阅读说明：本技术 一种氟叠氮取代的四元杂环化合物的制备和应用 (Preparation and application of fluorine azide substituted quaternary heterocyclic compound ) 是由 毕锡和 宁永泉 张欣宇 于 2019-09-30 设计创作，主要内容包括：本发明涉及药物中间体技术领域,尤其涉及一种氟叠氮取代的四元杂环的制备方法和应用。本发明提供的具有式Ⅰ所示结构氟叠氮取代的四元杂环可作为偕二甲基和羰基官能团的替代物以改善有机分子的生物学性质,并且也可作为潜在的氟胺化四元杂环的载体。本发明还提供了所述氟叠氮取代的四元杂环的制备方法,所述制备方法的具体过程是将具有式Ⅱ所示结构的烯基叠氮类化合物、氧化剂、氟源和溶剂混合,进行反应,得到氟叠氮取代的四元杂环。所述制备方法所用原料简便易得,操作简单、反应高效,可实现工业化合成。(The invention relates to the technical field of drug intermediates, in particular to a preparation method and application of a fluorine azide substituted quaternary heterocycle. The fluorine azide substituted quaternary heterocycle with the structure shown in the formula I can be used as a substitute of a gem-dimethyl functional group and a carbonyl functional group to improve the biological property of an organic molecule, and can also be used as a carrier of a potential fluorine aminated quaternary heterocycle. The invention also provides a preparation method of the fluorine azide substituted quaternary heterocyclic ring, which comprises the specific process of mixing the alkenyl azide compound with the structure shown in the formula II, an oxidant, a fluorine source and a solvent for reaction to obtain the fluorine azide substituted quaternary heterocyclic ring. The preparation method has the advantages of simple and easily obtained raw materials, simple operation, high reaction efficiency and realization of industrial synthesis.)

1. A fluorine azide substituted quaternary heterocycle has a structure shown in formula I:

in the formula I, R¹～R⁴Independently substituted or unsubstitutedAryl, substituted or unsubstituted C_1～15Alkyl, substituted or unsubstituted C_1～10Heteroalkyl, substituted or unsubstituted C_2～10Alkenyl of (a), substituted or unsubstituted C_3～10Alkynyl, substituted or unsubstituted C_1～10Alkoxy, -H, -S, -O, -N or-B;

when said R is¹～R⁴When independently substituted or unsubstituted aryl, the substituted or unsubstituted aryl is substituted or unsubstituted phenyl, substituted or unsubstituted C₅-C₁₀Heteroaryl or substituted or unsubstituted C₁₀-C₁₆A fused aryl group;

the R is¹～R⁴Wherein the substituent group is C_1～8Alkyl of (C)_1～8Fluoroalkyl group of (2), C_1～4Alkoxy group, -NR₃、-NO₂、-CX₃、-CN、-SO₃H、-CHO、-COR、-COOH、-S(＝O)₂One or more of-R, -COR, -X and-COOR;

the R is alkyl; and X is Cl, Br or F.

2. The fluoroazide substituted quaternary heterocycle of claim 1, wherein X is O, S, NH, NR.

R is C_1～8Alkyl of (C)_1～8Fluoroalkyl group of (2), C_1～4Alkoxy group, -NR₃、-NO₂、-CX₃、-CN、-SO₃H、-CHO、-COR、-COOH、-S(＝O)₂-R, -COR, -X and-COOR.

3. The fluoroazide substituted quaternary heterocycle of claim 1, wherein when said substituted or unsubstituted aryl is substituted or unsubstituted C₅-C₁₀When the heteroaryl is adopted, the heteroatom in the heteroaryl is one or more of O, S and N;

the number of the heteroatoms is 1-3.

4. The fluoroazide substituted tetragon of claim 1Heterocycle, wherein when said substituted or unsubstituted aryl is substituted or unsubstituted C₁₀-C₁₆When the fused aryl group is a naphthyl group, an anthryl group or a phenanthryl group.

5. The fluoroazide substituted quaternary heterocycle of claim 1, wherein said fluoroazide substituted quaternary heterocycle is:

6. the method for preparing a fluoroazide-substituted quaternary heterocycle of any one of claims 1 to 5, comprising the steps of:

mixing an alkenyl azide compound with a structure shown in a formula II, an oxidant, a fluorine source and a solvent, and reacting to obtain a fluorine azide substituted quaternary heterocycle; x is OH, NHR, SH;

7. the preparation method of claim 6, wherein the oxidant is one or more of hydrogen peroxide, tert-butyl hydroperoxide, 2, 3-dichloro-5, 6-dicyan p-benzoquinone, ceric ammonium nitrate, tert-butyl peroxybenzoate, m-chloroperoxybenzoic acid, di-tert-butyl peroxide, iodobenzene diacetic acid, iodine acetate, iodoxybenzene, a high-valent iodine reagent, potassium persulfate, potassium permanganate, nitrate, potassium hypochlorite and potassium perchlorate.

