CN117756736A - 2-oxazolidone-3-formamidine-5-methylene derivative and preparation method thereof - Google Patents
2-oxazolidone-3-formamidine-5-methylene derivative and preparation method thereof Download PDFInfo
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- formamidine
- oxazolidinone
- methylene derivative
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- oxazolidone
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- 238000002360 preparation method Methods 0.000 title claims abstract description 64
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- 239000002994 raw material Substances 0.000 claims description 41
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 32
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 23
- 239000003960 organic solvent Substances 0.000 claims description 22
- 239000013067 intermediate product Substances 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 20
- 239000003054 catalyst Substances 0.000 claims description 17
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 claims description 17
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- 239000011630 iodine Substances 0.000 claims description 16
- 229910052740 iodine Inorganic materials 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 15
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims description 15
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 12
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical group CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 4
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 101710134784 Agnoprotein Proteins 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- HHBCEKAWSILOOP-UHFFFAOYSA-N 1,3-dibromo-1,3,5-triazinane-2,4,6-trione Chemical compound BrN1C(=O)NC(=O)N(Br)C1=O HHBCEKAWSILOOP-UHFFFAOYSA-N 0.000 claims description 2
- RDZHCKRAHUPIFK-UHFFFAOYSA-N 1,3-diiodo-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(I)C(=O)N(I)C1=O RDZHCKRAHUPIFK-UHFFFAOYSA-N 0.000 claims description 2
- UUIVKBHZENILKB-UHFFFAOYSA-N 2,2-dibromo-2-cyanoacetamide Chemical compound NC(=O)C(Br)(Br)C#N UUIVKBHZENILKB-UHFFFAOYSA-N 0.000 claims description 2
- USXXIRQDHZXYHX-UHFFFAOYSA-N 2,3,4-tribromopyridine Chemical compound BrC1=CC=NC(Br)=C1Br USXXIRQDHZXYHX-UHFFFAOYSA-N 0.000 claims description 2
- XQKQROJYWLWDMP-UHFFFAOYSA-N 2-iodo-1,1-dioxo-1,2-benzothiazol-3-one Chemical compound C1=CC=C2S(=O)(=O)N(I)C(=O)C2=C1 XQKQROJYWLWDMP-UHFFFAOYSA-N 0.000 claims description 2
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims description 2
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 claims description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 239000003242 anti bacterial agent Substances 0.000 abstract description 2
- 229940088710 antibiotic agent Drugs 0.000 abstract description 2
- 230000004071 biological effect Effects 0.000 abstract description 2
- 238000001212 derivatisation Methods 0.000 abstract description 2
- 238000011160 research Methods 0.000 abstract description 2
- 238000012216 screening Methods 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 38
- 238000012512 characterization method Methods 0.000 description 34
- 238000004009 13C{1H}-NMR spectroscopy Methods 0.000 description 32
- 238000002955 isolation Methods 0.000 description 19
- 230000000052 comparative effect Effects 0.000 description 17
- 239000000047 product Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 101150003085 Pdcl gene Proteins 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- -1 2-oxazolidinone compound Chemical class 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- 102000012011 Isocitrate Dehydrogenase Human genes 0.000 description 2
- 108010075869 Isocitrate Dehydrogenase Proteins 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- RBZRMBCLZMEYEH-UHFFFAOYSA-N 1h-pyrazol-1-ium-1-carboximidamide;chloride Chemical compound Cl.NC(=N)N1C=CC=N1 RBZRMBCLZMEYEH-UHFFFAOYSA-N 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical group NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 description 1
- 229940093265 berberine Drugs 0.000 description 1
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
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- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229960003907 linezolid Drugs 0.000 description 1
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- RAMTXCRMKBFPRG-UHFFFAOYSA-N prop-2-ynyl carbonochloridate Chemical compound ClC(=O)OCC#C RAMTXCRMKBFPRG-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 229960003879 tedizolid Drugs 0.000 description 1
- XFALPSLJIHVRKE-GFCCVEGCSA-N tedizolid Chemical compound CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](CO)C2)=O)F)=N1 XFALPSLJIHVRKE-GFCCVEGCSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention relates to a 2-oxazolidone-3-formamidine-5-methylene derivative and a preparation method thereof, belonging to the technical field of organic synthesis. The structure of the 2-oxazolidone-3-formamidine-5-methylene derivative provided by the invention is shown in the formulas (I) - (III). The 2-oxazolidone-3-formamidine-5-methylene derivative provided by the invention can be applied to synthesis and activity screening of novel oxazolidone antibiotics, can provide technical support for further derivatization and biological activity research of 2-oxazolidone-3-formamidine derivative compounds, and has a wide application prospect.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a 2-oxazolidone-3-formamidine-5-methylene derivative and a preparation method thereof.
Background
2-oxazolidinone is a compound with an N, O-five membered ring structure, which is also a chemical intermediate for the synthesis of other drug molecules such as berberine and carmustine, in addition to being an important antibiotic (such as linezolid and tedizolid) and chiral ligand. 2-oxazolidinone-3-formamidine compounds are compounds in which the 3-position of the 2-oxazolidinone structure is replaced by formamidine groups, and the activity and preparation of the compounds are less studied at present.
Patent US20200206233 studies have found that 2-oxazolidinone-3-carboxamidine compounds are useful as inhibitors of mutant isocitrate dehydrogenase (mutant isocitrate dehydrogenase, mt-IDH). According to the patent, the compound is mainly formed by condensing a 2-oxazolidinone compound and a halogenide compound, and the reaction formula is as follows:
although the method is favorable for the modification of the 3-formamidine locus, the chemical modification of the 2-oxazolidone of the core parent nucleus structure is difficult, and the application of the 2-oxazolidone-3-formamidine compound is limited.
Disclosure of Invention
The invention aims to overcome the problems in the prior art and provide a 2-oxazolidone-3-formamidine-5-methylene derivative and a preparation method thereof.
The invention is realized by the following technical scheme:
the invention provides a 2-oxazolidone-3-formamidine-5-methylene derivative, wherein the structure of the 2-oxazolidone-3-formamidine-5-methylene derivative is shown as the formulas (I) - (III):
wherein R is H, alkyl, aryl, halogen or ether.
