CN111057039A - 5-azido-5-fluoro-1, 3-dioxygen cyclic group-2-ketone derivative and preparation method thereof - Google Patents

5-azido-5-fluoro-1, 3-dioxygen cyclic group-2-ketone derivative and preparation method thereof Download PDF

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CN111057039A
CN111057039A CN201911245933.6A CN201911245933A CN111057039A CN 111057039 A CN111057039 A CN 111057039A CN 201911245933 A CN201911245933 A CN 201911245933A CN 111057039 A CN111057039 A CN 111057039A
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fluoro
azido
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CN111057039B (en
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刘振华
陈慧敏
宁永泉
高雯
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Shandong Normal University
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Abstract

The invention belongs to the technical field of preparation of vinyl azide, and relates to a 5-azido-5-fluoro-1, 3-dioxygen cyclic-2-ketone derivative and a preparation method thereof. The chemical structure of the derivative is shown as formula (1):
Figure DDA0002307625960000011
wherein the content of the first and second substances,
Figure DDA0002307625960000012
represents a cyclic alkane compound selected from C3‑C10Cycloalkyl radical, C3‑C10Substituted cycloalkyl, C3‑C10One of the epoxyalkyl groups of (1). The method is completed by oxidizing fluorine cyclization reaction of vinyl azide, namely PhIF generated in situ by oxidizing agent PIDA and hydrofluoride Py & HF2HF reaction is completed and is very easyThe catalyst is easily prepared by the hydrogenation azide reaction of terminal alkyne; this method is effective in retaining the azide groups in the final product. The novel compounds have potential application value in organic and medicinal chemistry research.

Description

5-azido-5-fluoro-1, 3-dioxygen cyclic group-2-ketone derivative and preparation method thereof
Technical Field
The invention belongs to the technical field of preparation of vinyl azide, and relates to a 5-azido-5-fluoro-1, 3-dioxygen cyclic-2-ketone derivative and a preparation method thereof.
Background
The statements in this background of the invention section are merely intended to enhance an understanding of the general background of the invention and are not necessarily to be construed as admissions or any form of suggestion that this information constitutes prior art that is already known to a person of ordinary skill in the art.
Vinyl azide is an organic synthetic material that is readily prepared by hydrogenation of hydrocarbons. The enormous shift in this field of research reported in the literature over the past decade has witnessed the rapid development of vinyl azide chemistry. Most vinyl azide-based transformations typically undergo molecular N2The 2H-pyridine nitride and the vinyl nitride intermediate are generated, thereby providing diversified and structurally unique molecular frameworks. In the mechanical aspect, ethylene azide, an important C — N compound, is generally used for the synthesis of various N-containing molecules, and has been widely studied in recent years. In previous studies, the retention of azide groups in the final product was rare, but the desired organic azides could be obtained by this reaction and this study was a great challenge in the field of organic synthesis. For example, in 2017 Lopez et al reported a copper catalyzed [3+2 ]]Cycloaddition/allylazidation, rearranging the vinyl carbene precursor to vinyl azidation to form azidocyclopentene (e.lopez, l.a.lopez, angelw.chem.int.ed.2017, 56,5121; angelw.chem.2017, 129, 5203.); meanwhile, the Xu topic group reports Cu catalyzed asymmetry [4+2 ]]Cycloaddition of vinyl azides with unsaturated ketoesters to form various chiral cyclic azides (n.thirouphathi, f.wei, c. -h.tung, z.xu, nat. commun.2019,10,3158.); due to the important role of the azide group in organic synthesis, a new method for exploring the application of the azide group in organic synthesis becomes a hotspot of organic chemistry research.
Disclosure of Invention
The object of the present invention is to develop a new strategy by olefin functionalization, thus in situIntroducing a leaving group to N3The group remains intact during the transformation, thereby leaving the azide group in the final product. Therefore, the invention provides a 5-azido-5-fluoro-1, 3-dioxygen cyclic group-2-ketone derivative and a preparation method thereof. The method is completed by oxidizing fluorine cyclization reaction of vinyl azide, namely PhIF generated in situ by oxidizing agent PIDA and hydrofluoride Py & HF2The HF reaction is completed and is easily prepared by the hydrogenation azide reaction of terminal alkyne; this method is effective in retaining the azide groups in the final product.
In order to achieve the purpose, the technical scheme of the invention is as follows:
firstly, the invention discloses a compound 5-azido-5-fluoro-1, 3-dioxygen cyclic group-2-ketone derivative, the chemical structure of which is shown in formula (1):
Figure BDA0002307625940000021
wherein the content of the first and second substances,
Figure BDA0002307625940000022
represents a cyclic alkane compound selected from C3-C10Cycloalkyl radical, C3-C10Substituted cycloalkyl, C3-C10An alkylene oxide group of (1).
Secondly, the invention discloses a preparation method of the 5-azido-5-fluoro-1, 3-dioxygen cyclic group-2-ketone derivative, which takes a villiaumite compound generated in situ by vinyl azide, an oxidant and hydrofluoride as raw materials to react under the action of a solvent and at a set temperature to obtain the 5-azido-5-fluoro-1, 3-dioxygen cyclic group-2-ketone derivative.