8. The method according to claim 6, wherein the fluorine source is one or more selected from the group consisting of 1-chloromethyl-4-fluoro-1, 4-diazotized bicyclo 2.2.2 octane bis (tetrafluoroboric acid), N-fluorobisbenzenesulfonamide, 1-fluoro-3, 3-dimethyl-1, 2-benziodoxolane, triethylamine trihydrofluoride, pyridine hydrochloride fluoride, N-dimethylpropylurea hydrogen fluoride complex, iodobenzene difluoride, an iodobenzene difluoride derivative, penfenfluroether, and a metal fluoride salt.

9. The method according to claim 6, wherein the solvent is one or more selected from the group consisting of ethyl acetate, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, dimethyl sulfoxide, N-methylpyrrolidone, and N, N-dimethylformamide.

10. The method of claim 6, wherein the molar ratio of the alkenyl azide compound having the structure of formula ii to the oxidizing agent to the fluorine source is 1: (1-2): (5-7);

the reaction temperature is-78-80 ℃, and the reaction time is 1-24 h.

11. The use of the fluoro azide substituted quaternary heterocycle of claims 1-5 or the fluoro azide substituted quaternary heterocycle prepared by the preparation method of claims 6-9 as a precursor for the synthesis of various drugs, bioactive molecules and natural products.

Technical Field

The invention relates to the technical field of drug intermediates, in particular to a fluorine azide substituted quaternary heterocyclic compound and preparation and application thereof.

Background

The availability of organofluorides for synthesis of organofluoride in the field of life science and material science has become an important challenge in modern organic chemistry one of the most important advances in this process is the ability to construct in an efficient manner various saturated fluorinated heterocyclic compounds, such as saturated ternary, penta-, hexahydric and hepta-heterocycles ((a) Mennie, K. M., Banik, s.m., Reichert, E.C. & Jacobsen, e.n.j.am. chem.soc.2018,140,4797-4802.(b) Wu, t, Yin, G. & Liu, g.j.am. chem.2009, soc.2009,131, 16355.(c) Yuan, W. zab, blin. G., Liu., g.j.am. am. wo, g.m.2009, etc., 131, 54-16355.(c) the important heterocyclic compounds of the insecticide, such as the saturated ternary, n, M, o, K, M, o.

Disclosure of Invention

The invention aims to provide a fluorine azide substituted quaternary heterocyclic compound and preparation and application thereof.

In order to achieve the above object, the present invention provides the following technical solutions:

the invention provides a fluorine azide substituted quaternary heterocyclic compound, which has a structure shown in a formula I:

in the formula I, R¹～R⁴Independently is substituted or unsubstituted aryl, substituted or unsubstituted C_1～15Alkyl, substituted or unsubstituted C_1～10Heteroalkyl, substituted or unsubstituted C_2～10Alkenyl, substituted or unsubstitutedC_3～10Alkynyl, substituted or unsubstituted C_1～10Alkoxy, -H, -S, -O, -N or-B;

when said R is¹～R⁴When independently substituted or unsubstituted aryl, the substituted or unsubstituted aryl is substituted or unsubstituted phenyl, substituted or unsubstituted C₅-C₁₀Heteroaryl or substituted or unsubstituted C₁₀-C₁₆A fused aryl group;

the R is¹～R⁴Wherein the substituent group is C_1～8Alkyl of (C)_1～8Fluoroalkyl group of (2), C_1～4Alkoxy group, -NR₃、-NO₂、-CX₃、-CN、-SO₃H、-CHO、-COR、-COOH、-S(＝O)₂One or more of-R, -COR, -X and-COOR.

And X is O, S, NH or NR. R is C_1～8Alkyl of (C)_1～8Fluoroalkyl group of (2), C_1～4Alkoxy group, -NR₃、-NO₂、-CX₃、-CN、-SO₃H、-CHO、-COR、-COOH、-S(＝O)₂-one of-R, -COR, -X and-COOR; the R is alkyl or aryl; and X is Cl, Br or F.

When said substituted or unsubstituted aryl group is substituted or unsubstituted C₅-C₁₀When the heteroaryl is adopted, the heteroatom in the heteroaryl is one or more of O, S and N;

the number of the heteroatoms is 1-3.

When the substituted or unsubstituted aryl is substituted or unsubstituted C₁₀-C₁₆When the fused aryl group is a naphthyl group, an anthryl group or a phenanthryl group.

