CN113264899A - 1,3,5-oxadiazine compound and preparation and application thereof - Google Patents

1,3,5-oxadiazine compound and preparation and application thereof Download PDF

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CN113264899A
CN113264899A CN202110384431.2A CN202110384431A CN113264899A CN 113264899 A CN113264899 A CN 113264899A CN 202110384431 A CN202110384431 A CN 202110384431A CN 113264899 A CN113264899 A CN 113264899A
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oxadiazine
heteroaryl
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马永敏
张燚
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Taizhou University
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Abstract

The application relates to a 1,3,5-oxadiazine compound and preparation and application thereof, wherein the 1,3,5-oxadiazine compound has a structural general formula shown in a formula (I):
Figure DDA0003014248040000011
wherein R is1And R2Both aryl and heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1-5 substituents; said R1、R2The same or different. The compound has monoamine oxidase and lung cancer cell inhibitory activity. The preparation of the compound comprises: mixing amidine compounds, methyl donors and water, and catalyzing by a metal catalyst in the presence of an oxidant to obtain the catalyst. The preparation method has the advantages of cheap and easily-obtained raw materials and various structures; the substrate has wide applicability, is suitable for amidine compounds containing different functional groups, and has better application value and potential social and economic benefits; reaction atom channelHigh economical efficiency, insensitivity to air and humidity and accordance with the green chemical concept.

Description

1,3,5-oxadiazine compound and preparation and application thereof
Technical Field
The application relates to the technical field of pharmaceutical and chemical intermediate synthesis, in particular to a 1,3,5-oxadiazine compound and a preparation method and application thereof.
Background
Six-membered heterocyclic oxadiazines containing one oxygen atom and two nitrogen atoms are considered to be one of the most important skeletons due to their broad biological activities, such as cardiovascular, anti-tumor, insecticidal and Alzheimer's disease [ Synthesis and biological properties of hydro-oxadiazine-based heterocyclic derivatives, Mini-Rev Med chem.2011,11,642-657 ]. There are several types of oxadiazines, among which the construction of the skeleton of1, 2,4-, 1,3, 4-oxadiazines has been widely studied, and 1,3,5-oxadiazines have received little attention as An effective drug or pesticide intermediate [ a synergistic synthesis of functionalized2H-1,3,5-oxadiazines via metal-carbonoid-induced 1,2, 4-oxadiazine ring closure.
At present, the following methods are mainly used for synthesizing 1,3,5-oxadiazine compounds: 1) l-pyroglutamic acid and aldehyde are used as raw materials, and fused ring 1,3,5-oxadiazine (i) [1,3,5-oxadiazine frame by oxydgen vs. nirogen mapping of an N-acetylimide ion derived from N, O-bis-TMS pyroglutamic acid, chemistry 2017,2,10654-10660] is synthesized by electrochemical oxidation under the catalysis of acid. 2) 1,2,4-oxadiazole and alpha-diazo ester are taken as raw materials to react under the catalysis of Rh (II) or Cu (II) to obtain (ii) [ An effective synthesis of functional 2H-1,3,5-oxadiazines via metal-carbonoid-induced 1,2, 4-oxadiazine ring synthesis 2021,53, 348-. 3) N-methyl-N' -nitroguanidine reacts with two moles of aldehyde to provide 4-nitroimino-tetrahydro-1,3,5-oxadiazine (iii) by Mannich reaction [ Mannich-type reaction for synthesis of 3-methyl-4-nitrilo-tetrahydro-1, 3,5-oxadiazine. Synthesis Commun.2012,42,1950-1958 ]. 4) 4, 6-diamino-1, 3,5-Oxadiazines (iv) [ Oxadiazines and Dioxazines from Perhaloacetic acids and cyanamides.J Org chem.1966,31, 2568-. 5) 1,3,5-oxadiazine (v) [ Synthesis and Structure of 1-oxadiazine-3, 5-diaza-1,3, 5-oxadiazine-the 1-oxa-3,5-diaza-1,3, 5-oxadiazine/2H-1, 3,5-oxadiazine tau. chem Ber.1993,126,957-967] is formed by reaction of an N-lithium or N-trimethylsilyl substituted imine with an N-imidic acid derivative. 6) Condensation of 4-amino-1, 2, 4-triazole with an aromatic aldehyde followed by benzoyl isothiocyanate cyclization affords 1,3, 5-oxadiazin-4-thione (vi) [ Synthesis and biological activity of3- [4H- (1,2,4) -triazyl ] -2,6-diaryl-1,3, 5-oxadiazine-4-thio.
The reaction formula corresponding to the synthesis method in the 6 is as follows:
Figure BDA0003014248030000021
the above methods have substrate limitations and some adverse factors such as harsh reaction conditions or complex raw materials are used, so that the development of an efficient and practical synthetic method is still a considerable challenge. With the continuous attention paid to new drug discovery, the significance of developing a preparation method of a 1,3,5-oxadiazine compound which is easy to obtain raw materials, mild in reaction conditions and high in applicability of substrate functional groups is great.
