CN114133360A - Fluorine-containing benzo [ d ] -1, 3-oxazepine compound and synthetic method thereof - Google Patents
Fluorine-containing benzo [ d ] -1, 3-oxazepine compound and synthetic method thereof Download PDFInfo
- Publication number
- CN114133360A CN114133360A CN202111437942.2A CN202111437942A CN114133360A CN 114133360 A CN114133360 A CN 114133360A CN 202111437942 A CN202111437942 A CN 202111437942A CN 114133360 A CN114133360 A CN 114133360A
- Authority
- CN
- China
- Prior art keywords
- fluorine
- nmr
- reaction
- chloroform
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 229910052731 fluorine Inorganic materials 0.000 title claims abstract description 21
- 239000011737 fluorine Substances 0.000 title claims abstract description 21
- 125000005605 benzo group Chemical group 0.000 title claims abstract description 14
- 238000010189 synthetic method Methods 0.000 title abstract description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 10
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 10
- -1 tert-butyloxycarbonyl (Boc) Chemical class 0.000 claims description 41
- 238000006243 chemical reaction Methods 0.000 claims description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 15
- 239000002994 raw material Substances 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- 239000012752 auxiliary agent Substances 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- WMKGGPCROCCUDY-UHFFFAOYSA-N 1,5-diphenylpenta-1,4-dien-3-one Chemical compound C=1C=CC=CC=1C=CC(=O)C=CC1=CC=CC=C1 WMKGGPCROCCUDY-UHFFFAOYSA-N 0.000 claims description 4
- 239000007983 Tris buffer Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- PAGZTSLSNQZYEV-UHFFFAOYSA-L 2,2-dimethylpropanoate;palladium(2+) Chemical compound [Pd+2].CC(C)(C)C([O-])=O.CC(C)(C)C([O-])=O PAGZTSLSNQZYEV-UHFFFAOYSA-L 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical group [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- XMSZANIMCDLNKA-UHFFFAOYSA-N methyl hypofluorite Chemical compound COF XMSZANIMCDLNKA-UHFFFAOYSA-N 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- UMPZTUVEROYNCC-UHFFFAOYSA-N 2-prop-1-enylaniline Chemical compound CC=CC1=CC=CC=C1N UMPZTUVEROYNCC-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 29
- 239000000758 substrate Substances 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 6
- 239000000575 pesticide Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 238000006555 catalytic reaction Methods 0.000 abstract 2
- 229920001909 styrene-acrylic polymer Polymers 0.000 abstract 2
- 238000002360 preparation method Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 68
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 238000004293 19F NMR spectroscopy Methods 0.000 description 19
- 239000007858 starting material Substances 0.000 description 13
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000011160 research Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000003682 fluorination reaction Methods 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- SFJGCXYXEFWEBK-UHFFFAOYSA-N oxazepine Chemical group O1C=CC=CC=N1 SFJGCXYXEFWEBK-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- POHRXSDWWHUIMT-UHFFFAOYSA-N oxazepine-4-carboxamide Chemical compound NC(=O)C1=CC=CON=C1 POHRXSDWWHUIMT-UHFFFAOYSA-N 0.000 description 2
- JQJDQQDPTXAEAO-UHFFFAOYSA-N (2-prop-1-en-2-ylphenyl) carbamate Chemical compound C(N)(OC1=C(C=CC=C1)C(=C)C)=O JQJDQQDPTXAEAO-UHFFFAOYSA-N 0.000 description 1
- JUYWDXUELATAOI-UHFFFAOYSA-N 1,3-oxazepine Chemical group O1C=CC=CN=C1 JUYWDXUELATAOI-UHFFFAOYSA-N 0.000 description 1
- UEYQJQVBUVAELZ-UHFFFAOYSA-N 2-Hydroxynicotinic acid Chemical class OC(=O)C1=CC=CN=C1O UEYQJQVBUVAELZ-UHFFFAOYSA-N 0.000 description 1
- XEIWITZXIKXBSU-UHFFFAOYSA-N 3-fluoro-1,2-benzoxazepine Chemical class FC1=NOC2=C(C=C1)C=CC=C2 XEIWITZXIKXBSU-UHFFFAOYSA-N 0.000 description 1
- SLGIBJWUMUWIFH-UHFFFAOYSA-N 6,11-dihydrobenzo[c][1,5]benzoxazepine Chemical class C1OC2=CC=CC=C2NC2=CC=CC=C12 SLGIBJWUMUWIFH-UHFFFAOYSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000005781 Fludioxonil Substances 0.000 description 1
- 239000005784 Fluoxastrobin Substances 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 238000007316 Wagner-Meerwein rearrangement reaction Methods 0.000 description 1
- 150000003926 acrylamides Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- MUJOIMFVNIBMKC-UHFFFAOYSA-N fludioxonil Chemical compound C=12OC(F)(F)OC2=CC=CC=1C1=CNC=C1C#N MUJOIMFVNIBMKC-UHFFFAOYSA-N 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- UFEODZBUAFNAEU-NLRVBDNBSA-N fluoxastrobin Chemical compound C=1C=CC=C(OC=2C(=C(OC=3C(=CC=CC=3)Cl)N=CN=2)F)C=1C(=N/OC)\C1=NOCCO1 UFEODZBUAFNAEU-NLRVBDNBSA-N 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000001465 metallisation Methods 0.000 description 1
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000012363 selectfluor Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D267/02—Seven-membered rings
- C07D267/06—Seven-membered rings having the hetero atoms in positions 1 and 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a fluorine-containing benzo [ d ] -1, 3-oxazepine compound and a synthetic method thereof. The synthesis method is characterized in that N-tert-butyloxycarbonyl (Boc) protected o-amino styrene-acrylic molecules are used as substrates and react with fluorine reagents under the catalysis of palladium to prepare the N-tert-butyloxycarbonyl (Boc) protected o-amino styrene-acrylic molecules. The preparation method comprises the following steps: dissolving N-Boc protected o-aminophenylallyl molecules in a solvent, and reacting the o-aminophenylallyl molecules with a fluorine reagent under the catalysis of palladium at a certain temperature to obtain the compound containing the fluorobenzo [ d ] -1, 3-oxazepine structure. The synthesis method has the advantages of mild conditions, high yield, tolerance of various functional groups, capability of constructing various fluorinated hybrid structures, and potential application in the fields of biology, medicines, pesticides and the like.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a fluorine-containing benzo [ d ] -1, 3-oxazepine compound with wide application prospect in the fields of biology, medical treatment, pesticide and the like and a synthesis method thereof.
