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
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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 ℃.
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