Preferably, the 2-oxazolidinone-3-formamidine-5-methylene derivative is one of the following structures:
another object of the present invention is to provide a process for preparing the 2-oxazolidinone-3-formamidine-5-methylene derivative, comprising the steps of:
(1) Dissolving the raw materials 1 and 2 in an organic solvent A, stirring, adding N, N-diisopropylethylamine, and continuing stirring to obtain an intermediate product;
(2) Dissolving the intermediate product obtained in the step (1) and a catalyst silver salt in an organic solvent B, and stirring for reaction to obtain a 2-oxazolidone-3-formamidine-5-methylene derivative shown in the formula (1);
or dissolving the intermediate product obtained in the step (1), an iodine source and a catalyst in an organic solvent C, and stirring for reaction to obtain the 2-oxazolidone-3-formamidine-5-methylene derivative shown in the formula (2); when the iodine source comprises an iodine simple substance, the catalyst is tert-butyl hydroperoxide, and when the iodine source does not comprise an iodine simple substance, the catalyst is silver salt;
or, dissolving the intermediate product obtained in the step (1), a bromine source and a catalyst silver salt in an organic solvent D, and stirring for reaction to obtain a 2-oxazolidone-3-formamidine-5-methylene derivative shown in the formula (3);
the structure of the raw material 1 is shown as a formula (1), the structure of the raw material 2 is shown as a formula (2), and the structure of the intermediate product is shown as a formula (3):
according to the preparation method, the propargyloxycarbonyl substituted guanidyl compound is taken as a starting material, and under the action of the catalytic amount of the silver salt serving as a catalyst, the 2-oxazolidone-3-formamidine-5-methylene compound can be rapidly generated; further adding a bromine source to obtain a brominated derivative thereof; the iodinated derivative can be obtained by using an iodine source and tert-butyl hydroperoxide (TBHP) or silver salt as the reaction reagents. The preparation method provided by the invention has the advantages that the raw materials are simple and easy to obtain, the reaction is simple, efficient and quick, and the preparation method has a wide application prospect.
Preferably, the organic solvent a comprises at least one of dichloromethane, chloroform, methanol, ethanol, dimethyl sulfoxide, acetone, ethyl acetate, N-dimethylformamide, and tetrahydrofuran.
Preferably, in the step (1), the stirring time is 2-4 h; the stirring time is 0.5h-1.5h.
Preferably, in the step (1), the molar ratio of the raw material 1 and the raw material 2 to the N, N-diisopropylethylamine is 1: (1-2): (3-4).
Preferably, after the reaction in the step (1) is finished, the reaction solution is diluted with dichloromethane, washed with water, the organic phase is dried by brine and anhydrous sodium sulfate, filtered, and the filtrate is distilled under reduced pressure and separated by silica gel column chromatography (the eluent is petroleum ether: ethyl acetate= (1-3): 1) to obtain an intermediate product.
Preferably, in the step (2), the silver salt includes AgOTf, agNO 3 、AgSbF 6 、AgBF 4 、AgCO 2 CF 3 At least one of them.
More preferably, in the step (2), the silver salt is AgOTf.
Preferably, the organic solvent B includes at least one of acetonitrile, dichloromethane, chloroform, dimethyl sulfoxide, methanol, and acetone.
More preferably, the organic solvent B is acetonitrile.
Preferably, the iodine source comprises at least one of elemental iodine, iodine bis (pyridine) tetrafluoroborate, N-iodosuccinimide, iodine chloride, 1, 3-diiodo-5, 5-dimethylhydantoin, N-iodosaccharin.
Preferably, the organic solvent C includes at least one of dichloromethane, acetonitrile, acetone, and tetrahydrofuran.
More preferably, the organic solvent C is dichloromethane.
Preferably, the bromine source comprises at least one of N-bromosuccinimide, tribromopyridine, dibromohydantoin, N-bromoacetamide, phosphorus tribromide, carbon tetrabromide, 5-dibromomeldonic acid, dibromocyanoacetamide, and dibromoisocyanuric acid.
Preferably, the organic solvent D includes at least one of acetone, acetonitrile, dimethylformamide.
More preferably, the organic solvent D is acetone.
Preferably, in the step (2), the stirring reaction time is 40min-120min.
The reaction according to the invention can be carried out at room temperature, preferably at a temperature of 20℃to 37 ℃.
Preferably, in the step (2), when preparing the 2-oxazolidinone-3-formamidine-5-methylene derivative shown in the formula (1), the molar ratio of the intermediate product to the catalyst silver salt is 1: (0.05-0.2).
Preferably, in the step (2), when preparing the 2-oxazolidinone-3-formamidine-5-methylene derivative represented by the formula (2), the molar ratio of the intermediate product to the iodine source and the catalyst is 1: (1-2): (1-2).
Preferably, in the step (2), when preparing the 2-oxazolidinone-3-formamidine-5-methylene derivative shown in the formula (3), the molar ratio of the intermediate product to the N-bromosuccinimide and the catalyst silver salt is 1: (1-1.5): (0.05-0.2).
Preferably, after the reaction in the step (2) is finished, the reaction solution is decompressed and concentrated, and the obtained concentrate is separated by silica gel column chromatography (the polarity range of the eluent is petroleum ether and ethyl acetate= (2-8): 1) to obtain the 2-oxazolidone-3-formamidine-5-methylene derivative shown in the formula (1);
or, after the reaction, diluting the reaction solution with methylene chloride, washing with water, and adding Na to the obtained organic phase 2 S 2 O 3 Quenching of elemental I 2 Then the organic phase is washed by brine, dried by anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure and then separated by silica gel column chromatography (the eluent is petroleum ether, ethyl acetate= (10-13): 1) to obtain the 2-oxazolidone-3-formamidine-5-methylene derivative shown in the formula (2);
or, after the reaction, the reaction solution is diluted with dichloromethane, washed with water, the organic phase is washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure and then separated by silica gel column chromatography (the polarity range of the eluent is petroleum ether: ethyl acetate= (10-15): 1), thereby obtaining the 2-oxazolidinone-3-formamidine-5-methylene derivative shown in the formula (3).
The invention has the following beneficial effects:
(1) The 2-oxazolidone-3-formamidine-5-methylene derivative obtained by the invention can be applied to synthesis and activity screening of novel oxazolidone antibiotics, and meanwhile, through preliminary experimental tests, the 2-oxazolidone-3-formamidine-5-methylene derivative has certain inhibition activity on CT-26 cells, and has better application prospect.
(2) The preparation method provided by the invention has the advantages that the raw materials used are simple and easy to obtain, the reaction is simple, efficient and quick, the technical support can be provided for further derivatization and biological activity research of the 2-oxazolidinone-3-formamidine derivative compounds, and the preparation method has a wide application prospect.
Detailed Description
For a better description of the objects, technical solutions and advantages of the present invention, the present invention will be further described with reference to the following specific examples. It will be appreciated by persons skilled in the art that the specific embodiments described herein are for purposes of illustration only and are not intended to be limiting.
The test methods used in the examples are conventional methods unless otherwise specified; the materials, reagents and the like used, unless otherwise specified, are all commercially available.
