Dihydrofuran fused heteropyrrolizine derivative as well as preparation method and application thereof

Abstract

The invention provides a dihydrofuran fused heteropyrrolizine derivative as well as a preparation method and application thereof, and belongs to the technical field of organic synthetic chemistry. The preparation method of the dihydrofuran fused heteropyrrolizine derivative # imgabs0 # comprises the following steps: taking a 2-acyl-3-pyrrole acrylonitrile compound and styryl sulfosalt as initial raw materials, taking alkali as an accelerant, and reacting in an organic solvent to obtain the dihydrofuran fused heteropyrrolizine derivative # imgabs0 #. The preparation method of the dihydrofuran fused heteropyrrolizine derivative disclosed by the invention has the characteristics of mild reaction conditions, no need of a metal catalyst, excellent chemical selectivity and non-enantioselectivity and the like. The obtained product has good biological activity and potential medical and medicinal values.

Description

Technical Field

[0001] The invention relates to the field of organic synthetic chemistry, and in particular to a preparation method and application of a dihydrofuran fused pyrrolizine derivative. Background Art

[0002] Dihydrofuran derivatives are commonly found in natural products and active pharmaceutical intermediates, and are important structural units that constitute drug molecules. For example, the compound with the structural formula AD shown below has important medical and pharmaceutical value.

[0003]

[0004] In addition, the pyrrolizine ring constitutes the skeleton of many compounds with different biological effects, such as the compound shown in the structural formula EH above, which has remarkable effects in analgesia, anti-inflammatory, anti-cancer and anti-tumor. Efficiently splicing the above-mentioned advantageous structural units in the same compound will build an effective platform for the screening and discovery of new drugs. Although certain progress has been made in the synthesis of this type of compound, there are defects such as cumbersome operating steps, the use of expensive transition metal catalysts or harsh reaction conditions, and the development of a more atomic-economic and step-economical synthesis method is still challenging. Therefore, there is an urgent need to develop novel dihydrofuran-fused pyrrolizine compounds and metal-free catalyst preparation methods thereof. Summary of the invention

[0005] The invention provides a preparation method and application of a dihydrofuran-fused pyrrolizine derivative. The preparation method provides a new idea for the efficient synthesis of compounds containing dihydrofuran-fused pyrrolizine skeleton structural units.

[0006] A dihydrofuran-fused pyrrolizine derivative, the structural formula of which is shown in formula (I);

[0007]

[0008] In the formula: R1 is hydrogen, C1-C4 alkyl or alkoxy, aryl, substituted aryl or heteroaryl; R2 is selected from hydrogen, aryl or substituted aryl, halogen; R3 is selected from hydrogen, C1-C4 alkyl or alkoxy, halogen. The substituent on the substituted aryl is halogen, alkoxy, trifluoromethyl, C1-C6 alkyl or C1-C6 cycloalkyl;

[0009] Preferably, the structure of the novel dihydrofuran fused pyrrolizine derivative is:

[0010]

[0011] One of them.

[0012] The invention also provides a novel preparation method of dihydrofuran fused pyrrolizine derivatives, which has short reaction time, mild conditions and is easy to separate and purify.

[0013] A novel preparation method of dihydrofuran fused pyrrolizine derivatives, which uses 2-acyl-3-pyrrole acrylonitrile compounds and styryl sulfonate as raw materials, uses a base as a promoter, uses an organic solvent as a reaction medium at 0-40°C, and obtains a single isomer of the novel dihydrofuran fused pyrrolizine derivative with a non-corresponding selectivity greater than 20:1; the base and the 2-acyl-3-pyrrole acrylonitrile compound are added in a molar ratio of 0.5-3.0:1; and the 2-acyl-3-pyrrole acrylonitrile compound and the styryl sulfonate are added in a molar ratio of 1:1.0-5.0.

[0014] The structure of the preferred 2-acyl-3-pyrrole acrylonitrile compound is shown in the following formula (II):

[0015]

[0016] The definitions of R1 and R3 in formula (II) are consistent with those in formula (I).