Disclosure of Invention
The application provides a 1,3,5-oxadiazine compound and preparation and application thereof, and the preparation method has the advantages of easily available raw materials, mild reaction conditions and high applicability of substrate functional groups.
A1, 3,5-oxadiazine compound has a structural general formula shown in a formula (I):
Figure BDA0003014248030000031
wherein R is1And R2Both aryl and heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1-5 substituents; said R1、R2The same or different.
Optionally, the heteroaryl is a 5-to 6-membered heteroaryl, the 5-to 6-membered heteroaryl comprising 1,2,3, or 4 substituents independently selected from-C (═ O) NH-, -S (═ O)2NH-, -S (═ O) NH-, N, -O-, -S-, ═ O, ═ S, -C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O)2-, -NHC (═ O) NH-, -NHC (═ S) NH-, or-H2A heteroatom or heteroatom group of P (═ O) -NH-.
Optionally, the heteroaryl is thienyl, furyl, pyrrolyl or pyridyl.
Optionally, 1-5 substituents of the aryl or heteroaryl are respectively and independently selected from H, F, Cl, Br, I and NO2、NH2、OH、C1～3Alkyl radical, C1～3Alkoxy, phenyl; the C1-3 alkyl, C1-3 alkoxy or phenyl is optionally substituted by 1,2 or 3 substituentsThe 1,2 or 3 substituents of C1-3 alkyl, C1-3 alkoxy or phenyl are independently selected from H, F, Cl, Br, I and NO2、NH2、OH。
Optionally, 1-5 substituents of the aryl or heteroaryl are respectively and independently selected from H, F, Cl, Br, I and NO2、NH2OH, methyl, methoxy, trifluoromethyl or trifluoromethoxy.
Optionally, the R is1And R2Each independently selected from
Figure BDA0003014248030000041
Figure BDA0003014248030000042
Optionally, the 1,3,5-oxadiazine compound is:
Figure BDA0003014248030000043
the application also provides a preparation method of the 1,3,5-oxadiazine compound, which comprises the following steps:
mixing the amidine compound shown as the formula (II), a methyl donor and water, and catalyzing the mixture by a metal catalyst in the presence of an oxidant to prepare a 3, 4-disubstituted 1,3,5-oxadiazine compound shown as the formula (I);
Figure BDA0003014248030000044
the 1,3,5-oxadiazine compound is prepared by taking amidine and a water-containing methyl donor as raw materials and catalyzing the amidine and the water-containing methyl donor by a metal catalyst in the presence of an oxidant.
Optionally, the methyl donor is at least one of the structures shown below:
Figure BDA0003014248030000051
the methyl donor is more preferably DMSO.
Optionally, the oxidant is 1-chloromethyl-4-fluoro-1, 4-diazotized bicyclo 2.2.2 octane bis (Tetrafluoroboric acid) At least one of a salt (Selectfluor), hydrogen peroxide, t-butyl hydroperoxide, 3-chloroperoxybenzoic acid, potassium persulfate, sulfur trioxide-pyridine complex, and iodine. Further, 1-chloromethyl-4-fluoro-1, 4-diazobicyclo 2.2.2 octane bis (tetrafluoroborate) salt is preferable.
Optionally, the metal catalyst is at least one of copper trifluoromethanesulfonate, copper chloride, copper bromide, copper acetate, cuprous chloride, palladium acetate, zinc chloride, ferric chloride and nickel chloride. Further preferred is copper trifluoromethanesulfonate.
The reaction mechanism of the preparation method is shown as follows (raw materials take diarylamidine and DMSO as examples; metal catalyst takes copper ions as examples), CuIIFirstly oxidized to obtain CuIII(A) Then reacting with a substrate II to form copper-nitrene B, combining with DMSO to generate an intermediate C, inserting nitrene to form a new C-N bond to obtain an intermediate D, and leaving methylsulfonyl alcohol under the condition of water to obtain an intermediate E; similarly, repeating the above steps to introduce another molecule of DMSO to obtain intermediate F, and finally closing the ring to obtain the final product I.
Figure BDA0003014248030000061
Optionally, the amidine compound, the oxidant, the metal catalyst, the methyl donor and the water are mixed according to a molar ratio of 1:2:0.1: 2-50: 1-5; the reaction temperature is 40-150 ℃, and the reaction time is 1-30 hours. More preferably 1:2:0.1: 10-20: 3.
optionally, the reaction temperature is 40-150 ℃, and the reaction time is 1-30 hours.
The reaction temperature is inspected to find that the reaction can be well converted at about 110 ℃ to obtain the best yield, so that the reaction temperature is further preferably 80-120 ℃; the reaction time is inspected to find that the reaction obtains the optimal yield within 26 hours, the yield is not obviously influenced by prolonging the reaction time, and the yield is reduced by shortening the reaction time; therefore, the reaction time is more preferably 20 to 26 hours.
