阅读说明：本技术 一种多取代吡咯烷化合物及其制备方法和应用 (Polysubstituted pyrrolidine compound and preparation method and application thereof ) 是由 乔凯 刘临峰 马灿亮 李玉光 郭凯 于 2021-09-02 设计创作，主要内容包括：本发明公开了一种多取代吡咯烷化合物及其制备方法和应用,所述多取代吡咯烷化合物的结构如式(I)所示,其中,R～(1),R～(2)独立地选自氢、C1-C6烷基、C1-C6烷氧基或卤素。在金属催化剂、碱和惰性气体存在下,氮-氟代磺酰胺II与芳基乙炔III反应,生成所述多取代吡咯烷类化合物I；与现有技术相比,本发明提供了一种新的多取代吡咯烷化合物,该化合物可作为中枢神经兴奋药物,具有重要的研究价值。此外,本发明制备方法设计合理,收率高,反应时间短,成本低,为多取代吡咯的合成提供新的合成方法,具有工业应用前景。(The invention discloses a polysubstituted pyrrolidine compound and a preparation method and application thereof, wherein the polysubstituted pyrrolidine compound has a structure shown as a formula (I), wherein R is 1 ，R 2 Independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy or halogen. In the presence of a metal catalyst, alkali and inert gas, reacting nitrogen-fluoro sulfonamide II with aryl acetylene III to generate the polysubstituted pyrrolidine compound I; compared with the prior art, the invention provides a novel polysubstituted pyrrolidine compound which can be used as a central nervous excitant and has important research value. In addition, the preparation method has the advantages of reasonable design, high yield, short reaction time and low cost, provides a new synthesis method for the synthesis of the polysubstituted pyrrole, and has industrial application prospect.)

1. A polysubstituted pyrrolidine compound has the structure shown in formula (I):

wherein R is¹，R²Independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy or halogen.

2. The polysubstituted pyrrolidine compound of claim 1, wherein said R is¹，R²Independently selected from-H, -CH₃、-(CH₂)₅CH₃、-OCH₃、-OCH₂CH₃Or a halogen.

3. The polysubstituted pyrrolidine compound of claim 1, wherein said R is¹，R²Are all para-substituents and are the same group.

4. A process for the preparation of a polysubstituted pyrrolidine compound according to any one of claims 1 to 3 comprising the steps of:

in the presence of a metal catalyst, alkali and inert gas, reacting nitrogen-fluoro sulfonamide II with aryl acetylene III to generate the polysubstituted pyrrolidine compound I; the structural formulas of the nitrogen-fluoro sulfonamide II and the aryl acetylene III are shown as follows:

wherein R is¹，R²The method according to any one of claims 1 to 3.

5. The process for preparing a polysubstituted pyrrolidine compound according to claim 4, wherein the metal catalyst is selected from the group consisting of copper catalyst and nickel catalyst, and is used in an amount of 4-6% based on the amount of N-fluorosulfonamide II.

6. Polysubstituted pyridine according to claim 5A process for producing a pyrrolidine compound, characterized in that the copper catalyst is selected from Cu (CH)₃CN)₄PF₆The nickel catalyst is selected from nickel dibromide.

7. The process according to claim 4, wherein the base is selected from potassium tert-butoxide.

8. The process for preparing a polysubstituted pyrrolidine compound according to claim 4, wherein the solvent of the reaction is at least one of THF, DCE, toluene, acetonitrile, dioxane, EA, DCM.

9. The process for preparing a polysubstituted pyrrolidine compound according to claim 4, wherein the reaction is carried out at a temperature of 0 to 150 ℃ for a period of 2 to 24 hours.

10. Use of a polysubstituted pyrrolidine compound according to any one of claims 1 to 3 for the preparation of a central nervous system stimulant.

Technical Field

The invention belongs to the field of chemical synthesis, and particularly relates to a polysubstituted pyrrolidine compound, and a preparation method and application thereof.

Background

The pyrrolidine heterocyclic compound is widely existed in natural products and bioactive molecules, and has important research and application values. Common natural amino acids such as proline and hydroxyproline have a pyrrolidine nucleus. Many important drug molecules also have a pyrrolidine structure, such as amisulpride, the drug marketed for treating seasickness approved by the FDA in 2020, and the first 11-beta hydroxylase-inhibiting osildoldosterostat approved by the FDA all have a multi-substituted pyrrolidine structure. At present, no multi-substituted pyrrolidine compound with the same structure is reported.