The fluorine azide substituted quaternary heterocyclic ring is as follows:

the invention also provides a preparation method of the fluorine azide substituted quaternary heterocyclic compound, which comprises the following steps:

mixing an alkenyl azide compound with a structure shown in a formula II, an oxidant, a fluorine source and a solvent, and reacting to obtain a fluorine azide substituted quaternary heterocyclic compound; x is OH, NHR, SH;

preferably, the oxidant is one or more of hydrogen peroxide, tert-butyl hydroperoxide, 2, 3-dichloro-5, 6-dicyan p-benzoquinone, ammonium ceric nitrate, tert-butyl peroxybenzoate, m-chloroperoxybenzoic acid, di-tert-butyl peroxide, iodobenzene diacetic acid, iodine acetate, iodosobenzene, a high-valence iodine reagent, potassium persulfate, potassium permanganate, nitrate, potassium hypochlorite and potassium perchlorate.

Preferably, the fluorine source is one or more of 1-chloromethyl-4-fluoro-1, 4-diazotized bicyclo 2.2.2 octane bis (tetrafluoroboric acid), N-fluoro-bis-benzenesulfonamide, 1-fluoro-3, 3-dimethyl-1, 2-benziodoxolane, triethylamine trihydrofluoride, hydrogen fluoride pyridine hydrochloride, N-dimethylpropylurea hydrogen fluoride complex, iodobenzene difluoride derivative, boron trifluoride diethyl etherate, and metal fluoride salt.

Preferably, the solvent is one or more of ethyl acetate, tetrahydrofuran, toluene, dichloromethane, dichloroethane, dimethyl sulfoxide, N-methylpyrrolidone and N, N-dimethylformamide.

Preferably, the molar ratio of the alkenyl azide compound having the structure shown in formula II, the oxidant and the fluorine source is 1: (1-2): (5-7);

the reaction temperature is-78-80 ℃, and the reaction time is 1-24 h.

The invention also provides the application of the fluorine azide substituted quaternary heterocyclic compound or the fluorine azide substituted quaternary heterocyclic compound prepared by the preparation method in the scheme as a precursor for synthesizing various medicines, bioactive molecules and natural products.

The invention provides a fluorine azide substituted quaternary heterocyclic compound with a structure shown in a formula I, which can be used as a construction precursor of an ideal fluorine amino substituted quaternary heterocyclic compound. The invention also provides a preparation method of the fluorine azide substituted quaternary heterocyclic compound, which comprises the specific process of mixing the alkenyl azide compound with the structure shown in the formula II, an oxidant, a fluorine source and a solvent for reaction to obtain the fluorine azide substituted quaternary heterocyclic compound. The preparation method has the advantages of simple and easily obtained raw materials, simple operation, high reaction efficiency and realization of industrial synthesis.

Drawings

FIG. 1 is 2a¹Nuclear magnetic resonance spectrum of H-NMR;

FIG. 2 is 2a¹³Nuclear magnetic resonance spectrum of C-NMR;

FIG. 3 is 2a¹⁹Nuclear magnetic resonance spectrum of F-NMR;

FIG. 4 is 2b¹Nuclear magnetic resonance spectrum of H-NMR;

FIG. 5 is 2b¹³Nuclear magnetic resonance spectrum of C-NMR;

2b in FIG. 6¹⁹Nuclear magnetic resonance spectrum of F-NMR;

2c in FIG. 7¹Nuclear magnetic resonance spectrum of H-NMR;

2c in FIG. 8¹³Nuclear magnetic resonance spectrum of C-NMR;

2c in FIG. 9¹⁹Nuclear magnetic resonance spectrum of F-NMR;

2d in FIG. 10¹Nuclear magnetic resonance spectrum of H-NMR;

FIG. 11 is 2d¹³Nuclear magnetic resonance spectrum of C-NMR;

2d in FIG. 12¹⁹Nuclear magnetic resonance spectrum of F-NMR;

2e in FIG. 13¹Nuclear magnetic resonance spectrum of H-NMR;

2e in FIG. 14¹³Nuclear magnetic resonance spectrum of C-NMR；

2e in FIG. 15¹⁹Nuclear magnetic resonance spectrum of F-NMR;

2f in FIG. 16¹Nuclear magnetic resonance spectrum of H-NMR;

2f in FIG. 17¹³Nuclear magnetic resonance spectrum of C-NMR;

2f in FIG. 18¹⁹Nuclear magnetic resonance spectrum of F-NMR;

FIG. 19 is 2g¹Nuclear magnetic resonance spectrum of H-NMR;

FIG. 20 is 2g¹³Nuclear magnetic resonance spectrum of C-NMR;

FIG. 21 is 2g¹⁹Nuclear magnetic resonance spectrum of F-NMR;

2h in FIG. 22¹Nuclear magnetic resonance spectrum of H-NMR;

FIG. 23 is 2h¹³Nuclear magnetic resonance spectrum of C-NMR;

FIG. 24 is 2h¹⁹Nuclear magnetic resonance spectrum of F-NMR;

FIG. 25 is 2i¹Nuclear magnetic resonance spectrum of H-NMR;

FIG. 26 is 2i¹³Nuclear magnetic resonance spectrum of C-NMR;

2i in FIG. 27¹⁹Nuclear magnetic resonance spectrum of F-NMR.

Detailed Description