Background
Heterocyclic compounds widely exist in natural products, and have deep research and application in the fields of biology, medicine, materials and the like. Among them, the oxazepine structure has wide application in the field of pesticides in the field of biomedical science, for example: a kind of molecules containing an oxazepine structure are invented in WO2006/116764A1, "multicyclic Carboxypyridone derivative having HIV interaction activity and the human prediction", and have good anti-HIV effect; the patent WO1997JP00754 '5, 11-dihydrodibenzo [ b, e ] [1,4] oxazepine derivatives and pharmaceutical compositions-contacting the same' invents a drug containing an oxazepine structure, has diacylglycerol transferase inhibiting activity, and can be used for treating the dysfunction of the digestive tract. Australian patent No. AU2007309427B2 "fused bicyclic derivatives of 2, 4-diaminopyrimidine as ALK and c-Met inhibitors" invented a derivative containing an oxaazepine structure useful as an inhibitor of ALK and c-Met kinase to treat proliferative diseases. The similar structure widely exists in the field of medicine, so that the deep research and synthesis of the compound have important significance.
Research on fluoroheterocyclic compounds has been a focus of research. Fluoro groups have similar size, polarity and hydrogen bonding to hydroxyl groups, but the former have unique lipophilicity, steric electronic effect and conformational property, and thus are commonly used as modifying groups of hydroxyl groups to modify bioactive heterocycles. Related research has led to the development of a number of fluoro-heterocyclic bioactive drugs, such as temelotan, fluoxastrobin, fludioxonil, and the like. Among them, glycofluoride research has been a hotspot in the field of glycochemistry (Shimizu, M., Togo, H., Yo-koyama, M., Chemistry of glycofluoride. Synthesis 1998,6:799-822), in which the anomeric carbon in the structure has a unique homofluorocarbon substitution structure, so that the compounds are endowed with unique biological and chemical activities, and are widely applied as enzyme inhibitors or glycosylation reagents.
However, the methods for constructing homofluorocarbon substituted structures have been limited to date. The commonly used diethylaminosulfurtrifluoride fluorination methodology usually proceeds with hydroxyl group as a substrate. In recent years, synthesis of related molecules using olefins as substrates has been developed. Ulmer et al, 2016, used benzoyl-protected ortho-aminostyrene molecules to react with a high-valent iodine reagent, with phenyl-accompanied [1, 2] following high-valent iodine activation and fluorination]-migration reaction to synthesize fluorobenzo [ d]-1, 3-oxazepine structure. (Ulmer, A., Brunner, C., Arnold, A.M.,
A.,Gulder,T.A fluorination/aryl migra-tion/cyclization cascade for the metal-free synthesis of fluoro-benzoxazepines.Chem.Eur.J.2016,22, 3660-3664) Wu et al finally synthesize the compound containing the O and N five-membered heterocyclic ring by taking alpha-substituted acrylamide protected by N-Boc as a substrate through a series process of oxidation-palladium metallization and rearrangement fluorination. (Wu, H.; Yang, B.; Zhu, L.; Lu, R.; Li, G.; Lu, H.high-Valent Palla-di um-protein-expressed formed Normal Wagner-Meerwein rearrangement.Org.Lett.2016,18, 5804-one 5807) in which a substrate is an N-Boc-protected o-aminophenylpropene, benzo [ d.C. is effected under the above-mentioned reaction conditions]Construction of 1, 3-oxazepine structures. However, this reaction suffers from side reactions with a low yield. How to inhibit the occurrence of side reactions and improve the reaction yield is a technical problem.
Disclosure of Invention
The invention aims to provide a fluorine-containing benzo [ d ] -1, 3-oxazepine compound, and the invention also aims to provide a synthetic method of the fluorine-containing benzo [ d ] -1, 3-oxazepine compound, which has good substrate universality and potential application in the fields of biology, medicine, pesticide and the like.
The invention is realized by the following technical scheme:
a fluorine-containing benzo [ d ] -1, 3-oxazepine compound has a structural formula as follows:
wherein R is1Is methyl, benzyl, cyclopropylmethyl, tert-butyloxycarbonyl (Boc) or
R2Is methyl, ethyl,
R3Is fluorine, chlorine, bromine, methyl, methoxycarbonyl, methoxy, fluorine, nitro, acetyl or trifluoromethyl.
Preferred fluorochemical benzo [ d ] -1, 3-oxazepine compounds have the structural formula:
the invention also provides a method for synthesizing benzo [ d ] -1, 3-oxazepine skeleton, which has the following reaction formula:
the method comprises the following specific operation steps of adding N-tert-butoxycarbonyl protected o-aminophenylpropyl alkene 1 serving as a raw material and a fluorine reagent, a palladium catalyst, a reaction auxiliary agent and a solvent which are required equivalent into a reaction bottle, and reacting at a certain temperature; and after TLC tracking reaction is finished, filtering the mixture and then separating by using column chromatography to finally obtain the fluorine-containing benzo [ d ] -1, 3-oxygen nitrogen heterocyclic compound.