Further, the chemical structural formula of the vinyl azide is shown as a formula (2):
Figure BDA0002307625940000023
wherein the content of the first and second substances,
Figure BDA0002307625940000024
represents cyclic alkane compounds selected from C3-C10 cycloalkyl, C3-C10 substituted cycloalkyl and C3-C10 epoxy alkyl.
Further, the fluoride salt compound generated in situ from the oxidizing agent and the hydrofluoride salt (m.hf) is reacted by:
oxidizing agent + m.hf → fluoride salt.
Compared with the prior art, the invention has the following beneficial effects:
(1) based on long-term research on α -vinyl azide chemistry, the invention retains azide groups in the final product through oxidative fluorination of vinyl azide, i.e., through reaction with an oxidizing agent and a hydrofluoride compound to generate a fluoride salt in situ, and is readily prepared by the hydroazidation of a terminal alkyne.
(2) The method has the advantages of simple and efficient synthetic process, easy operation, wide substrate range, good functional group tolerance and moderate to good yield, and provides a plurality of new synthetic ideas for preparing valuable nitrogen-containing cyclic carbonate frameworks.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.
FIG. 1 is a drawing of Compound 2a prepared in example 1 of the present invention1Nuclear magnetic resonance spectrum of H-NMR.
FIG. 2 is a drawing of Compound 2a prepared in example 1 of the present invention13Nuclear magnetic resonance spectrum of C-NMR.
FIG. 3 is a drawing of Compound 2a prepared in example 1 of the present invention19Nuclear magnetic resonance spectrum of F NMR.
FIG. 4 is a drawing of Compound 2b, prepared according to example 7 of the invention1Nuclear magnetic resonance spectrum of H-NMR.
FIG. 5 is a drawing of Compound 2b, prepared according to example 7 of the invention13Nuclear magnetic resonance spectrum of C-NMR.
FIG. 6 is a drawing of Compound 2b, prepared according to example 7 of the invention19Nuclear magnetic resonance spectrum of F NMR.
FIG. 7 is a drawing of Compound 2c, prepared according to example 8 of the invention1Nuclear magnetic resonance spectrum of H-NMR.
FIG. 8 is a drawing of Compound 2c, prepared according to example 8 of the invention13Nuclear magnetic resonance spectrum of C-NMR.
FIG. 9 is a photograph of Compound 2c, prepared according to example 8 of the present invention19Nuclear magnetic resonance spectrum of F NMR.
FIG. 10 is a photograph of Compound 2d prepared in example 9 of the present invention1Nuclear magnetic resonance spectrum of H-NMR.
FIG. 11 is a photograph of Compound 2d prepared in example 9 of the present invention13Nuclear magnetic resonance spectrum of C-NMR.
FIG. 12 is a photograph of Compound 2d prepared in example 9 of the present invention19Nuclear magnetic resonance spectrum of F NMR.
FIG. 13 is a photograph of Compound 2e, prepared in example 10 of the present invention1Nuclear magnetic resonance spectrum of H-NMR.
FIG. 14 is a photograph of Compound 2e, prepared in example 10 of the present invention13Nuclear magnetic resonance spectrum of C-NMR.
FIG. 15 is a photograph of Compound 2e, prepared in example 10 of the present invention19Nuclear magnetic resonance spectrum of F NMR.
FIG. 16 is a photograph of Compound 2f prepared in example 11 of the present invention1Nuclear magnetic resonance spectrum of H-NMR.
FIG. 17 is a photograph of Compound 2f prepared in example 11 of the present invention13Nuclear magnetic resonance spectrum of C-NMR.
FIG. 18 is a photograph of Compound 2f prepared in example 11 of the present invention19Nuclear magnetic resonance spectrum of F NMR.
FIG. 19 is a graph of 2g of compound prepared in example 12 of the present invention1Nuclear magnetic resonance spectrum of H-NMR.
FIG. 20 is a graph of 2g of compound prepared in example 12 of the present invention13Nuclear magnetic resonance spectrum of C-NMR.
FIG. 21 is a drawing showing 2g of compound prepared in example 12 of the present invention19Nuclear magnetic resonance spectrum of F NMR.
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. 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 invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
The invention provides a method for generating 5-azido, 5-fluoro-1, 3-oxapent-2-one by oxidation reaction of fluorinated alkenyl azide.
In a typical embodiment of the present invention, there is provided an oxidation reaction of a fluorinated alkenyl azide to produce 5-azido, 5-fluoro-1, 3-oxapent-2-one having a chemical structure represented by the following formula (1),
Figure BDA0002307625940000041
wherein the content of the first and second substances,
Figure BDA0002307625940000042
represents a cyclic alkane compound selected from C3-C10Cycloalkyl radical, C3-C10Substituted cycloalkyl, C3-C10The heterocyclic group of (1).
In one or more embodiments of this embodiment, the C3-C10Cycloalkyl is selected from C3-C10Cycloalkyl radical, C3-C10A substituted cycloalkyl group.