[0017] The preferred structure of the styryl sulfonate is shown in the following formula (III):

[0018]

[0019] The definition of R2 in formula (III) is consistent with that in formula (I).

[0020] The preparation reaction equation of the novel dihydrofuran fused pyrrolizine derivative is as follows:

[0021]

[0022] The reaction principle is that under the action of base, 2-acyl-3-pyrrole acrylonitrile compounds lose protons to generate nitrogen anion intermediates, which then act as nucleophiles to attack styryl sulfide salts, followed by an intramolecular cascade reaction to complete the ring closure and leave dimethyl sulfide at the same time; the resulting DA-type cyclopropane-fused pyrrolizine will continue to undergo Cloke-Wilson rearrangement reaction under the action of base, and finally obtain novel dihydrofuran-fused pyrrolizine derivatives.

[0023] More preferably, the 2-acyl-3-pyrrole acrylonitrile compound is:

[0024]

[0025] One of them.

[0026] Preferably, the base is at least one of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, 1,8-diazabicyclo(5,4,0)-7-undecene (DBU) or triethylamine.

[0027] Preferably, the organic solvent is at least one of acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, xylene, ethyl acetate, tetrahydrofuran or N,N-dimethylformamide.

[0028] More preferably, the 2-acyl-3-pyrrole acrylonitrile compound and styryl sulfide are dissolved in an organic solvent, and a base accelerator is added at 0° C. to 40° C., and the stirring time is 0.25-2 h.

[0029] Preferably, after the reaction is completed, petroleum ether is preferably used as an eluent to elute the product, thereby obtaining a clean dihydrofuran-fused pyrrolizine derivative.

[0030] The purpose of the present invention is to provide the use of dihydrofuran-fused pyrrolizine derivatives, which are dihydrofuran-fused pyrrolizine derivatives with good biological activity. The pyrrolizine skeleton containing a bicyclic system is widely present in many natural products, alkaloids, drugs and artificially synthesized compounds, and the derivatives of such compounds show a variety of biological activities, such as analgesia, anti-inflammatory, anti-cancer and anti-tumor.

[0031] A pharmaceutical composition or carrier comprising the dihydrofuran-fused pyrrolizine derivatives of the present invention.

[0032] Compared with the prior art, the preparation method of the present invention has the following advantages:

[0033] (1) No metal catalysis is required and the reaction can be carried out under mild conditions;

[0034] (2) The halogen and pyrrole ring functional groups in dihydrofuran-fused pyrrolizine derivatives can be easily derivatized and transformed; in addition, the reaction efficiency can still be maintained in the gram-scale scale-up experiment, which shows that this method has great practical value;

[0035] (3) The reaction has the characteristics of high efficiency and good diastereoselectivity;

[0036] (4) A dihydrofuran-fused pyrrolizine derivative having a quaternary carbon stereocenter can be obtained, and the product has good pharmacological activity.

[0037] The invention uses a base-promoted reaction method to synthesize pyrrolizine derivatives containing dihydrofuran-fused pyrrolizine structural units, has mild reaction conditions and simple process, and will be of great significance for new drug screening. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0039] Figure 1 The dihydrofuran fused pyrrolizine prepared in Example 1 of the present invention 1 H NMR spectrum;

[0040] Figure 2 The dihydrofuran fused pyrrolizine prepared in Example 1 of the present invention 13 C NMR spectrum;

[0041] Figure 3 This is an application example of the present invention, using DMSO as a control, and is a graph of apoptosis of MCF-7 cancer cells;

[0042] Figure 4 This is an application example of the present invention, in which 10 μM 1-8 DMSO is used to treat MCF-7 cancer cell apoptosis; DETAILED DESCRIPTION

