Synthetic method and application of pyrrole [2, 3-c] quinoline compound

Abstract

The invention relates to a synthetic method and application of a pyrrole [2, 3-c] quinoline compound, and the synthetic method comprises the following steps: in a nitrogen environment, adding a compound Ts-substituted 1a and an ether solvent, and adding a compound Grignard reagent or magnesium 2a to obtain the pyrrole [2, 3-c] quinoline compound as shown in a formula (I), according to the synthetic method disclosed by the invention, the pyrrole [2, 3-c] quinoline compound with biological activity can be efficiently and simply synthesized.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthetic chemistry, and specifically relates to a synthesis method and application of a pyrrole [2,3-c] quinoline compound. Background Art

[0002] The heterocyclic 3H-pyrrolo[2,3-c]quinoline system and its closely related natural products, the marine quinolines, have attracted much attention in recent years due to their diverse biological activities. Since 1924, when 3H-pyrrolo[2,3-c]quinoline was discovered, the first natural product containing this core structure was isolated in 2006. These derivatives, named Marinoquinolines (MQ) after their discovery in marine natural products, are a new class of alkaloids with great biological and pharmacological potential. Their structures and biological activities, such as anti-plasmodial, anti-proliferative, acetylcholinesterase inhibitors, antibacterial and ion-sensing, have stimulated the development of new strategies for the natural marine quinolines and new pyrrolo[2,3-c]quinoline derivatives. The research on synthetic methodology of MQ-type natural products has maintained a vigorous development, and many literature reviews of related synthetic methods have been reported so far (Chem. Heterocycl. Com. 2021, 57, 12, 1155–1163, J. Org. Chem. 2020, 85, 650-663).

[0003] However, the inventors have found that the existing total synthesis methods of such natural products often require the pre-synthesis of functionalized pyrrole or quinoline substrates, and the experimental conditions of these existing methods have the disadvantage of being more harsh, or requiring multiple steps of reaction and complex reaction steps, and there are also certain technical difficulties in operation. Therefore, the development of a new method for the efficient de novo synthesis of MQs has attracted much attention. This type of synthetic strategy can easily construct the structure of MQs, which is of great significance for studying the synthetic application of such MQs alkaloids. Summary of the invention

[0004] The present invention provides a method for synthesizing a pyrrole [2,3-c] quinoline compound of formula (I), comprising:

[0005] Under nitrogen environment, add compound 1a, add ether solvent, add compound 2a to obtain formula (I);

[0006]

[0007] Wherein, R is a substituent on the pyridine ring of the quinoline part of the parent structure, and R is selected from one of methyl, isopropyl, benzyl, p-methoxyphenyl or hydrogen; the ether solvent is one or more of tetrahydrofuran and diethyl ether.

[0008] Furthermore, the preparation method of 1a comprises:

[0009] Step 1: Condensation reaction:

[0010]

[0011] Step 2: Reduction reaction

[0012]

[0013] Step 3: Formylation reaction

[0014]

[0015] Step 4: Dehydration reaction

[0016]

[0017] Step 5: Cross-heterocyclization reaction

[0018]

[0019] Furthermore, when adding compound 1a, 4A molecular sieve is also added, thereby reducing the water content in the solvent and increasing the reaction yield.

[0020] Furthermore, when adding 2a, a dropwise addition method is adopted to prevent the reaction from being too fast, thereby reducing the yield of the reaction.

[0021] The present invention also provides the use of the above-obtained pyrrole [2,3-c] quinoline compound of formula (I), when R is p-methoxyphenyl, in the preparation of biologically active pyrrole [2,3-c] quinoline compound analogs by demethylation under the action of boron tribromide.

[0022] The synthesis method of the present invention can realize efficient and simple synthesis of pyrrole [2,3-c] quinoline compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 It is the general structure of the pyrrole [2,3-c] quinoline compound prepared by the present invention;

[0024] Figure 2a The hydrogen nuclear magnetic resonance spectrum of the compound MQ A prepared in the present invention;

[0025] Figure 2b The carbon spectrum of the compound MQ A prepared in the present invention;

[0026] Figure 3a The hydrogen nuclear magnetic resonance spectrum of the compound MQ B prepared in the present invention;

[0027] Figure 3bThe carbon NMR spectrum of the compound MQ B prepared in the present invention;