The application also provides an application of the 1,3,5-oxadiazine compound in preparing a monoamine oxidase inhibitor or preparing an anti-lung cancer medicament.
Unless otherwise specified, the term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, including variations of deuterium and hydrogen, so long as the valency of the particular atom is normal and the substituted compound is stable.
The term "optionally substituted" means that it may or may not be substituted, and the kind and number of the substituents may be arbitrary on the basis of chemical realizability.
When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent, unless otherwise specified. Thus, for example, if a group is substituted with 0-2R, the group may optionally be substituted with up to two R, and there are separate options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
Unless otherwise specified, the term "C1-3Alkyl "is intended to mean a straight or branched saturated hydrocarbon group consisting of1 to 3 carbon atoms. Said C is1-3The alkyl group comprising C1-2And C2-3Alkyl, etc.; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C1-3Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
Unless otherwise specified, the term "C1-3Alkoxy "denotes those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule through an oxygen atom. Said C is1-3Alkoxy radicals comprising C1-2、C2-3、C3And C2Alkoxy, and the like. C1-3Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
Unless otherwise specified, the term "5-6 membered heteroaryl" in the present application denotes a monocyclic group consisting of 5 to 6 ring atoms with a conjugated pi-electron system, of which 1,2,3 or 4 ring atoms are independently selected from-C (═ O) NH-, -S (═ O)2NH-, -S (═ O) NH-, N, -O-, -S-, ═ O, ═ S, -C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O)2-, -NHC (═ O) NH-, -NHC (═ S) NH-, or-H2P (═ O) -NH-, and the remainder carbon atoms. Wherein the nitrogen atoms are optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S (O))pAnd p is 1 or 2). The 5-6 membered heteroaryl group may be attached to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl group includes 5-and 6-membered heteroaryl groups. Examples of such 5-6 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, and the like), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, and the like), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, and the like), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, and the like), triazolyl (1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, and 4H-1,2, 4-triazolyl, and the like), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, and the like), Thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, and the like), furyl (including 2-furyl, 3-furyl, and the like), thienyl (including 2-thienyl, 3-thienyl, and the like), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl, and the like), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, and the like).
Thus, in the present application:
the "said aryl or heteroaryl group is optionally substituted by 1 to 5 substituents" can also be understood as: the hydrogen atoms of the aryl groups are unsubstituted or any one or more (up to 5) hydrogen atoms are substituted; the hydrogen atoms of the heteroaryl group are unsubstituted or any one or more (up to 5) hydrogen atoms are substituted.
When a hydrogen atom of the aryl group is substituted, the substituent is selected fromH、F、Cl、Br、I、NO2、NH2、OH、C1～3Alkyl radical, C1～3An alkoxy group; when a plurality of hydrogen atoms of the aryl group are substituted, each substituent is independently selected from H, F, Cl, Br, I and NO2、NH2、OH、C1～3Alkyl radical, C1～3Alkoxy, each substituent may be the same or different; the heteroaryl group is understood identically to the aryl group.
"the C1-3 alkyl or C1-3 alkoxy is optionally substituted by 1,2 or 3 independently selected from H, F, Cl, Br, I, NO2、NH2OH substitution "is understood to mean: the hydrogen atoms of the C1-3 alkyl are not substituted or 1,2 or 3 hydrogen atoms are substituted, and when 1 of the hydrogen atoms is substituted, the substituent is selected from H, F, Cl, Br, I and NO2、NH2Or OH, wherein when 2 or 3 of them are substituted, each substituent is independently selected from H, F, Cl, Br, I, NO2、NH2Or OH, each substituent may be the same or different; c1-3 alkoxy is understood to be the same as C1-3 alkyl.
Compounds are named according to the conventional naming principles in the art or using software, and commercially available compounds are referred to by the supplier's catalog name.
Compared with the prior art, the application has at least one of the following beneficial effects:
(1) the preparation method has the advantages of cheap and easily-obtained raw materials and various structures; the substrate has wide applicability, is suitable for amidine compounds containing different functional groups, and has better application value and potential social and economic benefits;
(2) the preparation method has the advantages of high reaction atom economy, insensitivity to air and humidity, no need of controlling air and humidity in the reaction process, and accordance with the green chemistry concept.
(3) The compound prepared by the method has good monoamine oxidase inhibitory activity and lung cancer inhibitory activity.
Detailed Description
The technical solutions of the present application will be described clearly and completely with reference to the following embodiments, and it should be understood that the described embodiments are only a part of the embodiments of the present application, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein in the description of the present application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.
The starting materials used in the following examples are all commercially available products.
Example 1: preparation of3, 4-diphenyl-3, 6-dihydro-2H-1, 3,5-oxadiazines (Ia)
Figure BDA0003014248030000091
The reaction was stirred in a sealed tube with N-phenylbenzamidine (0.196g,1mmol), Selectfluor (0.638g,2mmol), copper triflate (0.036g,0.1mmol), DMSO (2mL), and water (50mg,3mmol) at 110 ℃ for 26 h. After the reaction was completed, water (15mL) was added, extraction was performed with ethyl acetate (3 × 8mL), the organic phases were combined and dried with anhydrous sodium sulfate, the solvent was dried under reduced pressure after filtration, and the filtrate was subjected to silica gel column chromatography to obtain the desired 3, 4-diphenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (Ia) in an amount of 0.152g as a white solid, yield: and 64 percent.