Raw material 2 of the present invention can be obtained by a literature preparation method (Tian, m.; yan, m.; baran, p.s.11-Step total synthesis of araiosamines.j.am.chem.soc.2016,138, 14234-14237.). The synthetic routes of the raw material 2 described in examples and comparative examples are shown below, and the preparation method includes the following steps:
(1) 1H-pyrazole-1-carboxamidine hydrochloride (132 mg,0.9 mmol) was dissolved in CH 2 Cl 2 (5 mL) and DMF (10 mL), stirring in an ice bath, then adding N, N-diisopropylethylamine (DIPEA, 297. Mu.L, 1.8 mmol) and propargyl chloroformate (160 mg,1.36 mmol) to the solution, stirring the obtained mixture in an ice bath for 2 hours, spinning the reaction solution dry after the reaction, diluting with water, extracting with dichloromethane twice, washing the organic phase with brine, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain an intermediate compound (white solid, 126mg,0.66mmol, 72.8%); the characterization data are as follows: 1 H NMR(400MHz,CDCl 3 )δ9.01(br,1H),8.46(d,J＝2.4Hz,1H),7.71(s,2H),6.44(s,1H),4.77(d,J＝2.4Hz,2H),2.49(t,J＝2.4Hz,1H)； 13 C NMR(101MHz,CDCl 3 )δ163.19,155.65,143.93,129.01,109.48,78.19,74.73,53.20；HRMS:(ESI)[M+H] + calc.for C 8 H 9 N 4 O 2 + ,193.07200,observed 193.07162.
(2) The intermediate compound (40 mg,0.2 mmol) obtained was dissolved in CH 2 Cl 2 To (12 mL) of the mixture was stirred in an ice bath, and then trifluoroacetic anhydride (62.70 mg,0.3 mmol) was added thereto, and the obtained mixture was stirred at room temperature for 2 hours, and after the completion of the reaction, the reaction mixture was washed with water, brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give raw material 2. The characterization data are as follows: 1 H NMR(400MHz,CDCl 3 )δ8.29(d,J＝2.8Hz,1H),7.75(d,J＝1.2Hz,1H),6.57(m,1H),4.86(d,J＝2.8Hz,2H),2.59(t,J＝2.4Hz,1H).
example 1
This example provides a process for the preparation of 2-oxazolidinone-3-formamidine-5-methylene derivatives comprising the steps of:
(1) Raw material 1a (1.0-fold equivalent) and raw material 2 (1.5-fold equivalent) were dissolved in Dichloromethane (DCM), stirred at room temperature for 3 hours, then N, N-diisopropylethylamine (DIPEA, 3.0-fold equivalent) was added, stirred at room temperature for 1 hour, after the reaction was completed, the reaction solution was diluted with dichloromethane, washed with water, the organic phase was dried over brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=1:1) to obtain intermediate 3a, the characterization data of which were as follows: 1 H NMR(400MHz,CDCl 3 )δ7.41(m,2H),7.29(m,3H),4.45(d,J＝2.4Hz,2H),2.33(t,J＝2.4Hz,1H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ162.9,160.9,136.2,129.8,127.0,126.2,79.1,73.6,51.7；HRMS(ESI)m/z:[M+H] + Calcd for C 11 H 12 N 3 O 2 218.0924; found 218.0928 the synthetic route is as follows:
(2) Dissolving the intermediate product 3a (1.0 equivalent) and AgOTf (0.1 equivalent) obtained in the step (1) in acetonitrile, stirring the mixture at room temperature for 1 hour, concentrating the reaction solution under reduced pressure after the reaction is finished, and separating the obtained concentrate by adopting silica gel column chromatography (the polarity range of the eluent is petroleum ether: ethyl acetate=2:1) to obtainThis example 2-oxazolidinone-3-formamidine-5-methylene derivative 4a; the nuclear magnetic yield is 99%; the characterization data are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.35(m,2H),7.07(m,1H),6.94(m,2H),6.09(q,J＝2.4Hz,1H),5.85(br,2H),4.95(t,J＝2.4Hz,2H),4.66(q,J＝2.0Hz,1H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ156.3,146.9,145.2,135.7,129.7,123.4,121.8,93.4,67.3；HRMS(ESI)m/z:[M+H] + Calcd for C 11 H 12 N 3 O 2 218.0924; found 218.0918 the synthetic route is as follows:
example 2
The preparation method of the 2-oxazolidone-3-formamidine-5-methylene derivative provided in this example is different from that of example 1 in that the same amount of raw material 1b is used to replace raw material 1a, and the other preparation methods are the same as those of example 1, so as to obtain intermediate 3b and 2-oxazolidone-3-formamidine-5-methylene derivative 4b of this example; 1b, 3b, 4b are as follows:
characterization data for intermediate 3b are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.43(dd,J＝7.6,4.0Hz,1H),7.32(m,2H),7.24(m,1H),7.17(m,1H),7.11(t,J＝7.2Hz,1H),6.98(m,3H),4.55(d,J＝2.4Hz,2H),2.37(t,J＝2.4Hz,1H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ162.7,160.3,156.4,151.4,129.8,128.0,127.6,127.4,124.2,123.8,119.7,118.6,79.0,73.7,51.9；HRMS(ESI)m/z:[M+H] + Calcd for C 17 H 16 N 3 O 3 310.1186；found 310.1191.
characterization data for this example 2-oxazolidinone-3-formamidine-5-methylene derivative 4b is as follows: 1 H NMR(400MHz,CDCl 3 )δ7.24(m,2H),7.16(m,1H),7.08(m,2H),7.03(d,J＝7.2Hz,1H),6.99(m,1H),6.89(m,2H),5.90(br,2H),5.56(q,J＝2.4Hz,1H),4.82(t,J＝2.4Hz,2H),4.36(q,J＝2.0Hz,1H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ158.0,156.1,147.3,144.8,138.7,135.1,129.5,125.4,124.6,123.8,122.3,121.9,117.0,93.4,67.2；HRMS(ESI)m/z:[M+H] + Calcd for C 17 H 16 N 3 O 3 310.1186; found 310.1189 isolation yield was 99%.
Example 3
The preparation method of the 2-oxazolidone-3-formamidine-5-methylene derivative provided in this example is different from that of example 1 in that the same amount of raw material 1c is used instead of raw material 1a, and the other preparation methods are the same as those of example 1, so as to obtain intermediate 3c and 2-oxazolidone-3-formamidine-5-methylene derivative 4c of this example; 1c, 3c, 4c are as follows:
characterization data for intermediate 3c are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.21(m,2H),6.93(m,2H),4.49(d,J＝2.4Hz,2H),3.82(s,3H),2.35(t,J＝2.4Hz,1H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ163.0,161.5,158.8,128.3,128.1,115.0,79.2,73.5,55.5,51.8；HRMS(ESI)m/z:[M+H] + Calcd for C 12 H 14 N 3 O 3 248.1030；found 248.1026.
characterization data for this example 2-oxazolidinone-3-formamidine-5-methylene derivative 4c is as follows: 1 H NMR(400MHz,CDCl 3 )δ6.88(m,4H),6.07(q,J＝2.4Hz,1H),5.84(br,2H),4.94(t,J＝2.4Hz,2H),4.64(q,J＝2.0Hz,1H),3.79(s,3H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ156.3,155.8,145.6,139.9,135.8,122.6,115.0,93.2,67.3,55.5；HRMS(ESI)m/z:[M+H] + Calcd for C 12 H 14 N 3 O 3 248.1030; found 248.1033 isolation yield was 78%.