Preferably, the fluorine reagent is 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt (Selectfluor) or 1-fluoro-4-methyl-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt (SelectfluorII); the equivalent ratio of the fluorine reagent to the raw material is 1-2: 1.
Preferably, the palladium catalyst is palladium acetate, palladium pivalate or tris (dibenzylidene) acetone dipalladium; the equivalent ratio of the palladium catalyst to the raw material is 0.05-0.1: 1.
Preferably, the reaction auxiliary agent is anhydrous sodium sulfate; the equivalent ratio of the reaction auxiliary agent to the raw material is 1-2: 1.
Preferably, the solvent is acetonitrile or a mixed solution of acetonitrile and dichloromethane; the volume ratio of the dichloromethane to the acetonitrile is 0-1: 1. Preferably, the reaction temperature is 5-40 ℃.
Has the advantages that:
the method has the advantages that the solvent for screening the reaction condition is a mixed solvent of dichloromethane and acetonitrile, anhydrous sodium sulfate is added in the reaction, the occurrence of side reaction is effectively inhibited, and the most appropriate palladium catalyst is screened according to different substrate reaction activities to promote the reaction. The method is convenient to operate, has good functional group tolerance, and can successfully and efficiently construct the fluorine-containing benzo [ d ] -1, 3-oxazepine framework through one-step reaction.
Detailed Description
The present invention is further described below with reference to specific examples, but the examples given should not be construed as limiting the scope of the claims.
Example 1:
synthesis of Compound 4-fluoro-1,4, 7-trimethy-4, 5-dihydrobenzol [ d ] [1,3] oxazepin-2(1H) -one (2a)
To a glass test tube was added the starting material tert-butyl me-thyl (4-methyl-2- (prop-1-en-2-yl) phenyl) carbamate (1a,26.1mg), followed by tris (dibenzylidene) acetone dipalladium (4.6mg,0.05 equiv) and anhydrous sodium sulfate (14.1mg, 1 equiv), followed by acetonitrile (1ml) and dichloromethane (1ml), and finally 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] s]Octane bis (tetrafluoroborate) salt (71mg, 2 eq) was reacted at 25 ℃ with stirring. The reaction was followed by TLC plates during the course of the reaction and was complete in about 4 hours. The reaction was then filtered through a short silica gel column and the filter cake was washed with ethyl acetate. The filtrate was collected, the solvent was evaporated under reduced pressure and the residue was separated by silica gel column chromatography to give 17mg of product 2a in 76% yield. Nuclear magnetic data:1H NMR(400MHz,Chloroform-d)δ7.48–7.34(m,1H),7.33–7.13(m,3H),3.48(s,3H),3.35(t,J＝13.8Hz,1H),3.06(d,J＝14.1Hz,1H),1.52(dd,J＝17.8,1.1Hz,3H).19F NMR(376MHz,Chloroform-d)δ-83.00.13C NMR(101MHz,CDCl3)δ151.67,141.67,129.49,129.33,128.77,126.16,121.66,121.42,41.30,37.48,23.68。
example 2:
synthesis of Compound 4-fluoro-8-methoxy-1,4-dimethyl-4, 5-dihydrobenzol [ d ] [1,3] oxazepin-2(1H) -one (2f)
To a glass test tube, the raw material tert-butyl me-thyl (5-methoxy-2- (prop-1-en-2-yl) phenyl) carbamate (1f,27.7mg) was added, followed by tris (dibenzylidene) acetone dipalladium (4.6mg,0.05 equiv) and anhydrous sodium sulfate (28.2mg, 2 equiv), followed by acetonitrile (1ml) and dichloromethane (1ml), and finally added
(69mg, 2 equiv.) the reaction was stirred at 5 ℃. The reaction was followed by TLC plates during the course of the reaction and was complete in about 24 hours. The reaction was then filtered through a short silica gel column and the filter cake was washed with ethyl acetate. The filtrate was collected, the solvent was evaporated under reduced pressure and the residue was separated by silica gel column chromatography to give 11mg of product 2f in 44% yield. Nuclear magnetic data:1H NMR(400MHz,Chloroform-d)δ7.16–7.04(m,1H),6.79–6.64(m,2H),3.82(s,3H),3.45(s,3H),3.23(d,J＝13.5Hz,1H),2.98(d,J＝14.3Hz,1H),1.50(dd,J＝17.8,1.1Hz,3H).19F NMR(470MHz,Chloroform-d)δ-83.53.13CNMR(101MHz,Chloroform-d)δ159.96,151.73,142.64,130.05,121.61,119.42,111.01,108.05,55.55,40.42(d,J＝32.8Hz),37.38,27.94,23.43(d,J＝27.2Hz)。