1H NMR(400MHz,CDCl3)δ7.54(d,J＝7.0Hz,2H),7.32–7.14(m,6H),7.03(t,J＝7.4Hz,1H),6.88(d,J＝7.2Hz,2H),5.39(s,2H),5.13(s,2H).13C NMR(101MHz,CDCl3)δ155.38,145.63,135.55,129.93,129.11,128.66,128.11,124.96,124.85,80.89,80.40HRMS(ESI):calcd.for C15H15N2O[M+H]+239.1179；found239.1175.
Example 2: preparation of3- (4-methoxyphenyl) -4-phenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (Ib)
Figure BDA0003014248030000101
N- (4-methoxyphenyl) benzamidine (0.226g,1mmol), Selectfluor (0.638g,2mmol), copper triflate (0.036g,0.1mmol), DMSO (2mL), and water (50mg,3mmol) were stirred in a sealed tube at 110 ℃ for 26 hours. After the reaction was completed, water (15mL) was added, extraction was performed with ethyl acetate (3 × 8mL), the organic phases were combined and dried over anhydrous sodium sulfate, the solvent was dried under reduced pressure after filtration, and the filtrate was subjected to silica gel column chromatography to obtain the desired 3- (4-methoxyphenyl) -4-phenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (Ib) as a white solid in an amount of 0.169g, yield: and 63 percent.
1H NMR(400MHz,CDCl3)δ7.53(d,J＝6.6Hz,2H),7.33–7.17(m,4H),6.84(d,J＝8.9Hz,2H),6.71(d,J＝8.8Hz,2H),5.37(s,2H),5.05(s,2H),3.71(s,3H).13C NMR(101MHz,CDCl3)δ156.97,155.61,138.86,135.71,129.77,128.70,128.04,126.51,114.35,81.24,80.42,55.36HRMS(ESI):calcd.for C16H17N2O2[M+H]+269.1285；found 269.1290.
Example 3: preparation of3- (4-fluorophenyl) -4-phenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (Ic)
Figure BDA0003014248030000111
N- (4-fluorophenyl) benzamidine (0.214g,1mmol), Selectfluor (0.638g,2mmol), copper triflate (0.036g,0.1mmol), DMSO (2mL) and water (50mg,3mmol) were stirred in a sealed tube at 110 ℃ for 26 hours. After the reaction was completed, water (15mL) was added, extraction was performed with ethyl acetate (3 × 8mL), the organic phases were combined and dried with anhydrous sodium sulfate, the solvent was dried under reduced pressure after filtration, and the filtrate was subjected to flash separation by silica gel column chromatography to obtain the desired 3- (4-fluorophenyl) -4-phenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (Ic) in an amount of 0.125g as a white solid, yield: 49 percent.
1H NMR(400MHz,CDCl3)δ7.52(d,J＝8.1Hz,2H),7.32–7.18(m,3H),6.89-6.85(m,4H),5.38(s,2H),5.07(s,2H).13C NMR(101MHz,CDCl3)δ160.00(d,J＝243Hz),155.27,141.92(d,J＝2.9Hz),135.36,130.03,128.65,128.18,126.62(d,J＝8.4Hz),115.97(d,J＝22.5Hz).13C NMR(101MHz,)δ156.97,155.61,138.86,135.71,129.77,128.70,128.04,126.51,114.35,81.24,80.42,55.36.HRMS(ESI):calcd.for C15H14FN2Om/z[M+H]+257.1090；found 257.1083.
Example 4: preparation of3- (3-methylphenyl) -4-phenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (Id)
Figure BDA0003014248030000121
N- (3-methylphenyl) benzamidine (0.210g,1mmol), Selectfluor (0.638g,2mmol), copper triflate (0.036g,0.1mmol), DMSO (2mL) and water (50mg,3mmol) were stirred in a sealed tube at 110 ℃ for 26 hours. After the reaction was completed, water (15mL) was added, extraction was performed with ethyl acetate (3 × 8mL), the organic phases were combined and dried over anhydrous sodium sulfate, the solvent was dried under reduced pressure after filtration, and the filtrate was subjected to silica gel column chromatography to obtain the desired 3- (3-methylphenyl) -4-phenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (Id) in an amount of 0.156g as a white solid in yield: 62 percent.
1H NMR(400MHz,CDCl3)δ7.54(d,J＝7.2Hz,2H),7.32-7.19(m,3H),7.05(t,J＝7.8Hz,1H),6.85(d,J＝7.6Hz,1H),6.72(s,1H),6.66(d,J＝7.9Hz,1H),5.38(s,2H),5.11(s,2H),2.23(s,3H).13C NMR(101MHz,)δ155.46,145.59,139.02,135.64,129.84,128.77,128.57,128.06,125.66,125.46,122.16,80.89,80.41,21.31.HRMS(ESI):calcd.for C16H17N2Om/z[M+H]+253.1335；found 253.1337.