Example 4
The preparation method of the 2-oxazolidone-3-formamidine-5-methylene derivative provided in this example is different from that of example 1 in that the same amount of raw material 1d is used to replace raw material 1a, and the other preparation methods are the same as those of example 1, so as to obtain intermediate 3d and the 2-oxazolidone-3-formamidine-5-methylene derivative 4d of this example; 1d, 3d, 4d are as follows:
characterization data for intermediate 3d are as follows: 1 H NMR(400MHz,d 6 -DMSO)δ9.02(br,1H),7.88(d,J＝7.6Hz,1H),7.38(m,2H),6.97(m,1H),4.56(d,J＝2.4Hz,2H),3.42(t,J＝2.4Hz,1H)； 13 C{ 1 H}NMR(101MHz,d 6 -DMSO)δ161.8,158.7,141.0,139.3,129.4,128.1,127.8,97.8,80.2,77.1,52.1；HRMS(ESI)m/z:[M+H] + Calcd for C 11 H 11 IN 3 O 2 343.9890；found 343.9880.
characterization data for this example 2-oxazolidinone-3-formamidine-5-methylene derivative 4d is as follows: 1 H NMR(400MHz,CDCl 3 )δ7.86(dd,J＝8.0,1.6Hz,1H),7.32(m,1H),6.94(dd,J＝8.0,1.6Hz,1H),6.79(m,1H),6.37(q,J＝2.0Hz,1H),5.90(br,2H),4.96(t,J＝2.4Hz,2H),4.70(q,J＝1.6Hz,1H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ156.3,148.7,145.4,139.7,135.2,129.6,125.0,121.7,94.8,93.1,67.4；HRMS(ESI)m/z:[M+H] + Calcd for C 11 H 11 IN 3 O 2 343.9890; found 343.9886 isolation yield was 85%.
Example 5
The preparation method of the 2-oxazolidone-3-formamidine-5-methylene derivative provided in this example is different from that of example 1 in that the same amount of raw material 1e is used for replacing raw material 1a, and the other preparation methods are the same as those of example 1, so as to obtain intermediate 3e and 2-oxazolidone-3-formamidine-5-methylene derivative 4e of this example; 1e, 3e, 4e are as follows:
characterization data for intermediate 3e are as follows: 1 H NMR(400MHz,d 6 -DMSO)δ8.91(br,1H),7.65(dd,J＝8.0,1.6Hz,1H),7.57(d,J＝8.0Hz,1H),7.36(m,1H),7.11(m,1H),4.57(d,J＝2.4Hz,2H),3.43(t,J＝2.4Hz,1H)； 13 C{ 1 H}NMR(101MHz,d 6 -DMSO)δ161.9,159.0,137.4,133.1,128.6,128.2,127.1,119.1,80.2,77.1,52.1；HRMS(ESI)m/z:[M+H] + Calcd for C 11 H 11 BrN 3 O 2 296.0029；found 296.0023.
characterization data for this example 2-oxazolidinone-3-formamidine-5-methylene derivative 4e are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.63(dd,J＝8.0,1.6Hz,1H),7.30(m,1H),6.97(m,2H),6.30(q,J＝2.4Hz,1H),5.89(br,2H),4.99(t,J＝2.4Hz,2H),4.72(q,J＝2.0Hz,1H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ156.2,145.4,145.2,135.3,133.5,128.7,124.7,122.9,116.9,94.3,67.4；HRMS(ESI)m/z:[M+H] + Calcd for C 11 H 11 BrN 3 O 2 296.0029; found296.0023 isolation yield was 91%.
Example 6
The preparation method of the 2-oxazolidone-3-formamidine-5-methylene derivative provided in this example is different from that of example 1 in that the same amount of raw material 1f is used to replace raw material 1a, and the other preparation methods are the same as those of example 1, so as to obtain intermediate 3f and 2-oxazolidone-3-formamidine-5-methylene derivative 4f of this example; 1f, 3f, 4f are as follows:
characterization data for intermediate 3f are as follows: 1 H NMR(400MHz,d 6 -DMSO)δ9.07(br,1H),7.44(m,2H),7.15(m,2H),4.58(d,J＝2.4Hz,2H),3.42(t,J＝2.4Hz,1H)； 13 C{ 1 H}NMR(101MHz,d 6 -DMSO)δ162.8,160.1,158.9(d,J＝241.1Hz),135.0(d,J＝2.9Hz),124.4(d,J＝8.4Hz),115.8(d,J＝22.6Hz),80.4,77.0,52.1； 19 F NMR(376MHz,d 6 -DMSO)δ-119.31(s,1F)；HRMS(ESI)m/z:[M+H] + Calcd for C 11 H 11 FN 3 O 2 236.0830；found236.0825.
characterization data for this example 2-oxazolidinone-3-formamidine-5-methylene derivative 4f are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.04(m,2H),6.89(m,2H),6.06(q,J＝2.4Hz,1H),5.87(br,2H),4.95(t,J＝2.4Hz,2H),4.66(q,J＝2.0Hz,1H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ160.4,157.1(d,J＝180.8Hz),145.7,142.8(d,J＝2.9Hz),135.7,122.9(d,J＝8.0Hz),116.4(d,J＝22.6Hz),93.5,67.3； 19 F NMR(376MHz,CDCl 3 )δ-120.63(s,1F)；HRMS(ESI)m/z:[M+H] + Calcd for C 11 H 11 FN 3 O 2 236.0830; found 236.0825 isolation yield was 76%.
Example 7
The preparation method of the 2-oxazolidone-3-formamidine-5-methylene derivative provided in this example is different from that of example 1 in that 1g of the same amount of raw material is used to replace 1a, and the other preparation methods are the same as those of example 1, so as to obtain 3g of intermediate product and 4g of 2-oxazolidone-3-formamidine-5-methylene derivative of this example; the structures of 1g, 3g and 4g are as follows:
characterization data for intermediate 3g are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.45(m,2H),7.24(m,2H),4.51(d,J＝2.4Hz,2H),2.36(t,J＝2.4Hz,1H),1.35(s,9H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ163.0,161.1,150.2,133.2,126.7,125.7,79.2,73.5,51.7,34.6,31.3；HRMS(ESI)m/z:[M+H] + Calcd for C 15 H 20 N 3 O 2 274.1550；found 274.1548.
characterization data for 4g of the present example 2-oxazolidinone-3-formamidine-5-methylene derivative are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.37(m,2H),6.88(m,2H),6.09(q,J＝2.4Hz,1H),5.86(br,2H),4.94(t,J＝2.4Hz,2H),4.64(q,J＝2.0Hz,1H),1.32(s,9H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ156.3,146.2,145.2,144.1,135.8,126.5,121.2,93.3,67.3,34.3,31.5；HRMS(ESI)m/z:[M+H] + Calcd for C 15 H 20 N 3 O 2 274.1550; found 274.1546 isolation yield was 80%.