[0043] Example 1

[0044] This embodiment provides a method for preparing dihydrofuran-fused pyrrolizine, and the specific steps and parameters are as follows: 2-acyl-3-pyrrole acrylonitrile (0.2mmol, 45mg), styryl sulfide (0.4mmol), and base (0.4mmol) are added to a clean and dry 10mL reaction bottle, and 2mL of acetonitrile is added. The reaction is carried out at room temperature, and the reaction is completed after 0.5 hour of TLC monitoring. The crude product is eluted with petroleum ether and dried to finally obtain pure dihydrofuran-fused pyrrolizine (II) with a yield of 89%. The product is characterized as follows:

[0045] Structural formula:

[0046]

[0047] Appearance: light yellow solid;

[0048] Melting point: 175-177°C;

[0049] 1H NMR (400MHz, CDCl3) δ7.99–7.97(m,2H),7.48–7.41(m,7H),7.37–7.32(m,1H),6.74(dd,J=2.5,1.0Hz,1H ),6.40–6.39(m,1H),6.27(d,J=3.5Hz,1H),6.10(s,1H),4.80(d,J=11.2Hz,1H),4.57(d,J=11.2Hz,1H).

[0050] 13 C NMR (101MHz, CDCl3) δ166.4,140.9,133.2,131.9,129.4,128.7,128.2,127.7,127.5,125.7,117.1,115.7,114.8,103.4,89.0,87.7,67.3,56.7.

[0051] HRMS: Theoretical value C 22 H 17 N2O + [M+H] + 325.1335, the detection value is 325.1334.

[0052] Example 2

[0053] This embodiment provides a method for preparing dihydrofuran-fused pyrrolizine, and the specific steps and parameters are the same as those in Example 1, except that R 1 The substituent is 2-methoxyphenyl. Finally, pure dihydrofuran-fused pyrrolizine (I-2) was obtained with a yield of 68%. The product is characterized as follows:

[0054] Structural formula:

[0055]

[0056] Melting point: 186-188°C;

[0057] 1 H NMR (400MHz, CDCl3) δ7.55(d,J=7.5Hz,1H),7.50–7.41(m,5H),7.35(t,J=7.0Hz,1H),6.97(t,J=7.8Hz,2H),6.76(d,J=1.0Hz ,1H),6.42(t,J=2.9Hz,1H),6.28(d,J=3.3Hz,1H),5.99(s,1H),4.80(d,J=11.3Hz,1H),4.59(d,J=11.3Hz,1H),3.94(s,3H);

[0058] 13 C NMR (101MHz, CDCl3) δ164.0,157.9,141.3,133.5,133.0,130.1,129.3,128.0,125 .9,120.3,117.2,116.4,115.6,114.6,111.4,103.2,91.4,88.8,67.6,57.0,55.1;

[0059] HRMS: Theoretical value C 23 H 19 N2O2 + [M+H] + 355.1441, the detection value is 355.1440.

[0060] Example 3

[0061] This embodiment provides a method for preparing dihydrofuran-fused pyrrolizine, and the specific steps and parameters are the same as those in Example 1, except that R 1 The substituent is 3-chlorophenyl. Finally, pure dihydrofuran-fused pyrrolizine (I-3) was obtained with a yield of 70%. The product is characterized as follows:

[0062] Structural formula:

[0063]

[0064] Melting point: 214-216°C;

[0065] 1 H NMR(400MHz, CDCl3)δ7.91(dd,J=10.5,4.8Hz,2H),7.46–7.34(m,7H),6.76–6.75(m,1H),6.41– 6.40(m,1H),6.28(d,J=3.5Hz,1H),6.11(s,1H),4.80(d,J=11.3Hz,1H),4.57(d,J=11.3Hz,1H);

[0066] 13 C NMR (101MHz, CDCl3) δ164.7,140.6,134.9,132.9,131.9,130.0,129.5,129. 3,128.3,127.5,125.7,125.6,116.6,115.9,114.9,103.6,89.1,67.4,56.6;

[0067] HRMS: Theoretical value C 22H 16 ClN2O + [M+H] + 359.0946, the detection value is 359.0946.