example 3:
synthesis of 4-fluoro-1-methyl-4- (pyrrolidinone-1-carbonyl) -4, 5-dihydrobenzol [ d ] [1,3] oxazepin-2(1H) -one (2o) compound
To a glass test tube were added the starting materials tert-butyl me-thyl (2- (3-oxo-3- (pyrrolidinyl-1-yl) prop-1-en-2-yl) phenyl) carbamate (1o,33.0mg), palladium acetate (2.3mg,0.1 equiv.), and anhydrous sodium sulfate (14.1mg, 1 equiv.), acetonitrile (2ml) was added, and finally 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] was added]Octane bis (tetrafluoroborate) salt (40mg, 1.1 eq) was reacted at 40 ℃ with stirring. The reaction was followed by TLC plates during the course of the reaction and was complete in about 3 hours. Then the reaction solution was filtered through a short silica gel column, and the filter cake was extracted with ethyl acetateAnd (6) washing. After the filtrate was collected, the solvent was evaporated under reduced pressure and the residue was separated by silica gel column chromatography to give 23mg of 2o as a product with a yield of 80%. Nuclear magnetic data:1H NMR(400MHz,Chloroform-d)δ7.50(dd,J＝7.6,1.4Hz,1H),7.38–7.10(m,3H),3.93(d,J＝14.1Hz,1H),3.89–3.73(m,2H),3.56–3.30(m,5H),3.17(dd,J＝15.8,14.1Hz,1H),1.97–1.63(m,4H).19F NMR(376MHz,Chloroform-d)δ-93.49.13C NMR(101MHz,CDCl3)δ161.54,161.25,150.12,141.26,131.61,129.22,128.38,126.23,120.70,117.94,115.52,47.22,37.61,26.42,23.34。
example 4:
synthesis of the compound 4-fluoro-N, N,1-trimethyl-2-oxo-1,2,4, 5-tetrahydrobenzol [ d ] [1,3] oxazepine-4-carboxamide (2p)
To a glass test tube were added the starting materials tert-butyl me-thyl (2- (3- (dimethylamino) -3-oxoprop-1-en-2-yl) phenyl) carbamate (1p,30.4mg), palladium pivalate (3.1mg,0.1 equiv.), and anhydrous sodium sulfate (14.1mg, 1 equiv.), acetonitrile (2ml) was added, and finally 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] was added]Octane bis (tetrafluoroborate) salt (40mg, 1.1 eq) was reacted at 40 ℃ with stirring. The reaction was followed by TLC plates during the course of the reaction and was complete in about 3 hours. The reaction was then filtered through a short silica gel column and the filter cake was washed with ethyl acetate. After the filtrate was collected, the solvent was evaporated under reduced pressure and the residue was separated by silica gel column chromatography to give 24.7mg of product 2p in 93% yield. Nuclear magnetic data:1H NMR(400MHz,Chloroform-d)δ7.52(dd,J＝7.8,1.4Hz,1H),7.33(td,J＝7.8,1.6Hz,1H),7.26–7.12(m,1H),3.93(d,J＝14.1Hz,1H),3.49(s,3H),3.28(d,J＝1.9Hz,3H),3.16(dd,J＝16.1,14.1Hz,1H),2.91(d,J＝1.2Hz,3H),1.26(d,J＝3.2Hz,1H).19F NMR(376MHz,Chloroform-d)δ-90.76.13C NMR(101MHz,CDCl3)δ162.80,149.95,141.15,131.65,129.26,128.33,126.17,120.62,118.35,115.91,38.14,37.58,36.8。
example 5
Using the same operating conditions and procedures as in example 1, compounds 2b-2e, 2g-2n were synthesized. The reaction yields and nuclear magnetic data were as follows:
compound 4-fluoro-1,4, 8-trimethy-4, 5-dihydrobenzol [ d][1,3]Oxazepin-2(1H) -one (2b) was obtained in a yield of 48% using tert-butyl methyl (5-methyl-2- (prop-1-en-2-yl) phenyl) carbamate as a starting material. Nuclear magnetic data:1H NMR(400MHz,Chloroform-d)δ7.05(d,J＝36.6Hz,3H),3.46(s,3H),3.29(s,1H),3.02(s,1H),2.38(s,3H),1.50(d,J＝17.8Hz,3H).19F NMR(376MHz,Chloroform-d)δ-83.19.13C NMR(101MHz,Chloroform-d)δ151.79,141.52,138.84,129.20,126.83,126.39,122.05,119.38,40.76(d,J＝32.8Hz),37.41,23.50(d,J＝27.2Hz),21.27。
compound 4-fluoro-1,4, 9-trimethy-4, 5-dihydrobenzol [ d][1,3]The yield of oxazepin-2(1H) -one (2c) from tert-butyl methyl (2-methyl-6- (prop-1-en-2-yl) phenyl) carbamate was 52%. Nuclear magnetic data:1H NMR(400MHz,Chloroform-d)δ7.24–7.02(m,3H),3.31(s,3H),3.01(dd,J＝14.1,1.8Hz,2H),2.34(s,3H),1.42(dd,J＝17.9,1.1Hz,3H).19FNMR(376MHz,Chloroform-d)δ-84.18.13C NMR(101MHz,Chloroform-d)δ152.99,140.38,132.57,131.48,130.69(d,J＝8.8Hz),126.99,121.40,119.09,41.04(d,J＝32.7Hz),37.92,23.16(d,J＝26.8Hz),18.89。