[0028] Figure 4a The hydrogen nuclear magnetic resonance spectrum of the compound MQ C prepared by the present invention;

[0029] Figure 4b The carbon NMR spectrum of the compound MQ C prepared by the present invention;

[0030] Figure 5a The hydrogen nuclear magnetic resonance spectrum of compound 3a prepared in the present invention;

[0031] Figure 5b The carbon NMR spectrum of compound 3a prepared in the present invention;

[0032] Figure 6a The hydrogen nuclear magnetic resonance spectrum of the compound MQ H prepared by the present invention;

[0033] Figure 6b The carbon NMR spectrum of the compound MQ H prepared by the present invention;

[0034] Figure 7a The hydrogen nuclear magnetic resonance spectrum of the compound MQ K prepared by the present invention;

[0035] Figure 7b The carbon nuclear magnetic resonance spectrum of the compound MQ K prepared in the present invention. DETAILED DESCRIPTION

[0036] The invention is illustrated by the following examples.

[0037] Source of reagents: The purity and origin of the experimental reagents used in the present invention and the model and origin of the experimental instruments are shown in Table 1 and Table 2, respectively.

[0038] Table 1 Experimental instruments

[0039]

[0040]

[0041] Table 2 Experimental drugs and reagents

[0042]

[0043]

[0044] In the following examples, the abbreviations represent the following meanings: CDCl3: deuterated chloroform; CD3OD: deuterated methanol; 1 HNMR: hydrogen nuclear magnetic resonance; 13C NMR: carbon nuclear magnetic resonance; HRMS (ESI): high resolution mass spectrometry (electrospray ionization); PE: petroleum ether; EA: ethyl acetate; DCM: dichloromethane.

[0045] Synthesis of 1a:

[0046] Using the easily available o-nitrophenylacetonitrile and polyformaldehyde as starting materials, condensation, reduction, formylation and further dehydration are performed to obtain a series of products. The reaction equation is shown in the figure:

[0047] Step 1: Condensation reaction:

[0048]

[0049] Step 2: Reduction reaction

[0050]

[0051] Step 3: Formylation reaction

[0052]

[0053] Step 4: Dehydration reaction

[0054]

[0055] Step 5: Cross-heterocyclization reaction

[0056]

[0057] Through the above five-step transformation, a series of reactions are carried out to synthesize compound 1a.

[0058] Example 1

[0059] This example provides a preparation process of the compound MQ A of formula I:

[0060]

[0061] In a 10 mL Shrek bottle equipped with a magnetic stirrer and a sealing stopper, compound 1a (0.2 mmol) and Molecular sieves (50 mg). The system was quickly sealed and replaced with nitrogen three times. Solvent THF (2 mL) was added, compound 2a (3.0 eq) was added dropwise within 30 s, and stirred at 80 ° C for 4 hours. The mixture was then cooled to room temperature, diluted with ethyl acetate, and transferred to a separatory funnel and extracted with saturated brine (10 mL) and ethyl acetate (10 mL*3). The combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 1: 1 to 1: 3) to obtain a white solid compound MQ A (25.5 mg, 0.14 mmol, 70% yield).

[0062] like Figure 2a , 2b As shown, the NMR and mass spectrometry data of MQ A: 1 H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H). 8.18 (dd, J 1 = 1.2 Hz, J 2 = 7.2 Hz,1H), 8.11 (dd, J 1 = 1.2 Hz, J 2 = 7.2 Hz, 1H), 7.60-7.52 (m, 2H), 7.43 (d, J = 2.8Hz, 1H), 7.09 (d, J = 2.8 Hz, 1H),2.87 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ 145.5,142.6, 128.7, 128.6, 128.0, 126.0, 125.8, 125.4, 123.1, 123.0, 102.1, 20.8.HRMS (ESI) m / z: [M+H]+ calcd for C 12 H 11 N2 + 183.0917; found 183.0917.

[0064] Example 2

[0065] This example provides a preparation process of the compound MQ B of formula I:

[0066]

[0067] In a 10 mL Shrek bottle equipped with a magnetic stirrer and a sealing stopper, compound 1a (0.2 mmol) and Molecular sieves (50 mg). The system was quickly sealed and replaced with nitrogen three times. Solvent THF (2 mL) was added, and compound 2b (3.0 eq) was added dropwise within 30 s, and stirred at 80 ° C for 4 hours. The mixture was then cooled to room temperature, diluted with ethyl acetate, and transferred to a separatory funnel and extracted with saturated brine (10 mL) and ethyl acetate (10 mL*3). The combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 1: 1 to 1: 3) to obtain a white solid compound MQ B (26.5 mg, 0.12 mmol, 59% yield).