[0068] Example 4

[0069] This embodiment provides a method for preparing dihydrofuran-fused pyrrolizine, and the specific steps and parameters are the same as those in Example 1, except that R 1 The substituent is 4-bromobenzene. Finally, pure dihydrofuran-fused pyrrolizine (I-4) was obtained with a yield of 73%. The product is characterized as follows:

[0070] Structural formula:

[0071]

[0072] Melting point: 227-229°C;

[0073] 1 H NMR (400MHz, CDCl3) δ7.85(d,J=8.6Hz,2H),7.57(d,J=8.6Hz,2H),7.46–7.40(m,4H),7.38–7.34(m,1H),6.79–6. 76(m,1H),6.42–6.40(m,1H),6.28(d,J=3.5Hz,1H),6.11(s,1H),4.80(d,J=11.2Hz,1H),4.57(d,J=11.2Hz,1H);

[0074] 13 C NMR (101MHz, CDCl3) δ164.2,139.7,131.9,131.0,128.4,127.9,127.2,125.5,125.4,124.6,115.8,114.8,113.8,102.5,88.0,87.3,66.3,55.6;

[0075] HRMS: Theoretical value C 22 H 16 BrN2O + [M+H] + 403.0441, the detection value is 403.0439.

[0076] Example 5

[0077] This embodiment provides a method for preparing dihydrofuran-fused pyrrolizine, and the specific steps and parameters are the same as those in Example 1, except that R1 The substituent is 3-trifluoromethylphenyl. Finally, pure dihydrofuran-fused pyrrolizine (I-5) was obtained with a yield of 74%. The product is characterized as follows:

[0078] Structural formula:

[0079]

[0080] Melting point: 209-211°C;

[0081] 1 H NMR (400MHz, CDCl3) δ8.25(d,J=8.0Hz,1H),8.18(s,1H),7.74(d,J=7.9Hz,1H),7.59(t,J=7.9Hz,1H),7.47–7.42(m,4H),7.39–7.34 (m,1H),6.77(d,J=1.5Hz,1H),6.43–6.41(m,1H),6.31(d,J=3.5Hz,1H),6.16(s,1H),4.82(d,J=11.3Hz,1H),4.60(d,J=11.3Hz,1H);

[0082] 13 C NMR (101MHz, CDCl3) δ164.5, 140.5, 132.9, 131.4 (d, J = 33.0Hz), 130.6, 129.5, 129.4, 128.5, 128 .4,125.6,124.9,124.4(d,J=4.0Hz),122.2,116.5,115.9,115.0,103.7,89.4,89.2,67.4,56.6;

[0083] 19 F NMR(376MHz, CDCl3)δ-62.89(s);

[0084] HRMS: Theoretical value C 23 H 16 F3N2O + [M+H] + 393.1209, the detection value is 393.1208.

[0085] Example 6

[0086] This embodiment provides a method for preparing dihydrofuran-fused pyrrolizine, and the specific steps and parameters are the same as those in Example 1, except that R 1The substituent is 3,5-xylyl. Finally, pure dihydrofuran-fused pyrrolizine (I-6) was obtained with a yield of 96%. The product is characterized as follows:

[0087] Structural formula:

[0088]

[0089] Melting point: 170-172°C;

[0090] 1 H NMR(400MHz, CDCl3)δ7.58(s,2H),7.40(d,J=4.3Hz,4H),7.35–7.29(m,1H),7.09(s,1H),6.72(dd,J=2.5,1.1Hz,1H) ,6.39–6.37(m,1H),6.27(d,J=3.5Hz,1H),6.04(s,1H),4.77(d,J=11.2Hz,1H),4.54(d,J=11.2Hz,1H),2.32(s,6H);

[0091] 13 C NMR (101MHz, CDCl3) δ166.9,141.1,138.4,133.7,133.3,129.4,128.1,127.6,125.7,125.3,103.4,88.9,87.5,67.2,56.7,21.3;

[0092] HRMS: Theoretical value C 24 H 21 N2O + [M+H] + 353.1648, the detection value is 353.1649.