compound 7-chloro-4-fluoro-1,4-dimethyl-4, 5-dihydrobenzol [ d][1,3]Oxazepin-2(1H) -one (2d) was obtained in a yield of 48% using tert-butyl methyl (4-chloro-2- (prop-1-en-2-yl) phenyl) carbamate as a starting material. Nuclear magnetic data:1H NMR(400MHz,Chloroform-d)δ7.41–7.32(m,1H),7.24(d,J＝2.4Hz,1H),7.14(d,J＝8.6Hz,1H),3.45(s,3H),3.41–3.22(m,1H),3.03(d,J＝14.1Hz,1H),1.54(dd,J＝17.8,1.1Hz,3H).19F NMR(376MHz,Chlo-roform-d)δ-83.24.13C NMR(101MHz,Chloroform-d)δ151.27,140.30,131.55–130.69(m),129.30,128.77,122.67,121.25,118.94,40.98(d,J＝33.7Hz),37.49,23.60(d,J＝26.9Hz)。
the compound methyl4-fluoro-1,4-dimethyl-2-oxo-1,2,4, 5-tetrahydrobenzol [ d [)][1,3]oxazepine-8-carboxylate (2e), as methyl 3- ((tert-butoxyc)aryl) (methyl) amino) -4- (prop-1-en-2-yl) benzoate was used as a starting material in a yield of 47%. Nuclear magnetic data:1H NMR(400MHz,Chloroform-d)δ7.98–7.81(m,2H),7.34(d,J＝7.7Hz,1H),3.96(s,3H),3.53(s,3H),3.40(t,J＝13.8Hz,1H),3.15(d,J＝14.0Hz,1H),1.60–1.43(m,3H).19F NMR(376MHz,Chloroform-d)δ-82.98.13C NMR(101MHz,Chloroform-d)δ166.00,151.31,141.99,134.25,130.95,129.67,127.20,122.50,52.55,41.33(d,J＝33.5Hz),37.56,27.43,23.63(d,J＝27.0Hz)。
compound 4,9-difluoro-1,4-dimethyl-4, 5-dihydrobenzol [ d][1,3]Oxazepin-2(1H) -one (2g) was obtained in a yield of 40% using tert-butyl methyl (2-fluoro-6- (prop-1-en-2-yl) phenyl) carbamate as a starting material. Nuclear magnetic data:1H NMR(500MHz,Chloroform-d)δ7.30–7.00(m,3H),3.46(d,J＝2.9Hz,3H),3.39(s,1H),3.14(d,J＝14.1Hz,1H),1.53(d,J＝17.8Hz,3H).19FNMR(470MHz,Chloroform-d)δ-83.38,-119.03.13C NMR(126MHz,Chloro-form-d)δ155.28,153.28,150.63,140.61,126.75,123.62,118.38–114.06(m),40.02,36.42,28.69,22.26。
compound 1,4, 4-trimethy-7-nitro-4, 5-dihydrobenzol [ d][1,3]Oxazepin-2(1H) -one (2H) was obtained in a yield of 65% using tert-butyl methyl (4-nitro-2- (prop-1-en-2-yl) phenyl) carbamate as a starting material. Nuclear magnetic data:1H NMR(400MHz,Chloroform-d)δ8.29(ddd,J＝8.9,2.7,0.6Hz,1H),8.17(d,J＝2.6Hz,1H),7.37(d,J＝8.8Hz,1H),3.54(s,3H),3.48–3.32(m,1H),3.23(d,J＝14.3Hz,1H),1.59(dd,J＝17.9,1.0Hz,3H).19F NMR(376MHz,Chlo-roform-d)δ-83.60.13C NMR(101MHz,CDCl3)δ150.64,147.38,144.83,130.56,124.36,121.84,121.15,118.82,77.03,41.48,37.64,23.65。
the compound 7-acetyl-4-fluoro-1,4, 4-trimethy-4, 5-dihydro-4l 5-benzol [ d][1,3]Oxazepin-2(1H) -one (2i) was obtained in a yield of 58% using tert-butyl methyl (4-acetyl-2- (prop-1-en-2-yl) phenyl) carbamate as a starting material. Nuclear magnetic data:1H NMR(400MHz,Chloroform-d)δ8.04–7.70(m,2H),7.30–7.20(m,1H),3.51(s,3H),3.38(t,J＝13.9Hz,1H),3.16(d,J＝14.2Hz,1H),2.63(s,3H),1.55(dd,J＝18.0,1.0Hz,3H).19F NMR(376MHz,Chloroform-d)δ-83.32.13C NMR(101MHz,Chloroform-d)δ196.59,151.15,145.84,134.50,129.48(d,J＝44.1Hz),121.24,119.09,41.31(d,J＝33.3Hz),37.48,26.61,23.52(d,J＝26.9Hz)。
the compound 4-fluoro-1,4-dimethyl-8- (trifluoromethyl) -4, 5-dihydrobenzol [ d][1,3]Oxazepin-2(1H) -one (2j) was obtained in a yield of 40% using tert-butyl methyl (2- (prop-1-en-2-yl) -5- (trifluoromethyl) phenyl) carbamate as a starting material. Nuclear magnetic data:1H NMR(400MHz,Chloroform-d)δ7.60–7.36(m,3H),3.52(s,3H),3.39(t,J＝13.9Hz,1H),3.15(d,J＝14.1Hz,1H),1.64–1.47(m,3H).19F NMR(376MHz,Chloroform-d)δ-62.61,-83.27.13C NMR(101MHz,Chloroform-d)δ151.09,142.32,133.23,131.35(d,J＝33.1Hz),130.12,122.87,121.22,118.90,118.41,41.19(d,J＝33.6Hz),37.51,23.56(d,J＝26.9Hz)。
compound tert-butyl4-fluoro-4-methyl-2-oxo-4, 5-dihydrobenzol [ d][1,3]Oxazepine-1(2H) -carboxylate (2k) was obtained in 46% yield from N, N-bis (tert-butylcarbonyl) -2- (prop-1-en-2-yl) aniline. Nuclear magnetic data:1H NMR(400MHz,Chloroform-d)δ7.43–7.29(m,4H),3.47(t,J＝14.0Hz,1H),3.09(d,J＝14.2Hz,1H),2.30–2.03(m,3H),1.51(s,9H).19F NMR(376MHz,Chloroform-d)δ-85.72.13C NMR(101MHz,Chloroform-d)δ150.77,143.92,137.23,130.47,129.20,128.20,127.92,126.51,120.50,118.17,40.83,31.02,27.76,23.75。