Example 5: preparation of3- (3-chlorophenyl) -4-phenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (Ie)
Figure BDA0003014248030000122
The reaction was stirred in a sealed tube with N- (3-chlorophenyl) benzamidine (0.230g,1mmol), Selectfluor (0.638g,2mmol), copper triflate (0.036g,0.1mmol), DMSO (2mL), and water (50mg,3mmol) at 110 ℃ for 26 hours. After the reaction was completed, water (15mL) was added, extraction was performed with ethyl acetate (3 × 8mL), the organic phases were combined and dried over anhydrous sodium sulfate, the solvent was dried under reduced pressure after filtration, and the filtrate was subjected to flash separation by silica gel column chromatography to obtain the desired 3- (3-chlorophenyl) -4-phenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (Ie) in an amount of 0.128g as a white solid in yield: and 47 percent.
1H NMR(400MHz,CDCl3)δ7.54(d,J＝7.2Hz,2H),7.32(d,J＝7.2Hz,1H),7.25(t,J＝7.2Hz,2H),7.08(t,J＝8.0Hz,1H),7.01(d,J＝8.4Hz,1H),6.92(t,J＝2.0Hz,1H),6.73(d,J＝7.2Hz,1H),5.38(s,2H),5.10(s,2H).13C NMR(101MHz,CDCl3)δ154.86,146.90,135.11,134.62,130.20,129.91,128.53,128.26,124.94,124.71,123.71,80.73,80.37.HRMS(ESI):calcd.for C15H14ClN2Om/z[M+H]+273.0795；found 273.0791.
Example 6: preparation of3- [ (1, 1' -biphenyl) -2-yl) ] -4-phenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (If)
Figure BDA0003014248030000131
N- [ (1, 1' -biphenyl-2-yl) ] benzamidine (0.272g,1mmol), Selectfluor (0.638g,2mmol), copper triflate (0.036g,0.1mmol), DMSO (2mL) and water (50mg,3mmol) were stirred in a sealed tube at 110 ℃ for 26 hours. After the reaction was completed, water (15mL) was added, extraction was performed with ethyl acetate (3 × 8mL), the organic phases were combined and dried over anhydrous sodium sulfate, the solvent was dried under reduced pressure after filtration, and the filtrate was subjected to silica gel column chromatography to obtain the desired 3- [ (1, 1' -biphenyl-2-yl) ] -4-phenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (If) as a white solid in an amount of 0.204g, yield: 65 percent.
1H NMR(400MHz,CDCl3)δ7.45–7.28(m,7H),7.27–7.21(m,2H),7.19–7.11(m,4H),6.93–6.87(m,1H),5.35-5.20(m,2H),4.87-4.75(m,2H).13C NMR(101MHz,CDCl3)δ154.89,142.67,139.20,136.49,135.53,131.59,129.63,129.18,128.55,128.49,128.09,127.80,127.36,127.26,125.92,80.58,80.42.HRMS(ESI):calcd.for C21H19N2Om/z[M+H]+315.1492；found 315.1489.
Example 7: preparation of3- [4 '-methyl- (1, 1' -biphenyl) -2-yl ] -4-phenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (Ig)
Figure BDA0003014248030000141
N- [4 '-methyl- (1, 1' -biphenyl-2-yl) ] benzamidine (0.286g,1mmol), Selectfluor (0.638g,2mmol), copper triflate (0.036g,0.1mmol), DMSO (2mL) and water (50mg,3mmol) were stirred in a sealed tube at 110 ℃ for 26 hours. After the reaction was completed, water (15mL) was added, extraction was performed with ethyl acetate (3 × 8mL), the organic phases were combined and dried with anhydrous sodium sulfate, the solvent was dried under reduced pressure after filtration, and the filtrate was subjected to silica gel column chromatography to obtain the desired 3- [4 '-methyl- (1, 1' -biphenyl-2-yl) ] -4-phenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (Ig) in an amount of 0.203g as a white solid, yield: 62 percent.
1H NMR(400MHz,CDCl3)δ7.34(t,J＝7.4Hz,4H),7.29-7.07(m,9H),6.86(d,J＝7.9Hz,1H),5.35-5.20(m,2H),4.84-4.72(m,2H),2.41(s,3H).13C NMR(101MHz,CDCl3)δ155.02,142.65,137.13,136.45,136.31,135.61,131.52,129.59,129.22,129.10,128.97,128.57,127.79,127.34,125.88,80.59,80.40,21.22.HRMS(ESI):calcd.for C22H21N2Om/z[M+H]+329.1648；found 329.1653.