[0093] Example 7

[0094] This embodiment provides a method for preparing dihydrofuran-fused pyrrolizine, and the specific steps and parameters are the same as those in Example 1, except that R 3 The substituent is methyl. Finally, pure dihydrofuran-fused pyrrolizine (I-7) was obtained with a yield of 88%. The product is characterized as follows:

[0095] Structural formula:

[0096]

[0097] Melting point: 135-137°C;

[0098] 1H NMR (400MHz, CDCl3) δ8.03–8.01(m,2H),7.52–7.43(m,7H),7.39–7.35(m,1H),6.21(d,J=3 .4Hz,1H),6.13–6.11(m,1H),4.69(d,J=11.1Hz,1H),4.45(d,J=11.1Hz,1H),2.30(s,3H);

[0099] 13 C NMR (101MHz, CDCl3) δ166.6,141.2,131.9,131.3,129.4,128.7,128.1,127 .8,127.6,125.7,125.3,117.4,112.2,103.1,89.7,87.7,67.3,55.2,11.9;

[0100] HRMS: Theoretical value C 23 H 19 N2O + [M+H] + 339.1492, the detection value is 339.1492.

[0101] Example 8

[0102] This embodiment provides a method for preparing dihydrofuran-fused pyrrolizine, and the specific steps and parameters are the same as those in Example 1, except that R 1 The substituent is thienyl. Finally, pure dihydrofuran-fused pyrrolizine (I-8) was obtained with a yield of 94%. The product is characterized as follows:

[0103] Structural formula:

[0104]

[0105] Melting point: 189-191°C;

[0106] 1 H NMR (400MHz, CDCl3) δ7.91–7.90(m,1H),7.54–7.52(m,1H),7.45–7.40(m,4H),7.36–7.32(m,1H),7.13(dd,J=4.8,4.0Hz,1H) ,6.75(d,J=1.4Hz,1H),6.41–6.40(m,1H),6.28(d,J=3.4Hz,1H),6.08(s,1H),4.78(d,J=11.2Hz,1H),4.56(d,J=11.2Hz,1H);

[0107] 13 C NMR (101MHz, CDCl3) δ161.6,140.9,132.9,130.8,130.5,129.9,129.4,128.2,128.1,125.6,116.8,115.8,114.9,103.7,89.7,85.7,67.2,57.0;

[0108] HRMS: Theoretical value C 20 H 15 N2OS + [M+H] + 331.0911, the detected value is 331.0912.

[0109] Application Example 1

[0110] The present embodiment provides a method for the scaled-up preparation of dihydrofuran-fused pyrrolizine, and the specific steps and parameters are as follows: 2-acyl-3-pyrrole acrylonitrile (20 mmol, 4.5 g), styryl sulfide (40 mmol), and base (40 mmol) are added to a clean and dry 250 mL reaction bottle, and 100 mL of dichloromethane is added as a solvent. The mixture is stirred at room temperature for 0.5 h, and the dihydrofuran-fused pyrrolizine (II) is finally obtained by column chromatography purification with a yield of 84%.

[0111] Application Example 2

[0112] This example provides a method for determining the cytotoxicity of a dihydrofuran-fused pyrrolizine derivative (1-8). The specific steps and parameters are as follows:

[0113] Cell culture: All cell lines used were purchased from the American Type Culture Collection, and MCF-7 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS). The cells were cultured at 37°C in a humidified atmosphere containing 5% carbon dioxide.

[0114] The cytotoxicity of the compounds was evaluated by MTT assay using MCF-7 cells. 3 The density of cells / well was seeded in a 96-well tissue culture plate. The relative cell growth V (%) relative to control cells cultured in medium without compound was calculated by the following formula: V% = ([A] experimenta1 -[A] blank ) / ([A] contro1 -[A] blank )×100%, where [A] experimenta1 is the absorbance value of the drug-treated cell wells; [A]blan k is the absorbance value of the well containing culture medium but no cells; [A] control is the absorbance value of the wells with untreated cells.