compound 1-benzyl-4-fluoro-4-methyl-4, 5-dihydrobenzol [ d][1,3]Oxazepin-2(1H) -one (2l) was obtained in a yield of 53% using tert-butyl benzyl (2- (prop-1-en-2-yl) phenyl) carbamate as a starting material. Nuclear magnetic data:1H NMR(400MHz,Chloroform-d)δ7.33–7.21(m,7H),7.21–7.10(m,2H),5.16(d,J＝15.2Hz,1H),4.99(d,J＝15.2Hz,1H),3.19–3.04(m,1H),2.92(d,J＝14.1Hz,1H),1.49(dd,J＝17.9,1.1Hz,3H).19F NMR(376MHz,Chloroform-d)δ-83.86.13C NMR(101MHz,CDCl3)δ152.06,140.49,136.55,130.18,130.10,129.60,129.59,127.84,127.78,126.43,122.17,121.85,119.54,77.39,53.88,41.29,23.61。
the compound 1- (cyclopropropylethyl) -4-fluoro-4-methyl-4, 5-dihydrobenzol [ d][1,3]Oxazepin-2(1H) -one (2m) was obtained in a yield of 47% using tert-butyl (cyclopropropylethyl) (2- (prop-1-en-2-yl) phenyl) carbamate as a starting material. Nuclear magnetic data:1H NMR(400MHz,Chloroform-d)δ7.41–7.06(m,4H),3.95(dd,J＝14.3,7.7Hz,1H),3.52(dd,J＝14.3,6.8Hz,1H),3.38(t,J＝13.7Hz,1H),2.98(d,J＝13.9Hz,1H),1.42(dd,J＝17.8,1.1Hz,3H),0.37(ddd,J＝7.9,2.7,1.6Hz,2H),0.33–0.23(m,1H),0.14–-0.04(m,2H).19F NMR(376MHz,Chloroform-d)δ-84.13.13C NMR(101MHz,Chloroform-d)δ151.81,140.69,130.76,129.48,129.17–128.17(m),126.29,122.59,121.58,119.27,54.86,41.09(d,J＝32.9Hz),23.46(d,J＝27.1Hz),9.95,3.67(d,J＝30.0Hz)。
compound 4-ethyl-4-fluoro-1-methyl-4, 5-dihydrobenzol [ d][1,3]Oxazepin-2(1H) -one (2n) was obtained in a yield of 40% using tert-butyl (2- (but-1-en-2-yl) phenyl) (methyl) carbamate as a starting material. Nuclear magnetic data:1H NMR(400MHz,Chloroform-d)δ7.42–7.33(m,1H),7.24–7.15(m,3H),3.48(s,3H),3.28(t,J＝13.9Hz,1H),3.11(d,J＝14.2Hz,1H),1.90–1.64(m,2H),1.02(t,J＝7.5Hz,3H).19F NMR(376MHz,Chloroform-d)δ-94.55.13C NMR(101MHz,Chloroform-d)δ151.88,141.75,129.47,128.66,126.03,122.96,121.37,120.62,39.32(d,J＝33.2Hz),37.53,29.37(d,J＝25.6Hz),6.80。
example 6
Using the same operating conditions and procedures as in example 4, compounds 2q-2v were synthesized. The reaction yields and nuclear magnetic data were as follows:
the compound 1-benzyl-4-fluoro-4- (pyrrolidin-1-yl) -4, 5-dihydrobenzol [ d ] [1,3] oxazepin-2(1H) -one (2q) was prepared from tert-butyl ben-yl (2- (3-oxo-3- (pyrrolidin-1-yl) prop-1-en-2-yl) phenyl) carbamate in a yield of 84%. 1H NMR (400MHz, Chloroform-d) δ 7.54-7.40 (m,1H), 7.39-7.08 (m,8H), 5.21-4.95 (m,2H), 3.90-3.71 (m,3H), 3.54-3.26 (m,2H),2.95(t, J ═ 14.8Hz,1H), 1.97-1.72 (m,4H), 13C NMR (101MHz, Chloroform-d) δ 161.34(d, J ═ 29.2Hz),150.55,140.17,136.32,131.75,129.85(d, J ═ 7.9Hz),128.77,128.35,127.92,127.72,126.45,121.42,118.04,115.61,54.13,47.18,46.92(d, J ═ 5.0Hz),37.46(d, J ═ 31.1Hz),28.76,26.38,23.31.19F (NMR 376, Chloroform-d) δ 94-16.16.
Compound 4-fluoro-1-methyl-4- (morpholino-4-carbonyl) -4, 5-dihydrobenzol [ d][1,3]Oxazepin-2(1H) -one (2r) was obtained in 73% yield from tert-butyl me-thyl (2- (3-morpholino-3-oxoprop-1-en-2-yl) phenyl) carbamate. Nuclear magnetic data:1H NMR(400MHz,Chloroform-d)δ7.61–7.46(m,1H),7.35(td,J＝7.8,1.7Hz,1H),7.25–7.14(m,2H),4.01–3.86(m,3H),3.73–3.56(m,5H),3.49(s,3H),3.18(dd,J＝16.2,14.2Hz,1H).19F NMR(376MHz,Chloroform-d)δ-90.17.13C NMR(101MHz,Chloroform-d)δ161.36(d,J＝29.0Hz),149.74,141.11,131.58,128.99(d,J＝8.1Hz),128.45,126.25,120.73,118.31,66.69(d,J＝23.4Hz),46.87,43.22,39.92–35.25(m),29.70。
the compound 8-bromo-4-fluoro-1-methyl-4- (pyrolidine-1-carbonyl) -4, 5-dihydrobenzol [ d][1,3]Oxazepin-2(1H) -one (2s) was obtained in 81% yield from tert-butyl (5-bromo-2- (3-oxo-3- (pyrrolidinyl-1-yl) prop-1-en-2-yl) phenyl) (methyl) carbamate. Nuclear magnetic data:1H NMR(400MHz,Chloroform-d)δ7.39–7.29(m,3H),3.90(d,J＝14.1Hz,1H),3.82(t,J＝6.7Hz,2H),3.53–3.33(m,5H),3.09(t,J＝14.8Hz,1H),1.96–1.69(m,4H).19F NMR(376MHz,Chloroform-d)δ-93.84.13CNMR(101MHz,CDCl3)δ161.34,161.05,149.71,142.44,133.00,129.25,128.21,123.97,121.65,117.67,115.23,47.21,37.57,26.38,23.32。