In this series of examples, said C3-C10Substituted cycloalkyl is cycloalkyl substituted by phenyl, alkyl;
in this series of examples, the alkyl group is from C1-C6Straight or branched chain alkyl.
In this series of examples, said C3-C10The heterocyclic group of (a) contains one or more heteroatoms selected from N, O, S; preferably O.
In one or more embodiments of this embodiment,
Figure BDA0002307625940000043
selected from the group consisting of cyclopentyl, cyclohexyl, 3-phenylcyclobutyl, 4-methylcyclohexyl, 4-ethylcyclohexyl, 4-dimethylcyclohexyl, 4-epoxyhexyl.
In another embodiment of the present invention, there is provided the above method for preparing 5-azido-5-fluoro-1, 3-dioxygen cyclic-2-one derivative, wherein a fluoro salt compound formed in situ from a vinyl azide, an oxidizing agent and a hydrofluoride salt is used as a raw material, and the raw material is reacted at a predetermined temperature in the presence of a solvent to obtain the 5-azido-5-fluoro-1, 3-dioxygen cyclic-2-one derivative.
Further, the chemical structural formula of the vinyl azide is shown as a formula (2):
Figure BDA0002307625940000044
wherein the content of the first and second substances,
Figure BDA0002307625940000045
represents a cyclic alkane compound selected from C3-C10Cycloalkyl radical, C3-C10Substituted cycloalkyl, C3-C10An alkylene oxide group of (1).
Further, the fluoride salt compound generated in situ from the oxidizing agent and the hydrofluoride salt (M.HF) is reacted in the process of
Oxidizing agent + m.hf → fluoride salt.
The reaction equation for obtaining the 5-azido-5-fluoro-1, 3-dioxygen cyclic-2-ketone derivative is as follows:
Figure BDA0002307625940000051
wherein the content of the first and second substances,
Figure BDA0002307625940000052
represents a cyclic alkane compound selected from C3-C10Cycloalkyl radical, C3-C10Substituted cycloalkyl, C3-C10An alkylene oxide group of (1).
In one or more embodiments of this embodiment, C is as described above3-C10Cycloalkyl is selected from C3-C10Cycloalkyl radical, C3-C10A substituted cycloalkyl group.
In this series of examples, said C3-C10Substituted cycloalkyl is cycloalkyl substituted by phenyl, alkyl;
in this series of examples, the alkyl group is from C1-C6A linear or branched alkyl group;
in this series of examples, said C3-C10The heterocyclic group of (a) contains one or more heteroatoms selected from N, O, S;
in one or more embodiments of this embodiment,
Figure BDA0002307625940000053
selected from the group consisting of cyclopentyl, cyclohexyl, 3-phenylcyclobutyl, 4-methylcyclohexyl, 4-ethylcyclohexyl, 4-dimethylcyclohexyl, 4-epoxyhexyl.
In one or more embodiments of this embodiment, the oxidizing agent is selected from the group consisting of PIDA, PhIO, PIFA, SelectFluoro, K2S2O8、H2O2One kind of (1). In the series of examples, the oxidant is selected from one of PIDA, PhIO and PIFA, and the oxidant can improve raw materialsWhile increasing the yield of the product. When the oxidizing agent is PIDA, the conversion of the raw material and the yield of the product can be further improved.
In one or more embodiments of this embodiment, the hydrofluoride salt is selected from py. hf, Et3One of HF, AgF and CsF. In this series of examples, the hydrofluoride salt is selected from Py. HF, Et3One of HF and AgF, the hydrofluoride can improve the conversion rate of raw materials. When the hydrofluoric acid salt is Py. HF, the conversion of the raw material and the yield of the product can be further improved.
In one or more embodiments of this embodiment, the set temperature is-20 to 60 ℃. When the reaction is carried out at the temperature, the conversion rate of raw materials can be improved, and the yield of products can be improved. Preferably 0-40 ℃, and when the reaction temperature is 25 +/-2 ℃, the conversion rate of raw materials and the yield of products can be further improved.
In one or more examples of this embodiment, the starting vinyl azide and the oxidizing agent are added to a solvent and dissolved, and then the reaction is carried out by adding a fluorine salt.
Further, the solvent is selected from ethanol, toluene, DMF, 1, 2-dichloroethane, CH3CN, 1, 4-dioxane, DMSO and glycol. In one or more embodiments of this embodiment, the solvent is DCM, DMSO, CHCl3And DMF, and the solvent can improve the conversion rate of raw materials and the yield of products. When the solvent is DCM, the conversion rate of raw materials and the yield of the product are higher.
In one or more embodiments of this embodiment, the molar ratio of vinyl azide, oxidizing agent, hydrofluoride salt is 1: 1-3: 1 to 10. In this series of examples, the molar ratio of vinyl azide, oxidizing agent, hydrofluoride salt is 1: 1: 10.
in one or more embodiments of the present invention, the reaction is performed under stirring, the stirring reaction time is 0-8 h, and the reaction time is not 0. In this series of examples, the reaction time was 4. + -. 0.2 h.
