CN113666944A - 2-oxa-1, 7-diazabicycloheptane derivatives and preparation method thereof - Google Patents
2-oxa-1, 7-diazabicycloheptane derivatives and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a 2-oxa-1, 7-diazabicycloheptane derivative and a preparation method thereof, belonging to the field of organic synthesis, wherein the preparation method of the compound comprises the steps of adding an organic solvent into a mixture of 2, 3-dihydro-1, 2-dinitrocyclobutene oxynitride (I) and maleimide (II), reacting, stirring for 2-24 hours at a certain temperature, and separating and purifying after the reaction is finished; the invention realizes the synthesis of the 2-oxa-1, 7-diazabicyclo [3.2.0] heptane derivative through the step cyclization-ring opening elimination reaction without catalyst catalysis, the compound simultaneously contains three heterocyclic structures of diazetidine, tetrahydroisoxazole and succinimide, and the preparation method has the advantages of mild reaction conditions, simple and convenient operation and the like.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a 2-oxa-1, 7-diazabicyclo [3.2.0] heptane derivative and a preparation method thereof.
Background
Nitrogen-containing polyheterocycle fused compounds are widely present in biologically active compounds and clinical drugs, such as clinical penicillin drugs and cephalosporins, which contain a β -lactam fused thiazolidine skeleton. Research shows that many fused heterocyclic compounds containing quaternary heterocyclic skeletons have good biological activity, including killing pests, resisting bacteria, diminishing inflammation, resisting malaria, resisting tuberculosis and the like. Based on this, the synthesis of fused heterocyclic compounds has attracted increasing attention. A simple and efficient synthesis method is found to realize efficient synthesis of the nitrogen-containing multi-heterocyclic fused compound, particularly the fused heterocyclic compound containing the quaternary heterocyclic skeleton, so that more candidate molecules can be provided for research and development of new drugs and drug screening, and a new method can be provided for synthesis of the drugs.
Diazetidine, tetrahydroisoxazole and succinimide are widely present in bioactive compounds, and at present, compounds containing two dominant skeletons are reported more, but the three heterocycles are fused by one-step chemical conversion.
Disclosure of Invention
An object of the present invention is to provide a 2-oxa-1, 7-diazabicyclo [3.2.0] heptane derivative having a novel structure, which can solve the above problems.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: a 2-oxa-1, 7-diazabicycloheptane derivative having the structure shown in formula iii below:
in the above formula III, R1The radicals are selected from aryl radicals; r2The group is selected from aryl, heteroaryl and condensed aryl; r2The radicals are selected from aralkyl, linear alkyl, branched alkyl, cycloalkyl.
As a preferred technical scheme: the R is1The group is selected from one of phenyl, p-chlorophenyl, p-bromophenyl, p-methylphenyl, m-bromophenyl and m-methylphenyl; the R is2Selected from p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethylphenyl, p-methylphenyl, m-chlorophenyl, m-bromophenyl, m-cyanophenyl, m-methylphenyl, m-methoxyphenyl, 2, 5-dimethylphenyl, 3, 4-dichlorophenyl, 2-naphthylOne of 2-benzofuran and 2-benzothiophene; the R is3One selected from benzyl, propyl, isopropyl, butyl, isobutyl, hexyl, allyl, cyclopentyl, 2-chloroethyl and 2,2, 2-trichloroethyl.
The invention provides 2-oxa-1, 7-diazabicyclo [3.2.0] heptane derivatives with a brand-new structure, which are typical multi-element fused heterocyclic compounds and simultaneously contain three heterocyclic structures of diazetidine, tetrahydroisoxazole and succinimide.
Based on the wide application of diazetidine, tetrahydroisoxazole and succinimide in the field of biomedicine, the 2-oxa-1, 7-diazabicyclo [3.2.0] heptane derivative synthesized by the invention simultaneously contains the novel multi-element fused ring compound of the three heterocycles, so the 2-oxa-1, 7-diazabicyclo [3.2.0] heptane derivative has important significance in the aspects of organic synthesis and biomedicine.
The second object of the present invention is to provide a process for preparing the above derivatives,
the technical scheme is that quantitative 2, 3-dihydro-1, 2-dinitrogen cyclobutene oxynitride I and maleimide II are sequentially weighed in a pressure-resistant pipe, then an organic solvent is added into a mixture of the two, the mixture is reacted and stirred for 2-72 hours at a certain temperature, and after the reaction is finished, separation and purification are carried out, so that the high-purity silicon dioxide is obtained.