Disclosure of Invention

The purpose of the invention is as follows: aiming at the defects of the prior art, the invention provides a polysubstituted pyrrolidine compound, and a preparation method and application thereof.

The technical scheme is as follows: in order to achieve the purpose, the invention adopts the following technical scheme:

a polysubstituted pyrrolidine compound has the structure shown in formula (I):

wherein R is¹，R²Independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy or halogen.

Preferably, said R is¹，R²Independently selected from-H, -CH₃、-(CH₂)₅CH₃、-OCH₃、-OCH₂CH₃Or a halogen.

Preferably, said R is¹，R²Are all para-substituents and are the same group.

The preparation method of the polysubstituted pyrrolidine compound comprises the following steps:

in the presence of a metal catalyst, alkali and inert gas, reacting nitrogen-fluoro sulfonamide II with aryl acetylene III to generate the polysubstituted pyrrolidine compound I; the structural formulas of the nitrogen-fluoro sulfonamide II and the aryl acetylene III are shown as follows:

wherein R is¹，R²As described above.

In the invention, nitrogen-fluoro sulfonamide II is reduced into a nitrogen free radical under the activation of a catalyst, then an addition reaction of an intramolecular free radical and olefin is carried out, and finally a free radical coupling reaction is carried out with aryl acetylene III to obtain a polysubstituted pyrrolidine structure.

Preferably, the metal catalyst is selected from a copper catalyst or a nickel catalyst, and the dosage of the metal catalyst is 4-6% of that of the nitrogen-fluoro sulfonamide II. The nickel catalyst has better applicability to the substrate in the invention and high catalytic efficiency.

Further preferably, the copper catalyst is selected from Cu (CH)₃CN)₄PF₆The nickel catalyst is selected from nickel dibromide.

Preferably, the base is selected from potassium tert-butoxide.

Preferably, the solvent for the reaction is at least one of THF, DCE, toluene, acetonitrile, dioxane, EA, DCM.

Preferably, the reaction temperature of the reaction is 0 to 150 ℃, too high a reaction temperature may result in an increase in by-products, and too low a reaction temperature may decrease the reaction conversion rate, and more preferably, the reaction temperature is 30 ℃. In the present invention, the result of the reaction can be checked by TLC, and the reaction can be completed by stirring the reaction at the temperature for 2 to 24 hours (preferably 12 hours).

The invention finally provides the application of the polysubstituted pyrrolidine compound in the preparation of central nervous excitation medicaments.

Has the advantages that: compared with the prior art, the invention provides a novel polysubstituted pyrrolidine compound which can be used as a central nervous excitant and has important research value. In addition, the preparation method has the advantages of reasonable design, high yield, short reaction time and low cost, provides a new synthesis method for the synthesis of the polysubstituted pyrrole, and has industrial application prospect.

Drawings

FIG. 1 shows the product obtained in example 1 of the present invention¹HNMR spectrogram.

FIG. 2 shows the product obtained in example 1 of the present invention¹³CNMR spectrogram.

Detailed Description

The invention will be better understood from the following examples. However, those skilled in the art will readily appreciate that the description of the embodiments is only for illustrating the present invention and should not be taken as limiting the invention as detailed in the claims.

Example 1

Adding Cu (CH) into a reaction tube filled with magnetons₃CN)₄PF₆(1.86mg, 0.05mmol), potassium tert-butoxide (11.2mg,0.1mmol), after replacement with argon, 1ml of anhydrous DCM, N-fluorosulfonamide (24.2mg, 0.1mmol), phenylacetylene (20.4mg, 0.2mmol) were added to the reaction tube under an argon atmosphere, and reacted at 30 ℃ for 12 hours, after completion of the reaction by TLC, by silica gel column chromatography (eluent: petroleum ether/ethyl acetate 10: 1), yielding I-a 25mg as a pale yellow solid.