Example 8
The preparation method of the 2-oxazolidone-3-formamidine-5-methylene derivative provided in this example is different from that of example 1 in that the same amount of raw material 1h is used to replace raw material 1a, and the other preparation methods are the same as those of example 1, so as to obtain intermediate 3h and 2-oxazolidone-3-formamidine-5-methylene derivative 4c of this example; the structures of 1h, 3h and 4h are as follows:
characterization data for intermediate 3h are as follows: 1 H NMR(400MHz,d 6 -DMSO)δ9.17(br,1H),6.70(s,2H),4.60(d,J＝2.4Hz,2H),3.76(s,6H),3.64(s,3H),3.40(t,J＝2.4Hz,1H)； 13 C{ 1 H}NMR(101MHz,d 6 -DMSO)δ162.8,160.1,153.3,134.7,134.2,100.9,80.5,76.9,60.5,56.3,52.2；HRMS(ESI)m/z:[M+H] + Calcd for C 14 H 18 N 3 O 5 308.1241；found308.1249.
characterization data for this example 2-oxazolidinone-3-formamidine-5-methylene derivative 4h are as follows: 1 H NMR(400MHz,CDCl 3 )δ6.17(s,2H),6.07(q,J＝2.4Hz,1H),5.94(br,2H),4.94(t,J＝2.4Hz,2H),4.66(q,J＝2.0Hz,1H),3.82(s,6H),3.81(s,3H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ156.2,154.1,145.7,143.0,135.7,133.9,99.1,93.5,67.3,61.0,56.1；HRMS(ESI)m/z:[M+H] + Calcd for C 14 H 18 N 3 O 5 308.1241; found 308.1236 isolation yield was 90%.
Example 9
The preparation method of the 2-oxazolidone-3-formamidine-5-methylene derivative provided in this example is different from that of example 1 in that the same amount of raw material 1i is used for replacing raw material 1a, and the other preparation methods are the same as those of example 1, so as to obtain intermediate 3i and 2-oxazolidone-3-formamidine-5-methylene derivative 4c of this example; 1i, 3i, 4i are as follows:
characterization data for intermediate 3i are as follows: 1 H NMR(400MHz,d 6 -DMSO)δ9.42(br,1H),7.77(s,2H),4.64(d,J＝2.4Hz,2H),3.47(t,J＝2.4Hz,1H)； 13 C{ 1 H}NMR(101MHz,d 6 -DMSO)δ162.0,158.6,140.6,133.0,123.3,121.4,80.1,77.4,52.4；HRMS(ESI)m/z:[M+H] + Calcd for C 11 H 9 Cl 3 N 3 O 2 319.9755；found 319.9752.
characterization data for this example 2-oxazolidinone-3-formamidine-5-methylene derivative 4i are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.00(s,2H),6.01(br,3H),4.95(t,J＝2.4Hz,2H),4.67(q,J＝2.0Hz,1H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ156.1,146.4,146.0,135.2,134.8,125.6,122.5,94.3,67.3；HRMS(ESI)m/z:[M+H] + Calcd for C 11 H 9 Cl 3 N 3 O 2 319.9755; found319.9724 isolation yield was 69%.
Example 10
The preparation method of the 2-oxazolidone-3-formamidine-5-methylene derivative provided in this example is different from that of example 1 in that the same amount of raw material 1j is used to replace raw material 1a, and the other preparation methods are the same as those of example 1, so as to obtain intermediate 3j and 2-oxazolidone-3-formamidine-5-methylene derivative 4j of this example; 1j, 3j, 4j are as follows:
characterization data for intermediate 3j are as follows: 1 H NMR(400MHz,d 6 -DMSO)δ8.94(br,1H),7.46(s,1H),7.36(d,J＝8.0Hz,1H),7.00(dd,J＝8.0,2.0Hz,1H),4.58(d,J＝2.4Hz,2H),3.43(t,J＝2.4Hz,1H),2.29(s,3H)； 13 C{ 1 H}NMR(101MHz,d 6 -DMSO)δ162.0,159.4,137.6,135.4,129.5,128.2,127.4,125.0,80.3,77.1,52.2,20.4；HRMS(ESI)m/z:[M+H] + Calcd for C 12 H 13 ClN 3 O 2 266.0691；found 266.0687.
characterization data for this example 2-oxazolidinone-3-formamidine-5-methylene derivative 4j are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.29(d,J＝8.0Hz,1H),6.81(m,2H),6.21(q,J＝2.4Hz,1H),5.84(br,2H),4.96(t,J＝2.4Hz,2H),4.68(q,J＝2.0Hz,1H),2.30(s,3H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ156.2,145.0,143.5,138.0,135.4,130.0,125.3,123.6,122.9,94.0,67.4,20.9；HRMS(ESI)m/z:[M+H] + Calcd for C 12 H 13 ClN 3 O 2 266.0691; found266.0689 isolation yield was 91%.
Example 11
This example provides a process for the preparation of 2-oxazolidinone-3-formamidine-5-methylene derivatives comprising the steps of:
(1) As in example 1;
(2) The intermediate 3a (1.0 equivalent) obtained in the step (1) and the simple substance I 2 (1.5-fold equivalent) and t-butyl hydroperoxide (TBHP, 1.5-fold equivalent) were dissolved in Dichloromethane (DCM), stirred at room temperature for 1 hour, and after the completion of the reaction, the reaction solution was diluted with dichloromethane, washed with water, and Na was added to the resulting organic phase 2 S 2 O 3 Quenching of elemental I 2 Then the organic phase is washed by brine, dried by anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure and then separated by silica gel column chromatography (the eluent is petroleum ether: ethyl acetate=10:1) to obtain the 2-oxazolidone-3-formamidine-5-methylene derivative 5a of the present example; the separation yield is 85%; the characterization data are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.40(t,J＝2.4Hz,1H),7.36(m,2H),7.09(t,J＝7.6Hz,1H),6.92(dd,J＝8.4,1.2Hz,2H),5.91(br,2H),4.86(d,J＝2.8Hz,2H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ156.5,146.3,145.2,134.6,129.8,123.7,121.8,71.7,60.7；HRMS(ESI)m/z:[M+H] + Calcd for C 11 H 11 IN 3 O 2 343.9890; found 343.9878 the synthetic route is as follows:
example 12
The preparation method of 2-oxazolidinone-3-formamidine-5-methylene derivative provided in this example is different from example 11 in that intermediate 3f is used instead of raw material intermediate 3a to prepare 2-oxazolidinone-3-formamidine-5-methylene derivative 5b of this example; 5b are structured as follows:
characterization data for this example 2-oxazolidinone-3-formamidine-5-methylene derivative 5b is as follows: 1 H NMR(400MHz,CDCl 3 )δ7.38(t,J＝2.8Hz,1H),7.05(m,2H),6.87(m,2H),5.92(br,2H),4.86(d,J＝2.8Hz,2H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ160.5,157.3(d,J＝171.4Hz),145.7,142.2(d,J＝2.6Hz),134.5,123.0(d,J＝7.7Hz),116.5(d,J＝22.3Hz),71.7,60.7； 19 F NMR(376MHz,CDCl 3 )δ-120.13(s,1F)；HRMS(ESI)m/z:[M+H] + Calcd for C 11 H 10 FIN 3 O 2 361.9796; found 361.9799 isolation yield was 85%.