In order to increase the purity of the product formed,in one or more examples of this embodiment, the suspended silica is stirred vigorously at-78 ℃, and the resulting mixture is then transferred to ethyl acetate, warmed to room temperature, and filtered. Extracting with extractant, and washing with detergent. Finally, the combined organic layers were passed over Na2SO4Drying, removing solvent under reduced pressure, and performing silica gel column chromatography to obtain 5-azido-5-fluoro-1, 3-dioxygen cyclic-2-ketone derivative.
In the series of embodiments, the extraction solvent adopted by the extraction is one or more of 1, 2-dichloroethane, toluene, nitromethane, ethyl acetate, diethyl ether, n-hexane, cyclohexane, petroleum ether or dichloromethane.
In this series of examples, the extraction solvent used for the extraction was dichloromethane.
In the series of embodiments, the extraction is performed 1-3 times, and 5-20 mL of the extraction solvent is used each time.
In this series of examples, the detergent used for extraction was brine.
In the series of embodiments, the washing is performed for 1-3 times, and 20-50 mL of the detergent is used each time.
In this series of examples, anhydrous Na was used to obtain the organic phase2SO4Drying and removing the organic solvent.
In the series of examples, the eluent of the silica gel column chromatography is petroleum ether and ethyl acetate.
In the series of embodiments, the volume ratio of petroleum ether to ethyl acetate is 1-20: 1 to 4.
In this series of examples, the volume ratio of petroleum ether to ethyl acetate was 10: 3. the eluent can be used for obtaining the 5-azido-5-fluoro-1, 3-dioxygen cyclic group-2-ketone derivative with higher purity.
In order to make the technical solutions of the present invention more clearly understood by those skilled in the art, the technical solutions of the present invention will be described in detail below with reference to specific embodiments.
Example 1
Compound 1a (i.e., tert-butyl 1- (1-azidovinyl) cyclohexylcarbonate (0.1336g, 0.5mmol), was oxidizedThe agent PIDA (0.3995g, 1.5mmol) was added to 2mL of solvent DCM and Py. HF (0.4956g, 5mmol) was added with stirring at 25 ℃ and stirring was continued until complete consumption of the vinyl azide was detected by TLC analysis (typically 1 min). The suspended silica (15 g per 1mmol of substrate) was stirred vigorously at-78 deg.C, and the resulting heterogeneous mixture was then transferred to a suspension in ethyl acetate, which was allowed to warm to room temperature. The resulting suspension was filtered, extracted 3 times with dichloromethane (3X 15mL) and washed 3 times with brine (3X 40 mL). Finally, the combined organic layers were passed over Na2SO4Drying, removing solvent under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetate10:3) to give product 2a as a colorless oil in 96% yield.
Example 2
Compound 1a (i.e., 1- (1-azidovinyl) cyclohexylcarbamic acid tert-butyl ester (0.1336g, 0.5mmol), oxidizing agent PhIO (0.3301g, 1.5mmol) were added to 2mL solvent DCM and Et was added with stirring at 25 deg.C3Hf (0.4956g, 5mmol), stirring was continued until complete consumption of vinyl azide was monitored by TLC analysis (typically 1 min). The suspended silica (15 g per 1mmol of substrate) was stirred vigorously at-78 deg.C, and the resulting heterogeneous mixture was then transferred to a suspension in ethyl acetate, which was allowed to warm to room temperature. The resulting suspension was filtered, extracted 3 times with dichloromethane (3X 15mL) and washed 1 time with brine (3X 40 mL). Finally, the combined organic layers were passed over Na2SO4Drying, removing solvent under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetate1) to yield the product 2a as a colorless oil in 71% yield.
Example 3
Compound 1a (i.e. tert-butyl 1- (1-azidovinyl) cyclohexylcarbonate (0.1336g, 0.5mmol), oxidizing agent PIFA (0.6451g, 1.5mmol) were added to 2mL solvent DCM at 25 deg.C, AgF ((0.4956g, 5mmol) was added with stirring, stirring was continued until complete consumption of vinyl azide was detected by TLC analysis (typically 1 min.) at-78 deg.C, suspension was stirred vigorouslySilica (15 g per 1mmol of substrate)), the resulting heterogeneous mixture was then transferred to a suspension in ethyl acetate, and the suspension was allowed to warm to room temperature. The resulting suspension was filtered, extracted 3 times with dichloromethane (3X 15mL) and washed 3 times with brine (3X 40 mL). Finally, the combined organic layers were passed over Na2SO4Drying, removing solvent under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetate10:3) to give product 2a as a colorless oil in 86% yield.