The reaction formula is as follows:
the 2, 3-dihydro-1, 2-dinitrocyclobutene oxynitride (I) has the following structure:
wherein R is2The group is selected from aryl, heteroaryl and condensed aryl; r3The radicals are selected from aralkyl, linear alkyl, branched alkyl, cycloalkyl.
The maleimide II has the following structure:
wherein R is1Selected from aryl groups.
The invention realizes the preparation of the 2-oxa-1, 7-diazabicyclo [3.2.0] heptane derivative through the stepwise cyclization-ring opening elimination reaction.
As a preferred technical scheme: the organic solvent is selected from one or more of dichloromethane, trichloromethane, 1, 2-dichloroethane, methyl tert-butyl ether, toluene, methanol and acetonitrile, and preferably trichloromethane. Because the reaction yield is highest in this solvent.
As a preferred technical scheme: the molar ratio of the 2, 3-dihydro-1, 2-dinitrocyclobutene oxynitride in the formula I to the maleimide in the formula II is 1: 1-1: 4, preferably 1: 1.5. Through actual condition screening, the molar ratio can not only ensure the rapid reaction, but also reduce the waste of maleimide.
As a preferred technical scheme: the concentration of the 2, 3-dihydro-1, 2-dinitrocyclobutene oxynitride in the formula I is 0.05-0.4 mol/L, and preferably 0.10 mol/L. At this concentration, the reaction has the highest yield with reduced solvent usage.
As a preferred technical scheme: the reaction temperature is 70 to 120 ℃, and more preferably 100 ℃. At this temperature, the yield of the reaction is the best.
As a preferred technical scheme: the reaction time is 2-72 hours.
The invention has the advantages that: the invention realizes the synthesis of the 2-oxa-1, 7-diazabicyclo [3.2.0] heptane derivative through one-step cyclization-ring opening elimination reaction, the reaction does not need a catalyst, the synthesized compound simultaneously has three heterocyclic structures of diazetidine, tetrahydroisoxazole and succinimide, and the preparation method has the advantages of mild reaction conditions, simple and convenient operation and the like.
Drawings
FIG. 1 is a hydrogen spectrum of the compound obtained in example 1;
FIG. 2 is a carbon spectrum of the compound obtained in example 1;
FIG. 3 is a hydrogen spectrum of the compound obtained in example 2;
FIG. 4 is a carbon spectrum of the compound obtained in example 2
FIG. 5 is a hydrogen spectrum of the compound obtained in example 3;
FIG. 6 is a carbon spectrum of the compound obtained in example 3;
FIG. 7 is a hydrogen spectrum of the compound obtained in example 4;
FIG. 8 is a carbon spectrum of the compound obtained in example 4.
Detailed Description
The invention will be further explained with reference to the drawings.
Example 1: synthesis of a Compound of the formula
The method comprises the following steps: dissolving 2, 3-dihydro-1, 2-dinitrocyclobutene oxynitride (0.2mmol of a reactant with the concentration of 0.1mol/L) and N-phenylmaleimide (0.3mmol) in dichloromethane (2.0mL) in a pressure-resistant tube, and stirring the reaction mixture at 70 ℃ for 24 hours (TLC monitoring); separating and purifying by column chromatography (petroleum ether: dichloromethane: 1:2) to obtain 31.9mg of the compound with yield of 35%;
the method 2 comprises the following steps: in a pressure resistant tube, the reaction mixture (0.2mmol of reactant concentration 0.1mol/L), N-phenylmaleimide (0.3mmol) was stirred at 100 ℃ for reaction for 36 hours (TLC monitoring); separating and purifying by column chromatography (petroleum ether: dichloromethane: 1:2) to obtain the compound of the above formula, 41.0mg, yield 45%;
the method 3 comprises the following steps: in a pressure-resistant tube, the reaction mixture (0.2mmol of reactant with the concentration of 0.1mol/L) and N-phenylmaleimide (0.3mmol) are stirred and reacted for 36 hours at the temperature of 130 ℃; separating and purifying by column chromatography (petroleum ether: dichloromethane: 1:2) to obtain the compound of the above formula, 10.9mg, yield 12%;
and (3) structural identification:1H NMR(300MHz,CDCl3) δ 7.51-7.40(m,7H),7.40-7.29(m,6H),7.25-7.18(m,2H),5.62(d, J ═ 8.2Hz,1H),5.39-5.15(dd, J ═ 12.3,22.2Hz,2H),4.07(dd, J ═ 8.4,5.7Hz,2H),3.97(d, J ═ 8.5Hz,1H), as shown in fig. 1;13C NMR(101MHz,CDCl3) δ 173.2,172.0,159.0,139.1,135.4,131.2,129.6,129.4,129.3,128.9,128.8,128.5,128.0,126.5,124.9,83.3,80.6,68.5,57.2,52.3 as shown in fig. 2.