Example 13
The preparation method of 2-oxazolidinone-3-formamidine-5-methylene derivative provided in this example is different from example 11 in that intermediate 3b is used instead of raw material intermediate 3a to prepare 2-oxazolidinone-3-formamidine-5-methylene derivative 5c of this example; the structure of 5c is as follows:
characterization data for this example 2-oxazolidinone-3-formamidine-5-methylene derivative 5c is as follows: 1 H NMR(400MHz,CDCl 3 )δ7.27(m,2H),7.18(m,1H),7.12(m,2H),7.03(m,2H),6.86(m,2H),6.72(t,J＝2.8Hz,2H),5.95(br,2H),4.72(d,J＝2.8Hz,2H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ157.8,156.3,147.2,144.8,138.2,133.7,129.5,125.6,124.9,123.8,122.7,122.4,116.6,71.5,60.6；HRMS(ESI)m/z:[M+H] + Calcd for C 17 H 15 IN 3 O 3 436.0153; found 436.0146 isolated yield was 83%.
Example 14
The preparation method of 2-oxazolidinone-3-formamidine-5-methylene derivative provided in this example is different from example 11 in that intermediate 3j is used instead of raw material intermediate 3a to prepare 2-oxazolidinone-3-formamidine-5-methylene derivative 5d of this example; the structure of 5d is as follows:
characterization data for this example 2-oxazolidinone-3-formamidine-5-methylene derivative 5d is as follows: 1 H NMR(400MHz,CDCl 3 )δ7.46(t,J＝2.8Hz,1H),7.29(d,J＝8.4Hz,1H),6.85(dd,J＝8.4,2.0Hz,1H),6.78(d,J＝2.0Hz,1H),5.89(br,2H),4.87(d,J＝2.8Hz,2H),2.30(s,3H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ156.4,145.0,142.9,138.1,134.3,130.0,125.5,123.6,123.4,71.7,61.0,20.9；HRMS(ESI)m/z:[M+H] + Calcd for C 12 H 12 ClIN 3 O 2 391.9657; found 391.9649 isolation yield was 90%.
Example 15
The preparation method of 2-oxazolidinone-3-formamidine-5-methylene derivative provided in this example is different from example 11 in that intermediate 3c is used instead of raw material intermediate 3a to prepare 2-oxazolidinone-3-formamidine-5-methylene derivative 5e of this example; 5e are structured as follows:
characterization data for this example 2-oxazolidinone-3-formamidine-5-methylene derivative 5e is as follows: 1 H NMR(400MHz,CDCl 3 )δ7.39(t,J＝2.8Hz,1H),6.88(m,4H),5.90(br,2H),4.86(d,J＝2.8Hz,2H),3.80(s,3H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ156.5,156.0,145.6,139.2,134.6,122.6,115.1,71.7,60.6,55.6；HRMS(ESI)m/z:[M+H] + Calcd for C 12 H 13 IN 3 O 3 373.9996; found 373.9989 isolation yield was 71%.
Example 16
The preparation method of 2-oxazolidinone-3-formamidine-5-methylene derivative provided in this example is different from example 11 in that intermediate 3d is used instead of raw material intermediate 3a to prepare 2-oxazolidinone-3-formamidine-5-methylene derivative 5f of this example; the structure of 5f is as follows:
characterization data for this example 2-oxazolidinone-3-formamidine-5-methylene derivative 5f are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.87(dd,J＝8.0,1.6Hz,1H),7.61(t,J＝2.8Hz,1H),7.32(m,1H),6.93(dd,J＝8.0,1.6Hz,1H),6.81(m,1H),5.93(br,2H),4.88(d,J＝2.8Hz,2H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ156.4,148.0,145.3,139.8,134.1,129.7,125.2,121.6,93.3,71.7,61.8；HRMS(ESI)m/z:[M+H] + Calcd for C 11 H 10 I 2 N 3 O 2 469.8857; found 469.8844 isolation yield was 91%.
Example 17
The procedure for the preparation of 2-oxazolidinone-3-formamidine-5-methylene derivative provided in this example differs from that of example 11 in that intermediate 3i was used in place of starting intermediate 3a to give 5g of 2-oxazolidinone-3-formamidine-5-methylene derivative of this example; the structure of 5g is as follows:
characterization data for 5g of the present example 2-oxazolidinone-3-formamidine-5-methylene derivative are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.30(t,J＝2.8Hz,1H),6.98(s,2H),6.08(br,2H),4.87(d,J＝2.8Hz,2H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ156.3,146.0,145.7,134.9,134.0,125.9,122.5,71.7,61.1；HRMS(ESI)m/z:[M+H] + Calcd for C 11 H 8 Cl 3 N 3 O 2 445.8721; found445.8712 isolation yield was 81%.
Example 18
This example provides a process for the preparation of 2-oxazolidinone-3-formamidine-5-methylene derivatives comprising the steps of:
(1) As in example 1;
(2) Dissolving the intermediate 3a (1.0 equivalent) obtained in the step (1), N-bromosuccinimide (NBS, 1.2 equivalent) and AgOTf (0.1 equivalent) in acetone (acetone), stirring for 1 hour at room temperature, diluting the reaction solution with dichloromethane after the reaction is finished, washing the reaction solution with water, washing the organic phase with brine, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating the filtrate by silica gel column chromatography (the polarity range of the eluent is petroleum ether: ethyl acetate=10:1) to obtain the 2-oxazolidinone-3-formamidine-5-methylene derivative 6a of the example; the isolation yield was 77%; the characterization data are as follows: 1 H NMR(400MHz,CDCl 3 )δ7.49(t,J＝2.8Hz,1H),7.38(m,2H),7.11(t,J＝7.6Hz,1H),6.94(m,2H),5.96(br,2H),4.97(d,J＝2.8Hz,2H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ156.1,146.3,145.0,132.3,129.8,123.7,121.8,90.8,68.1；HRMS(ESI)m/z:[M+H] + Calcd for C 11 H 11 BrN 3 O 2 296.0029; found 296.0032 the synthetic route is as follows:
example 19
The preparation method of 2-oxazolidinone-3-formamidine-5-methylene derivative provided in this example is different from example 18 in that intermediate 3b is used instead of raw material intermediate 3a to prepare 2-oxazolidinone-3-formamidine-5-methylene derivative 6b of this example; the structure of 6b is as follows:
characterization data for this example 2-oxazolidinone-3-formamidine-5-methylene derivative 6b is as follows: 1 H NMR(400MHz,CDCl 3 )；δ7.26(m,2H),7.18(m,1H),7.11(m,2H),7.01(m,2H),6.86(m,2H),6.79(t,J＝2.8Hz,1H),5.99(br,2H),4.82(d,J＝2.8Hz,2H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ157.8,155.9,147.3,144.6,138.1,131.6,129.5,125.5,124.9,123.7,122.6,122.3,116.6,90.8,68.0；HRMS(ESI)m/z:[M+H] + Calcd for C 17 H 15 BrN 3 O 3 388.0291; found 388.0297 isolation yield was 70%.
