetic acid, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dimethyl formamide or Isosorbide-5-Nitrae-dioxane.
5. the preparation method of 4-substituted amido-6-methoxycarbonyl benzo furo [2,3-d] pyrimidines according to claim 2, it is characterized in that: in step (1), described acid catalyst is HCl, H
2sO
4, AcOH or H
3pO
4.
6. 4-substituted amido-6-methoxycarbonyl benzo furo [2 according to claim 2,3-d] preparation method of pyrimidines, it is characterized in that: the reaction described in step (1), temperature of reaction is 60 ~ 140 DEG C, and the reaction times is 1 ~ 10 hour.
7. 4-substituted amido-6-methoxycarbonyl benzo furo [2 according to claim 2,3-d] preparation method of pyrimidines, it is characterized in that: the reaction described in step (2), temperature of reaction is 60 ~ 140 DEG C, and the reaction times is 1 ~ 10 hour.
8. 4-substituted amido-6-methoxycarbonyl benzo furo [2 according to claim 2,3-d] preparation method of pyrimidines, it is characterized in that: the mol ratio of described 2-Amino 3 cyano cumarone-5-carboxylate methyl ester and ortho-formiate is 1:(1.0 ~ 6.0).
9. 4-substituted amido-6-methoxycarbonyl benzo furo [2 according to claim 2,3-d] preparation method of pyrimidines, it is characterized in that: the mol ratio of 2-Amino 3 cyano cumarone-5-carboxylate methyl ester and aminated compounds is 1:(1.0 ~ 3.0).
10. 4-substituted amido-6-methoxycarbonyl benzo furo [2 according to claim 2,3-d] preparation method of pyrimidines, it is characterized in that: in step (2), described separating-purifying process is after the completion of reaction, reaction mixture is added to the water, successively after filtration, dry and recrystallization process.
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