Based on the three preparation methods in example 1 above, it was confirmed that the reaction temperature is preferably 100 ℃ in the synthesis of the 2-oxa-1, 7-diazabicyclo [3.2.0] heptane derivative, and if the reaction temperature exceeds 120 ℃, the yield of the reaction product is significantly reduced.
Example 2: synthesis of a Compound of the formula
In a pressure resistant tube, 2, 3-dihydro-1, 2-dinitrocyclobutene nitroxide, N-phenylmaleimide was dissolved in chloroform (2.0mL), and the reaction mixture was stirred at 100 ℃ for 24 hours (TLC monitoring). Separating and purifying by column chromatography (petroleum ether: dichloromethane: 1:2) to obtain the compound of the above formula, 45.0mg, yield 48%;
and (3) structural identification:1H NMR(300MHz,CDCl3) δ 7.48-7.42(m,3H),7.41-7.30(m,7H),7.23(d, J ═ 7.6Hz,4H),5.60(d, J ═ 8.2Hz,1H),5.27(dd, J ═ 6.3,18.0Hz,2H),4.06(dd, J ═ 8.3,5.9Hz,2H),3.94(d, J ═ 8.5Hz,1H),2.36(s,3H), as shown in fig. 3;13C NMR(101MHz,CDCl3) δ δ 173.3,172.0,159.0,138.9,136.1,135.4,131.2,130.0,129.6,129.3,128.8,128.5,128.0,126.5,124.9,83.3,80.6,68.5,57.2,52.4,21.3 as shown in fig. 4.
Example 3: synthesis of a Compound of the formula
In a pressure resistant tube, 2, 3-dihydro-1, 2-dinitrocyclobutene nitroxide, N-phenylmaleimide was dissolved in chloroform (2.0mL), and the reaction mixture was stirred at 100 ℃ for 24 hours (TLC monitoring). Separating and purifying by column chromatography (petroleum ether: dichloromethane: 1:2) to obtain the compound of the above formula, 45.0mg, yield 48%;
and (3) structural identification:1H NMR(300MHz,CDCl3) δ 7.52(t, J ═ 7.7Hz,2H),7.49-7.40(m,5H),7.39-7.34(m,1H),7.31-7.26(m,2H),5.58(d, J ═ 8.2Hz,1H),4.03(dd, J ═ 8.5Hz,2H),3.91(d, J ═ 8.4Hz,1H),1.51(s,9H), as shown in fig. 5;13C NMR(101MHz,CDCl3) δ 173.4,172.2,157.7,139.3,131.4,129.6,129.4,129.3,128.8,126.6,125.0,83.6,83.1,80.0,57.3,52.0,28.2 as shown in fig. 6.