¹H NMR(400MHz,CDCl₃)δ7.90–7.87(m,1H),7.61–7.58(m,1H),7.56–7.51(m,2H),7.41–7.34(m,2H),7.30–7.27(m,3H),3.91–3.80(m,1H),3.53–3.47(m,1H),3.20(dt,J＝10.2,7.4Hz,1H),2.97(dd,J＝16.7,3.6Hz,1H),2.71(dd,J＝16.8,9.0Hz,1H),2.04–1.89(m,2H),1.81–1.73(m,1H),1.62–1.54(m,1H)。

¹³C NMR(100MHz,CDCl₃)δ137.07,132.72,131.60,129.13,128.26,127.89,127.48,123.48,86.66,82.29,58.22,48.89,29.62,26.42,23.57。

HRMS(ESI)[M+H]calculatedfor[C₁₉H₂₀NO₂S]⁺326.1209,found 326.1207。

Of the resulting product¹HNMR spectrogram,¹³The CNMR spectrogram is shown in FIGS. 1 and 2.

Example 2

Adding Cu (CH) into a reaction tube filled with magnetons₃CN)₄PF₆(1.86mg, 0.05mmol), potassium tert-butoxide (11.2mg,0.1mmol), after replacement with argon, 1ml of anhydrous DCM, n-fluorosulfonamide I- (26.1mg, 0.1mmol), p-fluoroacetylene (24mg, 0.2mmol) were added to the reaction tube under an argon atmosphere, reacted at 30 ℃ for 12h, and after completion of the reaction was detected by TLC, column chromatography over silica gel (eluent: petroleum ether/ethyl acetate 10: 1) gave I-b26mg as a pale yellow solid. The structure was confirmed by high resolution mass spectrometry, HRMS (ESI) [ M + H ]]calculated for[C₁₉H₁₈F₂NO₂S]⁺362.1021，found 362.1019。

Example 3

Adding Cu (CH) into a reaction tube filled with magnetons₃CN)₄PF₆(1.86mg, 0.05mmol), potassium tert-butoxide (11.2mg,0.1mmol), after replacement with argon, 1ml of anhydrous DCM, N-fluorosulfonamide (26.1mg, 0.1mmol), p-fluoroacetylene (24mg, 0.2mmol) as a solvent were added to the reaction tube under an argon atmosphere, reacted at 30 ℃ for 12 hours, and after completion of the reaction, chromatographed on a silica gel column (eluent: petroleum ether/ethyl acetate 10: 1) by TLC to give I-c 26mg as a pale yellow solid. The structure was confirmed by high resolution mass spectrometry, HRMS (ESI) [ M + H ]]calculated for[C₂₁H₂₄NO₄S]⁺386.1421,found386.1420。

Example 4

Adding Cu (CH) into a reaction tube filled with magnetons₃CN)₄PF₆(1.86mg, 0.05mmol), potassium tert-butoxide (11.2mg,0.1mmol), after replacement with argon, 1ml of anhydrous DCM, N-fluorosulfonamide (32.7mg, 0.1mmol), p-hexylphenylacetylene (37mg, 0.2mmol) as a solvent were added to the reaction tube under an argon atmosphere, reacted at 30 ℃ for 12 hours, and after completion of the reaction, column chromatography on silica gel was carried out by TLC (eluent: petroleum ether/ethyl acetate 10: 1) to obtain I-d 36mg as a pale yellow solid. The structure was confirmed by high resolution mass spectrometry, HRMS (ESI) [ M + H ]]calculated for[C₃₁H₄₄NO₂S]⁺494.3088,found494.3085。

Example 5

Adding Cu (CH) into a reaction tube filled with magnetons₃CN)₄PF₆(1.86mg, 0.05mmol), potassium tert-butoxide (11.2mg,0.1mmol), 1ml of anhydrous DCM, N-fluorosulfonamide I-b (25.7mg, 0.1mmol), p-methylphenylacetylene (23.2mg, 0.2mmol) were added to the reaction tube under argon atmosphere after argon displacement, reacted at 30 ℃ for 12 hours, and the reaction was checked by TLC and then chromatographed on a silica gel column (eluent: petroleum ether/ethyl acetate 10: 1) to give I-e as a pale yellow solid (30 mg). The structure was confirmed by high resolution mass spectrometry, HRMS (ESI) [ M + H ]]calculated for[C₂₁H₂₄NO₂S]⁺354.1523,found 354.1519。

While the invention has been described with respect to a number of specific embodiments and methods, it will be appreciated by those skilled in the art that various modifications, additions and substitutions can be made without departing from the scope and spirit of the invention. All the components not specified in the present embodiment can be realized by the prior art.