[0068] like Figure 2a , 2b As shown, the NMR and mass spectrometry data of MQ B:

[0069] 1 H NMR(400MHz, CDCl3)δ9.03(s,1H).8.16(t,J=9.2Hz,2H),7.60-7.52(m,2H),7.43(d,J=2.8Hz ,1H),7.07(d,J=2.8Hz,1H),3.04(d,J=7.2Hz,2H),2.43-2.33(m,1H),0.99(d,J=7.2Hz,6H). 13 C NMR (100MHz, CDCl3) δ148.8,142.3,129.5,128.6,128.3,126.1,125.9,125.4,122.88,122.85,102.1,43.7,29.7,29.0,22.8.HRMS(ESI)m / z:[M+H] + calcdfor C 15 H 17 N2 + 225.1386; found 225.1377.

[0070] Example 3

[0071] This example provides a preparation process of the compound MQ C of formula I:

[0072]

[0073] In a 10 mL Shrek bottle equipped with a magnetic stirrer and a sealing stopper, compound 1a (0.2 mmol) and Molecular sieves (50 mg). The system was quickly sealed and replaced with nitrogen three times. Solvent THF (10 mL) was added, and compound 2c (3.0 eq) was added dropwise within 30 s, and stirred at 80 ° C for 4 hours. The mixture was then cooled to room temperature, diluted with ethyl acetate, and transferred to a separatory funnel and extracted with saturated brine (10 mL) and ethyl acetate (10 mL*3). The combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 1: 1 to 1: 3) to obtain a white solid compound MQ C (28.9 mg, 0.11 mmol, 56% yield).

[0074] like Figure 3a , 3b As shown, the NMR and mass spectrometry data of MQ C:

[0075] 1 H NMR (400MHz, CDCl3) δ8.39(s,1H),8.17(t,J=8.0Hz,2H),7.61(t,J=8.0Hz,1H),7.56(t,J=8.0Hz,1H),7.35(d,J= 7.2Hz,2H),7.32(d,J=7.2Hz,2H),7.28(t,J=7.2Hz,1H),7.23(d,J=3.2Hz,1H),7.00(d,J=3.2Hz,1H),4.60(s,3H) 13 C NMR (100MHz, CDCl3) δ147.2,141.9,137.9,129.2,129.0,128.9,128.5,128.1 ,127.0,126.6,126.3,125.7,123.1,122.9,101.6,42.2.HRMS(ESI)m / z:[M+H] + Calculate for C 18 H 15 N2 + 259.1230; found 259.1240.

[0076] Example 4

[0077] This example provides a preparation process of the compound MQ H precursor 3a of formula I:

[0078]

[0079] In a 10 mL Shrek bottle equipped with a magnetic stirrer and a sealing stopper, compound 1a (0.2 mmol) and Molecular sieves (50 mg). The system was quickly sealed and replaced with nitrogen three times. Solvent THF (2 mL) was added, and compound 2d (3.0 eq) was added dropwise within 30 s, and stirred at 80 ° C for 4 hours. The mixture was then cooled to room temperature, diluted with ethyl acetate, and transferred to a separatory funnel and extracted with saturated brine (10 mL) and ethyl acetate (10 mL*3). The combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 1: 1 to 1: 3) to obtain a white solid compound 3a (36.7 mg, 0.134 mmol, 67% yield).

[0080] like Figure 4a , 4b As shown, the NMR and mass spectrometry data of 3a:

[0081] 1 H NMR (400MHz, CDCl3) δ9.27 (s, 1H), 8.23-8.19 (m, 2H), 7.87 (d, J = 8.4Hz, 2H), 7.62-7.56 ( m,2H),7.42(q,J=2.8Hz,1H),7.12(q,J=2.8Hz,1H),7.01(q,J=8.4Hz,2H),3.82(s,3H). 13 C NMR (100MHz, CDCl3)160.5,146.6,143.0,130.9,129.6,129.5,129.1,127.4, 126.2,126.1,125.6,123.0,122.8,114.5,102.1,55.4.HRMS(ESI)m / z:[M+H] + calcdfor C 18 H 15 N2O + 275.1179; found 275.1167.