Example 20
The preparation method of 2-oxazolidinone-3-formamidine-5-methylene derivative provided in this example is different from example 18 in that intermediate 3f is used instead of raw material intermediate 3a to prepare 2-oxazolidinone-3-formamidine-5-methylene derivative 6c of this example; the structure of 6c is as follows:
characterization data for this example 2-oxazolidinone-3-formamidine-5-methylene derivative 6c is as follows: 1 H NMR(400MHz,CDCl 3 )δ7.44(t,J＝2.8Hz,1H),7.05(m,2H),6.86(m,2H),5.95(br,2H),4.95(d,J＝2.8Hz,2H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ160.5,157.1(d,J＝212.6Hz),145.5,142.2(d,J＝2.9Hz),132.3,123.0(d,J＝8.0Hz),116.5(d,J＝22.3Hz),90.9,68.1； 19 F NMR(376MHz,CDCl 3 )δ-120.15(s,1F)；HRMS(ESI)m/z:[M+H] + Calcd for C 11 H 10 FBrN 3 O 2 313.9935; found 313.9938 isolation yield was 73%.
Example 21
The preparation method of 2-oxazolidinone-3-formamidine-5-methylene derivative provided in this example is different from example 18 in that intermediate 3d is used to replace raw material intermediate 3a, thus obtaining 2-oxazolidinone-3-formamidine-5-methylene derivative 6d of this example; the structure of 6d is as follows:
characterization data for this example 2-oxazolidinone-3-formamidine-5-methylene derivative 6d is as follows: 1 H NMR(400MHz,CDCl 3 )δ7.87(dd,J＝8.0,1.6Hz,1H),7.66(t,J＝2.8Hz,1H),7.33(m,1H),6.93(dd,J＝8.0,1.6Hz,1H),6.81(m,1H),5.96(br,2H),4.98(d,J＝2.8Hz,1H)； 13 C{ 1 H}NMR(101MHz,CDCl 3 )δ156.0,148.0,145.1,139.8,131.9,129.7,125.3,121.6,93.3,91.7,68.2；HRMS(ESI)m/z:[M+H] + Calcd for C 11 H 10 BrIN 3 O 2 421.8996; found 421.8984 isolation yield was 56%.
Example 22
The process for preparing 2-oxazolidinone-3-formamidine-5-methylene derivative provided in this example is different from example 18 in that 3g of intermediate product is used instead of 3a of raw material intermediate product to prepare 2-oxazolidinone-3-formamidine-5-methylene derivative 6e of this example; the structure of 6e is as follows:
characterization data for this example 2-oxazolidinone-3-formamidine-5-methylene derivative 6e is as follows: 1H NMR (400 mhz, cdcl 3) delta 7.47 (t, j=2.8 hz, 1H), 7.37 (m, 2H), 6.86 (m, 2H), 5.95 (br, 2H), 4.95 (d, j=2.8 hz, 1H), 1.32 (s, 9H); 13C {1H } NMR (101 MHz, CDCl 3) delta 156.1,146.5,145.0,143.4,132.4,126.6,121.2,90.8,68.1,34.3,31.5; HRMS (ESI) M/z: [ M+H ] +Calcd for C15H19BrN3O2 352.0655; found 352.0661 isolation yield was 82%.
Example 23
The process for preparing 2-oxazolidinone-3-formamidine-5-methylene derivatives as provided in this example differs from that of example 1 in that in step (2), an equivalent amount of AgCO is used 2 CF 3 Instead of AgOTf, the rest of the preparation method is the same as in example 1, and the nuclear magnetic yield of the product 4a is 70%.
Example 24
The process for preparing 2-oxazolidinone-3-formamidine-5-methylene derivatives as provided in this example differs from that of example 1 in that in step (2), an equivalent amount of AgNO is used 3 Instead of AgOTf, the rest of the preparation method is the same as in example 1, and the nuclear magnetic yield of the product 4a is 90%.
Example 25
The process for preparing 2-oxazolidinone-3-formamidine-5-methylene derivatives as provided in this example differs from that of example 1 in that in step (2), an equivalent amount of AgSbF is used 6 Instead of AgOTf, the rest of the preparation method is the same as in example 1, and the nuclear magnetic yield of the product 4a is 98%.
Example 26
The process for preparing 2-oxazolidinone-3-formamidine-5-methylene derivatives as provided in this example differs from that of example 1 in that in step (2), an equivalent amount of AgBF is used 4 Instead of AgOTf, the rest of the preparation method is the same as in example 1, and the nuclear magnetic yield of the product 4a is 98%.
Example 27
The preparation method of the 2-oxazolidinone-3-formamidine-5-methylene derivative provided in this example is different from that in example 1 in that in step (2), acetonitrile is not used as an organic solvent, chloroform is used, and the other preparation methods are the same as those in example 1, so that the nuclear magnetic yield of the product 4a is 66%.
Example 28
The preparation method of the 2-oxazolidinone-3-formamidine-5-methylene derivative provided in the present example is different from that in the example 1 in that in the step (2), acetonitrile is not adopted as an organic solvent, dimethyl sulfoxide is adopted, and the other preparation methods are the same as those in the example 1, so that the nuclear magnetic yield of the product 4a is 81%.
Example 29
The difference between the preparation method of the 2-oxazolidinone-3-formamidine-5-methylene derivative provided in this example and that of example 1 is that in the step (2), acetonitrile is not used as an organic solvent, methanol is used, and the other preparation methods are the same as those of example 1, so that the nuclear magnetic yield of the product 4a is 64%.
Comparative example 1
The process for preparing 2-oxazolidinone-3-formamidine-5-methylene derivatives provided in this comparative example is different from example 1 in that in step (2), an equivalent amount of Ag is used 2 CO 3 Instead of AgOTf, the rest of the preparation method is the same as in example 1, and the nuclear magnetic yield of the product 4a is 0%.
Comparative example 2
The preparation method of the 2-oxazolidinone-3-formamidine-5-methylene derivative provided in this comparative example is different from that in example 1 in that in step (2), agOTf is replaced by an equal amount of AgF, and the other preparation methods are the same as those in example 1, and the nuclear magnetic yield of the product 4a is 20%.