the compound ethyl2- (4-fluoro-2-oxo-4- (pyrrolidine-1-carbonyl) -4, 5-dihydrobenzol [ d][1,3]Oxazepin-1(2H) -yl) acetate (2t) and ethyl N- (tert-butylcarbonyl) -N- (2- (3-oxo-3- (pyrrolidinyl-1-yl) prop-1-en-2-yl) phenyl) glycinate were used as raw materials, and the yield was 77%. Nuclear magnetic data:1H NMR(400MHz,Chloroform-d)δ7.53(dd,J＝7.5,1.5Hz,1H),7.37–7.19(m,2H),7.09(dd,J＝8.0,1.2Hz,1H),4.68(d,J＝17.5Hz,1H),4.49(d,J＝17.5Hz,1H),4.22(qd,J＝7.1,0.9Hz,2H),3.94(d,J＝14.1Hz,1H),3.88–3.72(m,2H),3.63(dd,J＝15.6,14.1Hz,1H),3.50–3.30(m,2H),1.95–1.76(m,3H),1.27(t,J＝7.1Hz,4H).19F NMR(470MHz,Chloroform-d)δ-93.99.13C NMR(101MHz,Chloroform-d)δ168.01,161.32(d,J＝29.1Hz),150.47,140.05,131.96,130.17(d,J＝8.3Hz),128.44,126.72,120.86,118.17,115.73,61.87,52.07,47.06(d,J＝31.0Hz),37.24(d,J＝31.4Hz),26.39,23.32,14.10。
the compound 1- (cyclopropropylethyl) -4-fluoro-4- (pyrrolidinyl-1-carbonyl) -4, 5-dihydrobenzol [ d][1,3]Oxazepin-2(1H) -one (2u) was obtained in a yield of 64% using tert-butyl (2- (3-oxo-3- (pyrrolidinyl-1-yl) prop-1-en-2-yl) phenyl) carbamate as a raw material. Nuclear magnetic data:1H NMR(400MHz,Chloroform-d)δ7.52(dd,J＝7.6,1.5Hz,1H),7.32(td,J＝7.7,1.6Hz,1H),7.24–7.15(m,2H),4.01–3.89(m,2H),3.88–3.73(m,2H),3.64(dd,J＝14.3,6.8Hz,1H),3.49–3.32(m,2H),3.27(dd,J＝15.5,14.1Hz,1H),1.98–1.67(m,4H),1.10(ddt,J＝7.9,6.8,4.9Hz,1H),0.55–0.41(m,2H),0.35(ddd,J＝10.6,4.7,1.9Hz,1H),0.25–0.11(m,1H).19F NMR(376MHz,Chlo-roform-d)δ-94.25.13C NMR(101MHz,Chloroform-d)δ161.48(d,J＝29.2Hz),150.31,140.27,131.65,130.44,128.31,126.35,121.80,117.93,115.50,55.08,47.05(d,J＝26.8Hz),37.43(d,J＝31.2Hz),27.11,26.39,23.32,9.91,3.68(d,J＝30.4Hz)。
the compound 4-fluoro-7-methoxy-1-methyl-4- (pyrolidine-1-carbonyl) -4, 5-dihydrobenzol [ d][1,3]Oxazepin-2(1H) -one (2v) was obtained in 80% yield from tert-butyl me-thyl (4-methoxy-2- (3-oxo-3- (pyrrolidinyl-1-yl) prop-1-en-2-yl) phenyl) carbamate. Nuclear magnetic data:1H NMR(400MHz,Chloroform-d)δ7.16–6.97(m,2H),6.85(dd,J＝8.8,2.9Hz,1H),3.99–3.76(m,6H),3.50–3.33(m,5H),3.14(dd,J＝16.0,14.1Hz,1H),1.95–1.75(m,4H).19F NMR(376MHz,Chloroform-d)δ-86.50–-101.74(m).13C NMR(101MHz,Chloroform-d)δ158.45,155.49,145.27,137.89,134.33,129.77,128.47,122.45,120.43,114.95,79.76,55.48,47.34(d,J＝279.4Hz),37.51(d,J＝115.8Hz),28.29,25.27(d,J＝197.9Hz)。
Claims (8)
1. a fluorine-containing benzo [ d ] -1, 3-oxazepine compound has a structural formula as follows:
wherein R is1Is methyl, benzyl, cyclopropylmethyl, tert-butyloxycarbonyl (Boc) or
R2Is methyl, ethyl,
R3Is fluorine, chlorine, bromine, methyl, methoxycarbonyl, methoxy, fluorine, nitro, acetyl or trifluoromethyl.
2. A fluorobenzo [ d ] -1, 3-oxazepine compound according to claim 1 having the formula:
3. a method for synthesizing the fluorobenzo [ d ] -1, 3-oxazepine compound as claimed in claim 1, which comprises the following specific steps of taking N-tert-butoxycarbonyl protected o-aminophenylpropene as a raw material, adding a required equivalent of a fluorine reagent, a palladium catalyst, a reaction auxiliary agent and a solvent into a reaction bottle, and reacting at a certain temperature; and after TLC tracking reaction is finished, filtering the mixture and then separating by using column chromatography to finally obtain the fluorine-containing benzo [ d ] -1, 3-oxygen nitrogen heterocyclic compound.
4. The method of claim 3, wherein the fluorine reagent is 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt or 1-fluoro-4-methyl-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt; the equivalent ratio of the fluorine reagent to the raw material is 1-2: 1.
5. The process of claim 3 wherein the palladium catalyst is palladium acetate, palladium pivalate, or dipalladium tris (dibenzylidene) acetone; the equivalent ratio of the palladium catalyst to the raw material is 0.05-0.1: 1.
6. The method of claim 3, wherein the reaction aid is anhydrous sodium sulfate; the equivalent ratio of the reaction auxiliary agent to the raw material is 1-2: 1.