Example 8: preparation of 4- (4-methoxyphenyl) -3-phenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (Ih)
Figure BDA0003014248030000151
4-methoxy-N-phenylbenzamidine (0.226g,1mmol), Selectfluor (0.638g,2mmol), copper triflate (0.036g,0.1mmol), DMSO (2mL) and water (50mg,3mmol) were stirred in a sealed tube at 110 ℃ for 26 hours. After the reaction was completed, water (15mL) was added, extraction was performed with ethyl acetate (3 × 8mL), the organic phases were combined and dried over anhydrous sodium sulfate, the solvent was dried under reduced pressure after filtration, and the filtrate was subjected to silica gel column chromatography to obtain the desired 4- (4-methoxyphenyl) -3-phenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (Ih) as a white solid in an amount of 0.172g, yield: and 64 percent.
1H NMR(400MHz,CDCl3)δ7.47(d,J＝8.9Hz,2H),7.19(t,J＝7.4Hz,2H),7.04(t,J＝7.5Hz,1H),6.88(d,J＝7.4Hz,2H),6.73(d,J＝8.7Hz,2H),5.37(s,2H),5.10(s,2H),3.75(s,3H).13C NMR(101MHz,CDCl3)δ160.90,146.01,130.15,129.09,127.92,124.93,113.44,80.92,80.43,55.21.HRMS(ESI):calcd.for C16H17N2O2m/z[M+H]+269.1285；found 269.1280.
Example 9: preparation of 4- (4-ethylphenyl) -3-phenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (Ii)
Figure BDA0003014248030000152
4-Ethyl-N-phenylbenzamidine (0.224g,1mmol), Selectfluor (0.638g,2mmol), copper triflate (0.036g,0.1mmol), DMSO (2mL) and water (50mg,3mmol) were stirred in a sealed tube at 110 ℃ for 26 hours. After the reaction was completed, water (15mL) was added, extraction was performed with ethyl acetate (3 × 8mL), the organic phases were combined and dried over anhydrous sodium sulfate, the solvent was dried under reduced pressure after filtration, and the filtrate was subjected to flash separation by silica gel column chromatography to obtain the desired 4- (4-ethylphenyl) -3-phenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (Ii) as a white solid in 0.154g, yield: 58 percent.
1H NMR(400MHz,CDCl3)δ7.44(d,J＝8.2Hz,2H),7.28(d,J＝8.0Hz,2H),7.05(d,J＝8.0Hz,2H),7.03(d,J＝7.6Hz,1H),6.90(d,J＝7.6Hz,2H),5.38(s,2H),5.11(s,2H),2.57(q,J＝7.6Hz,2H),1.16(t,J＝7.6Hz,3H).13C NMR(101MHz,CDCl3)δ155.28,146.24,145.90,132.90,129.04,128.57,127.59,124.83,124.61,80.88,80.44,28.61,15.17.HRMS(ESI):calcd.for C17H19N2Om/z[M+H]+267.1492；found 267.1488.
Example 10: preparation of 4- (4-fluorophenyl) -3-phenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (Ij)
Figure BDA0003014248030000161
4-fluoro-N-phenylbenzamidine (0.214g,1mmol), Selectfluor (0.638g,2mmol), copper triflate (0.036g,0.1mmol), DMSO (2mL) and water (50mg,3mmol) were stirred in a sealed tube at 110 ℃ for 26 hours. After the reaction was completed, water (15mL) was added, extraction was performed with ethyl acetate (3 × 8mL), the organic phases were combined and dried over anhydrous sodium sulfate, the solvent was dried under reduced pressure after filtration, and the filtrate was subjected to silica gel column chromatography to obtain the desired 4- (4-fluorophenyl) -3-phenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (Ij) in an amount of 0.133g as a white solid in yield: 52 percent.
1H NMR(400MHz,CDCl3)δ7.53(dd,J＝8.8,5.6Hz,2H),7.20(t,J＝7.9Hz,2H),7.06(t,J＝7.4Hz,1H),6.95–6.81(m,4H),5.37(s,2H),5.11(s,2H).13C NMR(101MHz,CDCl3)δ163.65(d,J＝248Hz),154.36,145.58,131.66(d,J＝3.0Hz),130.62(d,J＝8.5Hz),129.21,124.99,124.97,115.19(d,J＝21.7Hz),80.91,80.41.HRMS(ESI):calcd.for C15H14FN2Om/z[M+H]+257.1085；found 257.1080。
Example 11: preparation of 4- (3-methylphenyl) -3-phenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (Ik)
Figure BDA0003014248030000171
3-methyl-N-phenylbenzamidine (0.210g,1mmol), Selectfluor (0.638g,2mmol), copper triflate (0.036g,0.1mmol), DMSO (2mL), and water (50mg,3mmol) were stirred in a sealed tube at 110 ℃ for 26 hours. After the reaction was completed, water (15mL) was added, extraction was performed with ethyl acetate (3 × 8mL), the organic phases were combined and dried over anhydrous sodium sulfate, the solvent was dried under reduced pressure after filtration, and the filtrate was subjected to flash separation by silica gel column chromatography to obtain the desired 4- (3-methylphenyl) -3-phenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (Ik) in an amount of 0.154g as a white solid in yield: 61 percent.