[0082] Example 5

[0083] This example provides a preparation process of the compound MQ H of formula I:

[0084]

[0085] Compound 3a (0.1 mmol) and dichloromethane (3 mL) were added to a 10 mL pressure tube equipped with a magnetic stirrer and a sealing stopper. Boron tribromide (5.0 eq) was added dropwise at 0°C within one minute. After reacting for 1 hour, the mixture was heated to 40°C and reacted for 12 hours. Methanol (3 mL) was then added dropwise at -78°C. The mixture was then concentrated under reduced pressure and purified by column chromatography (DCM: MeOH = 50: 1 to 30: 1) to obtain a white solid compound MQ H (20.3 mg, 0.078 mmol, 78% yield).

[0086] like Figure 5a , 5b As shown, the NMR and mass spectrometry data of MQ H are:

[0087] 1 H NMR (400MHz, CD3OD) δ8.27-8.25(m,1H),8.09-8.07(m,1H),7.79(d,J=8.4Hz,2H),7.62(d, J=2.8Hz,1H),7.60-7.53(m,2H),7.17(d,J=2.8Hz,1H),7.04(d,J=8.4Hz,2H),3.35(s,1H) 13 C NMR(100MHz,CD3OD)δ160.5,148.5,142.4,130.1,130.0,129.1,127.9,126.8,126.7,126.1,125.4,122.9,122.8,116.9,102.5.HRMS(ESI)m / z:[M+H] + Calculate for C 17 H 13 N2O + 261.1022; found 261.1002.

[0088] Example 6

[0089] This example provides a preparation process of the compound MQ K of formula I:

[0090]

[0091] Compound 1a (0.2 mmol), magnesium metal (50 eq) and methanol (2 mL) were added to a 10 mL pressure tube equipped with a magnetic stirrer and a sealing stopper. Stir at 25 °C for 10 hours. The mixture was then diluted with ethyl acetate and transferred to a separatory funnel and extracted with saturated brine (10 mL) and ethyl acetate (10 mL*3). The combined organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-1:3) to obtain a white solid compound MQ K (16.4 mg, 0.098 mmol, 49% yield).

[0092] like Figure 6a , 6b As shown, the NMR and mass spectrometry data of MQ K:

[0093] 1 H NMR (400MHz, CDCl3) δ9.76 (s, 1H), 9.12 (s, 1H), 8.26-8.19 (m, 2H), 7.63-7.58 (m, 2H), 7.55 (d, J = 2.8Hz, 1H), 7.11 (dJ = 2.8Hz, 1H). 13 C NMR(100MHz, CDCl3)δ142.5,137.5,129.4,129.2,128.6,126.6,126.2,126.1,123.6,123.1,101.7.HRMS(ESI)m / z:[M+H] + Calculate for C 11 H9N2 + 169.0760; found 169.0755.

[0094] In the present invention, the molecular sieve serves to remove a small amount of water in the system, so as to reduce the consumption of the Grignard reagent by side reactions with water during the reaction.

Claims

1. A method for synthesizing a pyrrole [2,3-c] quinoline compound of formula (I), characterized in that: include: Under nitrogen environment, compound 1a and an ether solvent are added, compound 2a is added, and the mixture is purified to obtain formula (I); Wherein, R is a substituent on the pyridine ring of the quinoline part of the parent structure, and R is selected from methyl, isopropyl, benzyl, p-methoxyphenyl or hydrogen; the ether solvent is tetrahydrofuran, diethyl ether or a combination thereof.

2. The method according to claim 1, characterized in that The preparation method of 1a comprises: Step 1: Condensation reaction: Step 2: Reduction reaction Step 3: Formylation reaction Step 4: Dehydration reaction Step 5: Cross-heterocyclization reaction 3. The method according to claim 1, characterized in that When compound 1a was added, 4A molecular sieves were also added.

4. The method according to claim 1, characterized in that: When adding 2a, a dropwise addition method is adopted.

5. Use of the pyrrole [2,3-c] quinoline compound of formula (I) obtained according to claim 1, when R is p-methoxyphenyl, in the preparation of biologically active pyrrole [2,3-c] quinoline compound analogs by demethylation under the action of boron tribromide.

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