7. The method according to claim 3, wherein the solvent is acetonitrile or a mixed solution of acetonitrile and dichloromethane; the volume ratio of the dichloromethane to the acetonitrile is 0-1: 1.
8. The method according to claim 3, wherein the reaction temperature is 5 to 40 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111437942.2A CN114133360A (en) | 2021-11-30 | 2021-11-30 | Fluorine-containing benzo [ d ] -1, 3-oxazepine compound and synthetic method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111437942.2A CN114133360A (en) | 2021-11-30 | 2021-11-30 | Fluorine-containing benzo [ d ] -1, 3-oxazepine compound and synthetic method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114133360A true CN114133360A (en) | 2022-03-04 |
Family
ID=80389492
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111437942.2A Pending CN114133360A (en) | 2021-11-30 | 2021-11-30 | Fluorine-containing benzo [ d ] -1, 3-oxazepine compound and synthetic method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114133360A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007093904A1 (en) * | 2006-02-14 | 2007-08-23 | Pfizer Products Inc. | Benzoxazinone and benzoxazepinone oxazolidinones as antibacterial agents |
| CN101535276A (en) * | 2006-10-23 | 2009-09-16 | 赛福伦公司 | Fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-MET inhibitors |
| CN104016937A (en) * | 2014-05-09 | 2014-09-03 | 中科院广州化学有限公司 | N-aryl oxazepine ketone compound and preparation method thereof |
| CN105218477A (en) * | 2015-11-04 | 2016-01-06 | 华侨大学 | A kind of polysubstituted benzo [b] [Isosorbide-5-Nitrae] oxygen azatropylidene piperidine derivatives and preparation method thereof |
| CN113185536A (en) * | 2021-04-29 | 2021-07-30 | 河南师范大学 | Synthesis method of pyrazolidone benzo 1, 3-oxygen-nitrogen hetero-compound |
-
2021
- 2021-11-30 CN CN202111437942.2A patent/CN114133360A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007093904A1 (en) * | 2006-02-14 | 2007-08-23 | Pfizer Products Inc. | Benzoxazinone and benzoxazepinone oxazolidinones as antibacterial agents |
| CN101535276A (en) * | 2006-10-23 | 2009-09-16 | 赛福伦公司 | Fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-MET inhibitors |
| CN104016937A (en) * | 2014-05-09 | 2014-09-03 | 中科院广州化学有限公司 | N-aryl oxazepine ketone compound and preparation method thereof |
| CN105218477A (en) * | 2015-11-04 | 2016-01-06 | 华侨大学 | A kind of polysubstituted benzo [b] [Isosorbide-5-Nitrae] oxygen azatropylidene piperidine derivatives and preparation method thereof |
| CN113185536A (en) * | 2021-04-29 | 2021-07-30 | 河南师范大学 | Synthesis method of pyrazolidone benzo 1, 3-oxygen-nitrogen hetero-compound |
Non-Patent Citations (1)
| Title |
|---|
| HONGMIAO WU，ET AL.: "High-Valent Palladium-Promoted Formal Wagner−Meerwein Rearrangement", 《ORG. LETT.》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6776330B2 (en) | Antibacterial compound | |
| CN110317212B (en) | Synthesis of polycyclic carbamoylpyridone compounds | |
| WO2021113595A1 (en) | Phosphorus derivatives as kras inhibitors | |
| CA2934537C (en) | Synthesis of an antiviral compound | |
| WO2021053495A1 (en) | Bifunctional degraders and their methods of use | |
| CA2737038A1 (en) | Amide compounds, compositions and uses thereof | |
| JP6118470B2 (en) | Imidazole derivatives used as antiviral agents and their use in the manufacture of pharmaceuticals | |
| CA3214014A1 (en) | Bicyclic substituted aromatic carboxylic acid compounds | |
| TW202227397A (en) | Bicyclic-heterocycle derivatives and related uses | |
| JP2021520381A (en) | Substituted pyridines and pyrimidines and their use as GLUN2B receptor regulators | |
| KR20220020915A (en) | Pyrazine carbamates and their use as GluN2B receptor modulators | |
| AU2010289802B2 (en) | Synthesis of a neurostimulative piperazine | |
| CN110396080B (en) | Vonoprazan fumarate metabolite and preparation method of deutero metabolite thereof | |
| JP7086075B2 (en) | Biphenyl compounds as CCR2 / CCR5 receptor antagonists | |
| CN116969976A (en) | Deubiquitinase inhibitor and application thereof | |
| CN114524812A (en) | Crystal form preparation and synthesis method of 1, 4-dihydro-1, 6-naphthyridine compound | |
| KR102537616B1 (en) | 1,3,4-Oxadiazole Derivative Compounds as Histone Deacetylase 6 Inhibitor, and the Pharmaceutical Composition Comprising the same | |
| CN110330498B (en) | Spiro (3, 3' -phenylpyrrole alkoxylated indole) liver X receptor regulator and preparation method and application thereof | |
| CN114133360A (en) | Fluorine-containing benzo [ d ] -1, 3-oxazepine compound and synthetic method thereof | |
| CN110914243B (en) | As AT 2 Carboxylic acid derivatives of R receptor antagonists | |
| CN113444107B (en) | Synthetic method and anticancer activity of succinimide spiro-fused sultams compound | |
| WO2023061492A1 (en) | 2-oxo-3-azabicyclo[3.1.0]hexane derivative | |
| CN117751113A (en) | Aromatic acetylene derivative and preparation method and application thereof | |
| CA3117113A1 (en) | 1,2,3,4-tetrahydroquinoxaline derivative, preparation method therefor and application thereof | |
| CN110283170B (en) | Preparation of compound and application of compound in inhibiting growth of various tumor cells |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20220304 |