Example 4
Compound 1a (i.e., 1- (1-azidovinyl) cyclohexylcarbamic acid tert-butyl ester (0.1336g, 0.5mmol), oxidant PIDA (0.1132g, 0.5mmol) was added to 2mL of solvent CHCl3At 25 deg.C, CsF (0.04956g, 0.5mmol) was added with stirring and stirring was continued until complete consumption of the vinyl azide was monitored by TLC analysis (typically 1 min). The suspended silica (15 g per 1mmol of substrate) was stirred vigorously at-78 deg.C, and the resulting heterogeneous mixture was then transferred to a suspension in ethyl acetate, which was allowed to warm to room temperature. The resulting suspension was filtered, extracted 1 time with dichloromethane (3X 15mL) and washed 2 times with brine (3X 40 mL). Finally, the combined organic layers were passed over Na2SO4Drying, removing solvent under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetate1:1) to give product 2a as a colorless oil in 59% yield.
Example 5
Compound 1a (i.e. tert-butyl 1- (1-azidovinyl) cyclohexylcarbonate (0.1336g, 0.5mmol), the oxidant PIDA (0.3995g, 1.5mmol) were added to 2mL of solvent DCM and at 0 ℃, Py · HF (0.4956g, 5mmol) was added with stirring and stirring continued until complete consumption of the vinyl azide was detected by TLC analysis (typically 1 min.) the suspended silica (15 g per 1mmol of substrate) was stirred vigorously at-78 ℃), and the resulting heterogeneous mixture was transferred to a suspension in ethyl acetate and the suspension was allowed to warm to room temperature. The resulting suspension was filtered, extracted 3 times with dichloromethane (3X 15mL) and washed 3 times with brine (3X 40 mL).Finally, the combined organic layers were passed over Na2SO4Drying, removing solvent under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetate10:3) to give product 2a as a colorless oil in 84% yield.
Example 6
Compound 1a (i.e. tert-butyl 1- (1-azidovinyl) cyclohexylcarbonate (0.1336g, 0.5mmol), the oxidant PIDA (0.3995g, 1.5mmol) were added to 2mL of solvent DCM and at 40 ℃, Py · HF (0.4956g, 5mmol) was added with stirring and stirring continued until complete consumption of the vinyl azide was detected by TLC analysis (typically 1 min.) the suspended silica (15 g per 1mmol of substrate) was stirred vigorously at-78 ℃), and the resulting heterogeneous mixture was transferred to a suspension in ethyl acetate and the suspension was allowed to warm to room temperature. The resulting suspension was filtered, extracted 3 times with dichloromethane (3X 15mL) and washed 3 times with brine (3X 40 mL). Finally, the combined organic layers were passed over Na2SO4Drying, removing solvent under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetate10:3) to give product 2a as a colorless oil in 78% yield.
The reaction formulae of examples 1 to 6 are as follows:
Figure BDA0002307625940000081
referring to fig. 1-3, the nmr spectra of compound 2a are:
(2a)1H NMR(600MHz,CDCl3)δ3.87(dd,J＝13.8Hz,J＝12.0Hz,1H),3.49(dd,J＝27.0Hz,J＝13.8Hz,1H),2.23-2.21(m,1H),1.82-1.58(m,8H),1.31-1.24(m,1H).13C NMR(150MHz,CDCl3)δ150.4,114.8(d,J＝242.9Hz),88.9(d,J＝25.7Hz),50.6(d,J＝29.1Hz),31.8(d,J＝4.5Hz),29.0(d,J＝9.8Hz),24.3,21.7,21.0.19F NMR(470MHz,CDCl3)δ-116.99(dd,J＝27.3Hz,J＝11.8Hz).IR(KBr,cm-1):2113,1824.
example 7
Compound 1b (i.e. 1- (1-stack)Nitrogen vinyl) -3-phenyl cyclobutyl carbo-t-butyl ester (0.1576g, 0.5mmol), oxidizing agent PIDA (0.3995g, 1.5mmol) were added to 2mL solvent DCM and, at 25 deg.C, Py. HF (0.4956g, 5mmol) was added with stirring and stirring was continued until complete consumption of vinyl azide was monitored by TLC analysis (typically 1 min). The suspended silica (15 g per 1mmol of substrate) was stirred vigorously at-78 deg.C, and the resulting heterogeneous mixture was then transferred to a suspension in ethyl acetate, which was allowed to warm to room temperature. The resulting suspension was filtered, extracted 3 times with dichloromethane (3X 15mL) and washed 3 times with brine (3X 40 mL). Finally, the combined organic layers were passed over Na2SO4Drying, removing solvent under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetate10:3) to give product 2b as a colorless oil in 70% yield.
The reaction formula is shown as follows:
Figure BDA0002307625940000091
referring to fig. 4-6, the nmr spectra of compound 2b are:
(2b)1H NMR(600MHz,CDCl3)δ7.30-7.28(m,major,2H,minor,1H),7.20-7.16(m,major,3H,minor,4H),3.92(d,J＝13.8Hz,J＝8.4Hz,major,1H),3.80-3.75(m,minor,2H),3.71(dd,J＝21.6Hz,J＝13.8Hz,major,1H),3.55(dd,J＝20.4Hz,J＝13.8Hz,minor,1H),3.37-3.31(m,major,1H),3.16-3.12(m,major,1H),2.96-2.91(m,major,1H),2.77-2.71(m,minor,2H),2.68(dd,J＝13.2Hz,J＝9.0Hz,major,1H),2.64-2.57(m,major,1H,minor,2H).13C NMR(150MHz,CDCl3)major productδ148.6,141.6,127.8,126.0,125.4,113.3(d,J＝241.2Hz),83.9(d,J＝29.3Hz),50.5(d,J＝32.6Hz,),37.5(d,J＝5.6Hz),34.8(d,J＝5.3Hz),28.5.19F NMR(470MHz,CDCl3)δ-114.53-(-111.93)(m,major),-115.1-(115.2)(m,minor).IR(KBr,cm-1):2113,1835.