1H NMR(400MHz,CDCl3)δ7.44(s,1H),7.23(d,J＝6.7Hz,1H),7.18(t,J＝7.4Hz,2H),7.11–7.00(m,3H),6.88(d,J＝7.2Hz,2H),5.38(s,2H),5.12(s,2H),2.27(s,3H).13C NMR(101MHz,CDCl3)δ155.52,145.77,137.87,135.54,130.70,129.19,129.08,127.85,125.84,124.87,124.74,80.87,80.44,21.33.HRMS(ESI):calcd.for C16H17N2Om/z[M+H]+253.1335；found 253.1333.
Example 12: preparation of 4- (2-methylphenyl) -3-phenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (Il)
Figure BDA0003014248030000181
The reaction was stirred in a sealed tube for 26 hours at 110 ℃ with 2-methyl-N-phenylbenzamidine (0.210g,1mmol), Selectfluor (0.638g,2mmol), copper triflate (0.036g,0.1mmol), DMSO (2mL) and water (50mg,3 mmol). After the reaction was completed, water (15mL) was added, extraction was performed with ethyl acetate (3 × 8mL), the organic phases were combined and dried over anhydrous sodium sulfate, the solvent was dried under reduced pressure after filtration, and the filtrate was subjected to silica gel column chromatography to obtain the desired 4- (2-methylphenyl) -3-phenyl-3, 6-dihydro-2H-1, 3,5-oxadiazine (Il) in an amount of 0.161g as a white solid in yield: and 64 percent.
1H NMR(400MHz,CDCl3)δ7.32(d,J＝7.6Hz,1H),7.20–7.05(m,4H),7.05–6.93(m,2H),6.82(d,J＝7.9Hz,2H),5.34(s,2H),5.17(s,2H),2.33(s,3H).13C NMR(101MHz,CDCl3)δ154.97,143.86,136.30,135.49,130.57,129.72,129.06,128.79,125.56,124.97,124.64,80.16,79.75,19.79.HRMS(ESI):calcd.for C16H17N2Om/z[M+H]+253.1335；found 253.1337.
Examples 13 to 35:
the N-phenylbenzamidine derivative (II) (1mmol), Selectfluor (0.638g,2mmol), copper triflate (0.036g,0.1mmol), DMSO (2mL) and water (50mg,3mmol) were stirred in a sealed tube at 110 ℃ for 26 hours. After the reaction is finished, adding water (15mL), extracting with ethyl acetate (3X 8mL), combining organic phases, drying with anhydrous sodium sulfate, filtering, decompressing and spin-drying the filtrate to remove the solvent, and quickly separating by silica gel column chromatography to obtain the required 1,3,5-oxadiazine derivative (I), wherein the reaction formula is shown as the following formula; the raw material selection and the results are shown in table 1.
Figure BDA0003014248030000191
TABLE 1
Example number Compound numbering Ar1 Ar2 Yield (%)
13 Im 4-FC6H4 4-OMeC6H4 52
14 In 4-FC6H4 4-MeC6H4 50
15 Io 4-FC6H4 3-FC6H4 46
16 Ip 3-ClC6H4 4-EtC6H4 47
17 Iq 3-ClC6H4 4-FC6H4 42
18 Ir 3-ClC6H4 3-MeC6H4 51
19 Is 3-MeC6H4 4-OMeC6H4 63
20 It 3-MeC6H4 3-MeC6H4 58
21 Iu 3-MeC6H4 3-FC6H4 49
22 Iv 2-PhC6H4 4-OMeC6H4 64
23 Iw 2-PhC6H4 3-MeC6H4 60
24 Ix 2-PhC6H4 3-FC6H4 55
25 Iy 4-ClC6H4 4-OMeC6H4 50
Results of biological Activity test
Monoamine oxidase and lung cancer cell strain A-549 inhibitor
6 compounds (Ib, Ic, Ih, Ik, Is, Iv) were selected to evaluate the ability of the compounds of the present application to inhibit monoamine oxidase (MAO). This application performed MAO inhibition activity tests in vitro on 5 selected compounds according to the method adopted by Yang Qing et al in the European journal of pharmaceutical chemistry 2009, Novel 4H-1,3, 4-oxadizin-5 (6H) -ones with hydrophilic and long alkyl chains, design, synthesis, and biological diversity on inhibition of monoamine oxidase, chitin biosyntheses and tumor cell Eur.J.Med.chem.2009,44, 2113-2121. These test compounds have moderate MAO inhibitory activity (see table 2).
In addition, the application also tests the anti-cancer activity of the 6 selected compounds in the lung cancer cell strain A-549, and the results are shown in Table 2. These results indicate that the compounds of the present application have moderate to good inhibition of A-549 activity, IC of compounds Ic, Ik and Iv50Values higher than 30. mu. mol/L, and IC of Compounds Ib, Ih and Is50The value was less than 20. mu. mol/L.