[0115] For the MCF-7 cell toxicity test, commercially available Licofelone was selected as a standard for comparison, and the IC of Licofelone reference substance was measured under the same conditions. 50 The value is 8.5μM. The test results of other selected compounds are shown in the following table. Figure 3 and 4 The apoptosis profiles of MCF-7 cancer cells treated with DMSO as a control and 10 μM 1-8 DMSO were shown respectively. The results showed that the series of compounds had good biological activity.

[0116]

[0117] It should be further explained that the above implementation modes are only used for understanding the technical solutions of the present invention, and are not used to limit the protection scope of the present invention. Any obvious adjustments and improvements made to the technical solutions of the present invention within the technical concept of the present invention should also fall within the protection scope of the present invention.

Claims

1. A dihydrofuran fused pyrrolizine derivative, characterized in that The structure is shown in formula (I), In the formula: R1 is hydrogen, C1-C4 alkyl or alkoxy, aryl, substituted aryl or heteroaryl; R2 is selected from hydrogen, aryl or substituted aryl, halogen; R3 is selected from hydrogen, C1-C4 alkyl or alkoxy, halogen. The substituent on the substituted aryl is halogen, alkoxy, trifluoromethyl, C1-C6 alkyl or C1-C6 cycloalkyl.

2. The dihydrofuran-fused pyrrolizine derivative according to claim 1, characterized in that: The structure of the dihydrofuran fused pyrrolizine derivative is: One of them.

3. The method for preparing the dihydrofuran-fused pyrrolizine derivatives according to claim 1 or 2, characterized in that: Using 2-acyl-3-pyrrole acrylonitrile compounds and styryl sulfide as starting materials, using a base as a promoter, and using an organic solvent as a reaction medium, the reaction is carried out at 0-40° C. to obtain a product having a structure as shown in formula (I); In the formula: R1 is hydrogen, C1-C4 alkyl or alkoxy, aryl, substituted aryl or heteroaryl; R2 is selected from hydrogen, aryl or substituted aryl, halogen; R3 is selected from hydrogen, C1-C4 alkyl or alkoxy or halogen, and the substituent on the substituted aryl is halogen, alkoxy, trifluoromethyl, C1-C6 alkyl or C1-C6 cycloalkyl; The structure of the 2-acyl-3-pyrrole acrylonitrile compound is shown in the following formula (II): The definitions of R1 and R3 in formula (II) are consistent with those in formula (I); The structure of the styryl sulfonate is shown in the following formula (III): The definition of R2 in formula (III) is consistent with that in formula (I).

4. The method for preparing the dihydrofuran-fused pyrrolizine derivative according to claim 3, characterized in that: The 2-acyl-3-pyrrole acrylonitrile compound is: One of them.

5. The method for preparing the dihydrofuran-fused pyrrolizine derivative according to claim 3, characterized in that: The base is at least one of cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) or triethylamine.

6. The method for preparing the dihydrofuran-fused pyrrolizine derivative according to claim 3, characterized in that: The organic solvent is at least one of acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, xylene, ethyl acetate, tetrahydrofuran or N,N-dimethylformamide.

7. The method for preparing the dihydrofuran-fused pyrrolizine derivative according to claim 3, characterized in that: The 2-acyl-3-pyrrole acrylonitrile compound, styryl sulfide salt and base are added in a molar ratio of 1:1.0-5.0:0.5-3.

0.

8. The method for preparing the dihydrofuran-fused pyrrolizine derivative according to claim 3, characterized in that: The 2-acyl-3-pyrrole acrylonitrile compound and styryl sulfide are dissolved in an organic solvent, and a base accelerator is added at 0° C. to 40° C., and the stirring time is 0.25-2 hours.

9. A pharmaceutical composition or carrier, characterized in that The invention comprises the dihydrofuran-fused pyrrolizine derivative according to claim 1 or 2.

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