example 8
Compound 1c, i.e., tert-butyl 1- (1-azidovinyl) cyclopentylcarbonate (0.1266g, 0.5mmol), was oxidizedThe agent PIDA (0.3995g, 1.5mmol) was added to 2mL of solvent DCM and Py. HF (0.4956g, 5mmol) was added with stirring at 25 ℃ and stirring was continued until complete consumption of the vinyl azide was detected by TLC analysis (typically 1 min). The suspended silica (15 g per 1mmol of substrate) was stirred vigorously at-78 deg.C, and the resulting heterogeneous mixture was then transferred to a suspension in ethyl acetate, which was allowed to warm to room temperature. The resulting suspension was filtered, extracted 3 times with dichloromethane (3X 15mL) and washed 3 times with brine (3X 40 mL). Finally, the combined organic layers were passed over Na2SO4After drying and removal of the solvent under reduced pressure, chromatography on silica gel (eluent V petroleum ether: V ethyl acetate 10:3) afforded product 2c as a colorless oil in 85% yield.
The reaction formula is shown as follows:
Figure BDA0002307625940000092
referring to fig. 7-9, the nmr spectra of compound 2c are:
(2c)1H NMR(600MHz,CDCl3)δ3.83(dd,J＝13.8Hz,J＝10.8Hz,1H),3.50(dd,J＝24.6Hz,J＝13.8Hz,1H),2.12-2.02(m,2H),1.89-1.74(m,6H).13C NMR(150MHz,CDCl3)δ149.3,113.6(d,J＝256.5Hz),97.2(d,J＝26.0Hz),50.4(d,J＝30.5Hz),34.0(d,J＝4.8Hz),31.5(d,J＝5.9Hz),22.6,21.5.19F NMR(564MHz,CDCl3)δ-109.19(d,J＝24.6Hz,J＝10.8Hz).IR(KBr,cm-1):2104,1814.
example 9
Compound 1d (i.e. tert-butyl 4-methyl-1- (1-azidovinyl) cyclohexylcarbonate (0.1406g, 0.5mmol), the oxidant PIDA (0.3995g, 1.5mmol) were added to 2mL of solvent DCM, Py · HF (0.4956g, 5mmol) was added with stirring at 25 ℃, stirring was continued until complete consumption of the vinyl azide was detected by TLC analysis (typically 1 min.) suspended silica (15 g per 1mmol of substrate) was stirred vigorously at-78 ℃), and the resulting heterogeneous mixture was transferred to a suspension in ethyl acetate and the suspension was allowed to warm to room temperature. Then will obtainThe suspension was filtered, extracted 3 times with dichloromethane (3X 15mL) and washed 3 times with brine (3X 40 mL). Finally, the combined organic layers were passed over Na2SO4Drying, removing solvent under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetate10:3) to give product 2d as a colorless oil in 84% yield.
The reaction formula is shown as follows:
Figure BDA0002307625940000101
referring to fig. 10-12, the nmr spectra of compound 2d are:
(2d)1H NMR(600MHz,CDCl3)δ3.81(t,J＝13.2Hz,1H),3.47(dd,J＝26.4Hz,J＝13.8Hz,1H),1.93-1.76(m,6H),1.52-1.38(m,3H),0.95(d,J＝7.2Hz,3H).13C NMR(150MHz,CDCl3)δ149.3,113.8(d,J＝242.7Hz),88.0(d,J＝25.8Hz),49.8(d,J＝29.3Hz),26.5,26.2(d,J＝4.2Hz),25.9,25.1,23.9(d,J＝9.6Hz),16.2.19F NMR(470MHz,CDCl3)δ-116.73(dd,J＝26.4Hz,J＝11.8Hz).IR(KBr,cm-1):2116,1841.
example 10
Compound 1e (i.e. tert-butyl 1- (1-azidovinyl) -4, 4-dimethylcyclohexylcarbonate (0.1476g, 0.5mmol), the oxidant PIDA (0.3995g, 1.5mmol) were added to 2mL of solvent DCM and at 25 ℃ Py · HF (0.4956g, 5mmol) was added with stirring and stirring continued until complete consumption of the vinyl azide was detected by TLC analysis (typically 1 min.) the suspended silica (15 g per 1mmol of substrate) was stirred vigorously at-78 ℃), and the resulting heterogeneous mixture was then transferred to a suspension in ethyl acetate and the suspension was allowed to warm to room temperature. The resulting suspension was filtered, extracted 3 times with dichloromethane (3X 15mL) and washed 3 times with brine (3X 40 mL). Finally, the combined organic layers were passed over Na2SO4Drying, removing solvent under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetate10:3) to give 2e as a colorless oil in 90% yield.