TABLE 2
Compound (I) IC50 for MAO(μmol/L) IC50 for A-549(μmol/L)
Ib 96 16.4
Ic 520 85.5
Ih 160 9.85
Ik 180 44.2
Is 84 12.3
Iv 230 36.8
The above-mentioned embodiments only express several embodiments of the present application, and the description thereof is more specific and detailed, but not construed as limiting the claims. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the concept of the present application, which falls within the scope of protection of the present application. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (10)

1. The 1,3,5-oxadiazine compound is characterized by having a structural general formula shown as a formula (I):
Figure FDA0003014248020000011
wherein R is1And R2Both aryl and heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1-5 substituents; said R1、R2The same or different.
2. The 1,3,5-oxadiazine according to claim 1, wherein the heteroaryl is a 5-6 membered heteroaryl, and the 5-6 membered heteroaryl comprises 1,2,3 or 4 moieties independently selected from-C (═ O) NH-, -S (═ O)2NH-, -S (═ O) NH-, N, -O-, -S-, ═ O, ═ S, -C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O)2-, -NHC (═ O) NH-, -NHC (═ S) NH-, or-H2A heteroatom or heteroatom group of P (═ O) -NH-.
3. The 1,3,5-oxadiazine according to claim 1, wherein the heteroaryl group is a thienyl, furyl, pyrrolyl or pyridyl group.
4. The 1,3,5-oxadiazine compound according to claim 1, wherein 1-5 substituents of the aryl or heteroaryl are independently selected from H, F, Cl, Br, I, NO2、NH2、OH、C1～3Alkyl radical, C1～3Alkoxy, phenyl; the C1-3 alkyl, C1-3 alkoxy or phenyl is optionally substituted by 1,2 or 3 substituents, and the 1,2 or 3 substituents of the C1-3 alkyl, C1-3 alkoxy or phenyl are independently selected from H, F, Cl, Br, I and NO2、NH2、OH。
5. The 1,3,5-oxadiazine compound according to claim 1, wherein 1-5 substituents of the aryl or heteroaryl are independently selected from H, F, Cl, Br, I, NO2、NH2OH, methyl, methoxy, trifluoromethyl or trifluoromethoxy.
6. The method for producing a 1,3,5-oxadiazine compound according to any one of claims 1 to 5, comprising:
mixing the amidine compound shown as the formula (II), a methyl donor and water, and catalyzing the mixture by a metal catalyst in the presence of an oxidant to prepare a 3, 4-disubstituted 1,3,5-oxadiazine compound shown as the formula (I);
Figure FDA0003014248020000021
7. the production method according to claim 6, wherein the methyl donor is at least one of the following structures:
Figure FDA0003014248020000022
8. the production method according to claim 6, wherein the oxidizing agent is at least one of 1-chloromethyl-4-fluoro-1, 4-diazotized bicyclo 2.2.2 octane bis (tetrafluoroborate) salt (Selectfluor), hydrogen peroxide, t-butyl hydroperoxide, 3-chloroperoxybenzoic acid, potassium persulfate, sulfur trioxide-pyridine complex, and iodine; the metal catalyst is at least one of copper trifluoromethanesulfonate, copper chloride, copper bromide, copper acetate, cuprous chloride, palladium acetate, zinc chloride, ferric chloride and nickel chloride.
9. The preparation method according to claim 6, wherein the molar ratio of the amidine compound to the oxidant to the metal catalyst to the methyl donor to water is 1:2:0.1:2 to 50: 1-5; the reaction temperature is 40-150 ℃, and the reaction time is 1-30 hours.
10. The use of the 1,3,5-oxadiazines according to any one of claims 1 to 5 for the preparation of monoamine oxidase inhibitors or for the preparation of anti-lung cancer drugs.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1324350A (en) * 1998-11-04 2001-11-28 默克专利股份有限公司 Benzoylpyridazines
CN1436179A (en) * 2000-04-21 2003-08-13 盐野义制药株式会社 Oxadiazole derivs. having anticancer effects
WO2017202481A1 (en) * 2016-05-27 2017-11-30 Valoralia I Más D, SL Dihydrooxadiazine compounds for treating infections and cancer
CN112225709A (en) * 2020-10-26 2021-01-15 安徽海顺化工有限公司 Synthesis method and synthesis device of 3-methyl-4-nitroimino-1, 3, 5-oxadiazine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1324350A (en) * 1998-11-04 2001-11-28 默克专利股份有限公司 Benzoylpyridazines
CN1436179A (en) * 2000-04-21 2003-08-13 盐野义制药株式会社 Oxadiazole derivs. having anticancer effects
WO2017202481A1 (en) * 2016-05-27 2017-11-30 Valoralia I Más D, SL Dihydrooxadiazine compounds for treating infections and cancer
CN112225709A (en) * 2020-10-26 2021-01-15 安徽海顺化工有限公司 Synthesis method and synthesis device of 3-methyl-4-nitroimino-1, 3, 5-oxadiazine

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