Comparative example 3
The process for preparing 2-oxazolidinone-3-formamidine-5-methylene derivatives provided in this comparative example differs from that of example 1 in that in step (2), an equivalent amount of PdCl is used 2 Instead of AgOTf, the rest of the preparation method is the same as in example 1, and the nuclear magnetic yield of the product 4a is 3%.
Comparative example 4
The process for preparing 2-oxazolidinone-3-formamidine-5-methylene derivatives provided in this comparative example differs from that of example 1 in that in step (2), an equivalent amount of PdCl is used 2 (dppf). DCM was used instead of AgOTf, and the other preparation methods were the same as in example 1, with a nuclear magnetic yield of 0% for product 4 a.
Comparative example 5
The process for preparing 2-oxazolidinone-3-formamidine-5-methylene derivatives provided in this comparative example differs from that of example 1 in that in step (2), an equivalent amount of PdCl is used 2 (dppf) AgOTf was replaced, the rest of the preparation was the same as in example 1,the nuclear magnetic yield of product 4a was 0%.
Comparative example 6
The process for preparing 2-oxazolidinone-3-formamidine-5-methylene derivatives provided in this comparative example differs from that of example 1 in that in step (2), pd (OAc) is used in an equivalent amount 2 Instead of AgOTf, the rest of the preparation method is the same as in example 1, and the nuclear magnetic yield of the product 4a is 20%.
Comparative example 7
The process for preparing 2-oxazolidinone-3-formamidine-5-methylene derivatives provided in this comparative example differs from that of example 1 in that in step (2), an equivalent amount of PdCl is used 2 (PPh 3 ) 2 Instead of AgOTf, the rest of the preparation method is the same as in example 1, and the nuclear magnetic yield of the product 4a is 0%.
Comparative example 8
The preparation method of the 2-oxazolidinone-3-formamidine-5-methylene derivative provided in the comparative example is different from that in the example 1 in that in the step (2), agOTf is replaced by equivalent amount of CuI, and the other preparation methods are the same as those in the example 1, and the nuclear magnetic yield of the product 4a is 5%.
Finally, it should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the scope of the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solution of the present invention may be modified or substituted equally without departing from the spirit and scope of the technical solution of the present invention.
Claims (10)
1. The 2-oxazolidone-3-formamidine-5-methylene derivative is characterized in that the structure of the 2-oxazolidone-3-formamidine-5-methylene derivative is shown as the formulas (I) - (III):
wherein R is H, alkyl, aryl, halogen or ether.
2. The 2-oxazolidinone-3-formamidine-5-methylene derivative according to claim 1, wherein the 2-oxazolidinone-3-formamidine-5-methylene derivative is one of the following structures:
3. a process for the preparation of a 2-oxazolidinone-3-formamidine-5-methylene derivative as claimed in claim 1 or 2 comprising the steps of:
(1) Dissolving the raw materials 1 and 2 in an organic solvent A, stirring, adding N, N-diisopropylethylamine, and continuing stirring to obtain an intermediate product;
(2) Dissolving the intermediate product obtained in the step (1) and a catalyst silver salt in an organic solvent B, and stirring for reaction to obtain a 2-oxazolidone-3-formamidine-5-methylene derivative shown in the formula (1);
or dissolving the intermediate product obtained in the step (1), an iodine source and a catalyst in an organic solvent C, and stirring for reaction to obtain the 2-oxazolidone-3-formamidine-5-methylene derivative shown in the formula (2); when the iodine source comprises an iodine simple substance, the catalyst is tert-butyl hydroperoxide, and when the iodine source does not comprise an iodine simple substance, the catalyst is silver salt;
or, dissolving the intermediate product obtained in the step (1), a bromine source and a catalyst silver salt in an organic solvent D, and stirring for reaction to obtain a 2-oxazolidone-3-formamidine-5-methylene derivative shown in the formula (3);
the structure of the raw material 1 is shown as a formula (1), the structure of the raw material 2 is shown as a formula (2), and the structure of the intermediate product is shown as a formula (3):
4. the process for producing a 2-oxazolidinone-3-formamidine-5-methylene derivative according to claim 3, wherein in the step (1), the stirring time is 2h to 4h; the stirring time is 0.5h-1.5h.
5. The process for producing a 2-oxazolidinone-3-formamidine-5-methylene derivative according to claim 3, wherein in the step (1), the molar ratio of the starting material 1 and the starting material 2 to the N, N-diisopropylethylamine is 1: (1-2): (3-4).
6. The method for producing 2-oxazolidinone-3-formamidine-5-methylene derivative according to claim 3, wherein in the step (2), the silver salt comprises AgOTf, agNO 3 、AgSbF 6 、AgBF 4 、AgCO 2 CF 3 At least one of them.
7. The method for producing 2-oxazolidinone-3-formamidine-5-methylene derivative according to claim 3, wherein the organic solvent A comprises at least one of dichloromethane, chloroform, methanol, ethanol, dimethyl sulfoxide, acetone, ethyl acetate, N-dimethylformamide, and tetrahydrofuran;
and/or the organic solvent B comprises at least one of acetonitrile, dichloromethane, chloroform, dimethyl sulfoxide, methanol and acetone;
and/or the organic solvent C comprises at least one of dichloromethane, acetonitrile, acetone and tetrahydrofuran;
and/or the organic solvent D comprises at least one of acetone, acetonitrile and dimethylformamide.
8. The method for producing 2-oxazolidinone-3-formamidine-5-methylene derivative according to claim 3, wherein in the step (2), the iodine source comprises at least one of iodine simple substance, bis (pyridine) tetrafluoroboronate, N-iodosuccinimide, iodine chloride, 1, 3-diiodo-5, 5-dimethyl hydantoin, N-iodosaccharin; and/or the bromine source comprises at least one of N-bromosuccinimide, tribromopyridine, dibromohydantoin, N-bromoacetamide, phosphorus tribromide, carbon tetrabromide, 5-dibromomeldrenic acid, dibromocyanoacetamide, and dibromoisocyanuric acid.
9. The process for producing a 2-oxazolidinone-3-formamidine-5-methylene derivative according to claim 3, wherein the stirring reaction is carried out in the step (2) for 40min to 120min.
10. The process for producing a 2-oxazolidinone-3-formamidine-5-methylene derivative according to claim 3, wherein in the step (2), when the 2-oxazolidinone-3-formamidine-5-methylene derivative represented by the formula (1) is produced, the molar ratio of the intermediate product to the catalyst silver salt is 1: (0.05-0.2);
and/or, when preparing the 2-oxazolidinone-3-formamidine-5-methylene derivative shown in the formula (2), the molar ratio of the intermediate product to the iodine source and the catalyst is 1: (1-2): (1-2);
and/or, when preparing the 2-oxazolidinone-3-formamidine-5-methylene derivative shown in the formula (3), the molar ratio of the intermediate product to N-bromosuccinimide and the catalyst silver salt is 1: (1-1.5): (0.05-0.2).
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