The reaction formula is shown as follows:
Figure BDA0002307625940000111
referring to fig. 13-15, the nmr spectra of compound 2e are:
(2e)1H NMR(600MHz,CDCl3)δ3.89(dd,J＝13.8Hz,J＝11.4Hz,1H),3.52(dd,J＝27.6Hz,J＝13.8Hz,1H),2.11-2.02(m,1H),1.92-1.80(m,2H),1.65-1.52(m,3H),1.48-1.36(m,2H),0.99(s,3H),0.97(s,3H).13C NMR(150MHz,CDCl3)δ149.3,114(d,J＝242.7Hz),87.7(d,J＝25.7Hz),49.8(d,J＝29.1Hz),33.3,32.5,30.9,28.2,27.2(d,J＝4.4Hz),24.5(d,J＝9.3Hz),22.3.19F NMR(564MHz,CDCl3)δ-116.52(dd,J＝33.8Hz,J＝14.1Hz).IR(KBr,cm-1):2109,1796.
example 11
Compound 1f (i.e. tert-butyl 4-ethyl-1- (1-azidovinyl) cyclohexylcarbonate (0.1459g, 0.5mmol), the oxidant PIDA (0.3995g, 1.5mmol) were added to 2mL of solvent DCM, Py · HF (0.4956g, 5mmol) was added with stirring at 25 ℃, stirring was continued until complete consumption of the vinyl azide was detected by TLC analysis (typically 1 min.) the suspended silica (15 g per 1mmol of substrate) was stirred vigorously at-78 ℃), and the resulting heterogeneous mixture was transferred to a suspension in ethyl acetate and the suspension was allowed to warm to room temperature. The resulting suspension was filtered, extracted 3 times with dichloromethane (3X 15mL) and washed 3 times with brine (3X 40 mL). Finally, the combined organic layers were passed over Na2SO4Drying, removing solvent under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetate10:3) to give product 2f as a colorless oil in 89% yield.
The reaction formula is shown as follows:
Figure BDA0002307625940000112
referring to fig. 16-18, the nmr spectra of compound 2f are:
(2f)1H NMR(600MHz,CDCl3)δ3.80(dd,J＝13.8Hz,J＝11.4Hz,1H),3.52(dd,J＝26.4Hz,J＝13.8Hz,1H),1.92-1.88(m,1H),1.83-1.74(m,4H),1.56-1.47(m,4H),1.34-1.30(m,2H),0.86(t,J＝7.2Hz,3H),.13C NMR(150MHz,CDCl3)δ149.3,113.8(d,J＝242.8Hz),88.1(d,J＝25.8Hz),49.8(d,J＝29.3Hz),32.3,26.5(d,J＝4.2Hz),24.3,23.9(d,J＝9.6Hz),23.7,22.6,11.2.19F NMR(470MHz,CDCl3)δ-116.74(dd,J＝26.4Hz,J＝11.8Hz).IR(KBr,cm-1):2098,1834.
example 12
Compound 1g (i.e. 4- (1-azidovinyl) tetrahydro-2H-pyran-4-ylcarbonate tert-butyl ester (0.1345g, 0.5mmol), oxidant PIDA (0.3995g, 1.5mmol) were added to 2mL of solvent DCM, Py · HF (0.4956g, 5mmol) was added with stirring at 25 ℃, stirring was continued until complete consumption of the vinyl azide was detected by TLC analysis (typically 1 min.) the suspended silica (15 g per 1mmol of substrate) was stirred vigorously at-78 ℃, and the resulting heterogeneous mixture was transferred to a suspension in ethyl acetate and the suspension was allowed to warm to room temperature. The resulting suspension was filtered, extracted 3 times with dichloromethane (3X 15mL) and washed 3 times with brine (3X 40 mL). Finally, the combined organic layers were passed over Na2SO4Drying, removing solvent under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetate10:3) to yield 2g of product as colorless oil in 94% yield.
The reaction formula is shown as follows:
Figure BDA0002307625940000121
referring to fig. 19-21, the nmr spectra of compound 2g are:
(2g)1H NMR(600MHz,CDCl3)δ3.98-3.90(m,2H),3.85(dd,J＝13.2Hz,J＝10.8Hz,1H),3.68-3.61(m,2H),3.45(dd,J＝26.4Hz,J＝13.2Hz,1H),2.05-1.97(m,3H),1.57-1.53(m,1H).13C NMR(150MHz,CDCl3)δ148.7,113.1(d,J＝242.6Hz),85.3(d,J＝27.2Hz),62.7,61.6,49.5(d,J＝29.3Hz),30.9(d,J＝5.3Hz),28.7(d,J＝9.3Hz).19F NMR(470MHz,CDCl3)δ-117.58(dd,J＝26.4Hz,J＝10.8Hz).IR(KBr,cm-1):2105,1847.
the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. A5-azido-5-fluoro-1, 3-dioxide cyclic group-2-ketone derivative is characterized in that: the chemical structure is shown as formula (1):
Figure FDA0002307625930000011
wherein the content of the first and second substances,
Figure FDA0002307625930000012
represents a cyclic alkane compound selected from C3-C10Cycloalkyl radical, C3-C10Substituted cycloalkyl, C3-C10One of the epoxyalkyl groups of (1).