Example 4: synthesis of a Compound of the formula
In a pressure resistant tube, 2, 3-dihydro-1, 2-dinitrocyclobutene nitroxide, N-phenylmaleimide was dissolved in chloroform (2.0mL), and the reaction mixture was stirred at 100 ℃ for 24 hours (TLC monitoring). Separating and purifying by column chromatography (petroleum ether: dichloromethane: 1:2) to obtain the compound of the above formula (43.3 mg, 50% yield);
and (3) structural identification:1h NMR (600MHz, CDCl3) δ 7.53-7.49(m,2H),7.48-7.44(m,3H),7.44-7.41(m,2H),7.39-7.33(m,1H),7.29-7.27(m,2H),5.59(d, J ═ 8.2Hz,1H),5.29-5.17(m,1H),4.05(dd, J ═ 8.3,5.1Hz,2H),3.92(d, J ═ 8.4Hz,1H),1.92-1.85(m,2H),1.84-1.80(m,1H),1.80-1.75(m,3H),1.62-1.58(m,2H), as shown in fig. 7;13c NMR (151MHz, CDCl3) delta 173.3,172.1,158.8,139.2,131.3,129.7,129.6,129.4,128.8,126.5,125.0,83.1,80.5,80.4,57.3,52.1,32.9,32.8,23.7,23.7 as shown in FIG. 8.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (8)
- A2-oxa-1, 7-diazabicycloheptane derivative characterized by having a structure represented by the following structural formula (III):
in the above structural formula (III), R1Radicals selected from the group consisting of aryl radicals R2The group is selected from aryl, heteroaryl and condensed aryl; r3The radicals are selected from aralkyl, linear alkyl, branched alkyl, cycloalkyl. - 2. The 2-oxa-1, 7-diazabicycloheptane derivative of claim 1, characterized in that: the R is1The group is selected from one of phenyl, p-chlorophenyl, p-bromophenyl, p-methylphenyl, m-bromophenyl and m-methylphenyl; the R is2The group is selected from one of phenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethylphenyl, p-methylphenyl, m-chlorophenyl, m-bromophenyl, m-cyanophenyl, m-methylphenyl, m-methoxyphenyl, 2, 5-dimethylphenyl, 3, 4-dichlorophenyl, 2-naphthyl, 2-benzofuran and 2-benzothiophene; the R is3One selected from benzyl, propyl, isopropyl, butyl, isobutyl, hexyl, allyl, cyclopentyl, 2-chloroethyl and 2,2, 2-trichloroethyl.
- 3. The process for producing a 2-oxa-1, 7-diazabicycloheptane derivative according to claim 1 or 2, characterized by mixing a 2, 3-dihydro-1, 2-dinitrocyclobutene nitroxide represented by the following formula (i) and a maleimide represented by the following formula (ii), adding an organic solvent under stirring, heating, continuously stirring until the reaction is completed, and separating and purifying to obtain the compound;the 2, 3-dihydro-1, 2-dinitrocyclobutene oxynitride (I) has the following structure:
wherein R is2The group is selected from aryl, heteroaryl and condensed aryl; r3The radicals are selected from aralkyl, linear alkyl, branched alkyl, cycloalkyl;the maleimide (II) has the following structure:
wherein R is1Selected from aryl groups. - 4. The preparation method according to claim 3, wherein the organic solvent is selected from one or more of dichloromethane, trichloromethane, 1, 2-dichloroethane, methyl tert-butyl ether, toluene and acetonitrile, preferably trichloromethane.
- 5. The process according to claim 3, wherein the molar ratio of the 2, 3-dihydro-1, 2-diazocyclobutene nitroxide of formula (I) to the maleimide of formula (II) is from 1:1 to 1:4, preferably 1: 1.5.
- 6. The method according to claim 3, wherein the concentration of the 2, 3-dihydro-1, 2-diazocyclobutene oxynitride of formula (I) is 0.05 to 0.3mol/L, preferably 0.10 mol/L.
- 7. The method according to claim 3, wherein the reaction temperature is 70 to 120 ℃, preferably 100 ℃.
- 8. The method according to claim 3, wherein the reaction time is 2 to 72 hours, preferably 24 hours.
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| CN112480124A (en) * | 2020-12-16 | 2021-03-12 | 成都大学 | Trifluoromethyl substituted chiral tetrahydropyrrole [1,2-c ] quinazoline-3, 5-diketone and preparation method thereof |
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| CN112480124A (en) * | 2020-12-16 | 2021-03-12 | 成都大学 | Trifluoromethyl substituted chiral tetrahydropyrrole [1,2-c ] quinazoline-3, 5-diketone and preparation method thereof |
Non-Patent Citations (2)
| Title |
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| LI-WEN SHEN,等: "α‑Nitrosostyrenes as Three-Atom Units for the (3+1) Cyclization Reaction: Facile Access to 2,3-Dihydrodiazete N‑Oxides and Their Diversified Synthetic Conversions" * |
| SEN ZHAO，等: "An efficient synthesis of 2-isoxazolines from a-haloketone oximes and dimethyl sulfonium salts" * |
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