2. The 5-azido-5-fluoro-1, 3-dioxan-2-one derivative of claim 1, wherein: said C is3-C10Substituted cycloalkyl is cycloalkyl substituted by phenyl, alkyl; preferably, the alkyl group is selected from C1-C6A linear or branched alkyl group;
preferably, said C3-C10The heterocyclic group of (a) contains one or more heteroatoms, more preferably, the heteroatoms are selected from N, O, S; further preferably, the heteroatom is selected from O.
3. The 5-azido-5-fluoro-1, 3-dioxan-2-one derivative of claim 1, wherein: said C is3-C10The cycloalkyl is selected from cyclopentyl and cyclohexyl;
or, said C3-C10The substituted cycloalkyl is selected from 3-phenylcyclobutyl, 4-methylcyclohexyl, 4-ethylcyclohexyl, 4-dimethylcyclohexyl;
or, said C3-C10The heterocyclic group of (A) is selected from 4-epoxyhexyl;
or the like, or, alternatively,
Figure FDA0002307625930000013
is one selected from the group consisting of cyclopentyl, cyclohexyl, 3-phenylcyclobutyl, 4-methylcyclohexyl, 4-ethylcyclohexyl, 4-dimethylcyclohexyl, and 4-epoxyhexyl.
4. A preparation method of 5-azido-5-fluoro-1, 3-dioxide cyclic group-2-ketone derivatives is characterized in that: the method is characterized in that a fluorine salt compound generated in situ by vinyl azide, an oxidant and a hydrofluoride is used as raw materials and reacts under the action of a solvent at a set temperature to obtain the product.
5. The process for producing 5-azido-5-fluoro-1, 3-dioxol-2-one derivatives as defined in claim 4, wherein: the chemical structural formula of the vinyl azide is shown in the specification
Figure FDA0002307625930000014
Wherein the content of the first and second substances,
Figure FDA0002307625930000015
represents a cyclic alkane compound selected from C3-C10Cycloalkyl radical, C3-C10Substituted cycloalkyl, C3-C10An alkylene oxide group of (1).
6. The process for producing 5-azido-5-fluoro-1, 3-dioxan-2-one derivatives as claimed in claim 5, wherein: said C is3-C10Substituted cycloalkyl being substituted by phenyl, alkylCycloalkyl groups of (a); preferably, the alkyl group is selected from C1-C6A linear or branched alkyl group;
preferably, said C3-C10The heterocyclic group of (a) contains one or more heteroatoms, more preferably, the heteroatoms are selected from N, O, S; further preferably, the heteroatom is selected from O.
7. The 5-azido-5-fluoro-1, 3-dioxan-2-one derivative of claim 5, wherein: said C is3-C10The cycloalkyl is selected from cyclopentyl and cyclohexyl;
or, said C3-C10The substituted cycloalkyl is selected from 3-phenylcyclobutyl, 4-methylcyclohexyl, 4-ethylcyclohexyl, 4-dimethylcyclohexyl;
or, said C3-C10The heterocyclic group of (A) is selected from 4-epoxyhexyl;
or the like, or, alternatively,
Figure FDA0002307625930000021
is one selected from the group consisting of cyclopentyl, cyclohexyl, 3-phenylcyclobutyl, 4-methylcyclohexyl, 4-ethylcyclohexyl, 4-dimethylcyclohexyl, and 4-epoxyhexyl.
8. The process for producing 5-azido-5-fluoro-1, 3-dioxolyl-2-one derivatives by oxidation according to any one of claims 4 to 7, wherein: the oxidant is one of PIDA, PhIO and PIFA, preferably the oxidant is PIDA;
or, the hydrofluoride salt is Py. HF, Et3One of n.hf, AgF, preferably, the hydrofluoride salt is py.hf;
or the set temperature is-20-60 ℃, preferably 0-40 ℃, and more preferably 25 +/-2 ℃.
9. The process for producing 5-azido-5-fluoro-1, 3-dioxolyl-2-one derivatives by oxidation according to any one of claims 4 to 7, wherein: adding the raw materials into a solvent for dissolving, and then adding an oxidant and a hydrofluoride for reaction;
preferably, the solvent is DCM, DMSO, CHCl3Or DMF; more preferably DCM.
10. The process for producing 5-azido-5-fluoro-1, 3-dioxolyl-2-one derivatives by oxidation according to any one of claims 4 to 7, wherein: the molar ratio of vinyl azide, oxidizing agent, hydrofluoride salt is 1: 1-3: 1-10; preferably, the molar ratio of vinyl azide, oxidizing agent, hydrofluoride salt is 1: 1: 10; or the reaction time is 0-8 h, the reaction time is not 0, and the reaction time is 4 +/-0.2 h.
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