The invention relates to a spiro [cyclopenta [c] carbazole-1, 1apos; -isoindoline]-3apos,-isoindoline]-3apos Chiral synthesis method of-ketone compounds

Abstract

The invention belongs to the technical field of synthesis of organic compounds, and particularly relates to a chiral synthesis method of spiro [cyclopenta [c] carbazole-1, 1 '-isoindoline]-3'-ketone compounds. The compound synthesized by the invention has an isoindolinone skeleton and a carbazole active fragment at the same time. The carbazole compound and the isoindolinone compound are successfully combined in a cyclization mode for the first time, and the chiral compound can be prepared. The invention provides a synthesis method of a chiral spiro [cyclopenta [c] carbazole-1, 1 '-isoindoline]-3'-ketone compound, which has the advantages of mild reaction conditions, green and environment-friendly catalyst, easiness in operation, few synthesis steps, easiness in purification and separation of products, capability of obtaining higher yield and high stereoselectivity, easiness in amplification of reaction, high yield, high yield and high yield, and is suitable for large-scale production of the chiral spiro [cyclopenta [c] carbazole-1, 1 '-isoindoline]-3'-ketone compound. And the method has a wide application prospect.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic compound synthesis, and in particular relates to a chiral synthesis method of spiro[cyclopenta[c]carbazole-1,1'-isoindoline]-3'-ketone compounds. Background Art

[0002] Isoindolinone compounds are a class of compounds with significant biological activity. Due to their unique pharmacological activity, they have been closely watched by chemists in the field of anti-tumor drug research and development in recent years.

[0003] Carbazoles are an important class of heterocyclic compounds with remarkable biological activity. Currently, a variety of carbazole-based anticancer drugs have been approved for chemotherapy, such as ellipticine, celiptium, and alectinib, demonstrating the potential of carbazole derivatives as anticancer drug candidates.

[0004] In recent years, molecular hybridization has emerged as an effective tool for drug design and development, integrating two or more drug-active groups into a single, unique molecule. This novel hybrid molecule has enormous potential to address the current shortage of highly effective, low-toxic therapeutics for cancer treatment by increasing the affinity between the drug and its target.

[0005] In the prior art, there are no synthetic methods for combining isoindolinone compounds with active carbazole fragments, nor are there synthetic methods for cyclizing carbazole into the backbone of other compounds. In particular, there are no reported chiral preparation methods for spirocyclizing active carbazole fragments with isoindolinone compounds to generate spiro[cyclopenta[c]carbazole-1,1'-isoindoline]-3'-one compounds.

[0006] Based on the principle of pharmacodynamic fragment splicing, a series of spiro[cyclopenta[c]carbazole-1,1'-isoindoline]-3'-one compounds synthesized using molecular hybridization strategy, which have both an isoindolinone skeleton and an active fragment carbazole, have broad application prospects in the field of anti-tumor drugs. Summary of the Invention

[0007] The purpose of the present invention is to solve the existing problems and provide a chiral synthesis method of spiro[cyclopenta[c]carbazole-1,1'-isoindoline]-3'-ketone compounds.

[0008] The present invention is achieved through the following technical solutions:

[0009] A chiral synthesis method for a spiro[cyclopenta[c]carbazole-1,1'-isoindoline]-3'-one compound, comprising: adding an isoindolinone-propargyl alcohol compound and a carbazole compound to a solvent, dichloromethane, under the catalysis of a chiral phosphoric acid catalyst, reacting at 20°C, and purifying to obtain a chiral spiro[cyclopenta[c]carbazole-1,1'-isoindoline]-3'-one compound;

[0010] The synthesis reaction system process is as follows:

[0011]

[0012] Wherein, R1 is an alkyl group, a trimethylsilyl group or an aryl group;

[0013] R2 is hydrogen, alkyl, alkoxy, hydroxy, cyano, amino, nitro, halo or phenyl;

[0014] R3 is halogen, alkyl or aryl.

[0015] Furthermore, the chiral phosphoric acid catalyst is chiral phosphoric acid catalyst Cat.1, and its structure is as follows:

[0016]

[0017] Furthermore, the structural formula of the isoindolinone-propargyl alcohol compound is as follows:

[0018]

[0019] The preparation method of the isoindolinone-propargyl alcohol compound is as follows:

[0020] 2.5 equivalents of alkyne were dissolved in 2 mL / mmol of tetrahydrofuran, cooled to -78°C, and then 2.5 equivalents of n-butyl lithium were added. After stirring at -78°C for 30 minutes, 1.0 equivalent of a phthalimide compound was added and dissolved in 3 mL / mmol of tetrahydrofuran. After stirring at -78°C for 15 minutes, the mixture was reacted at room temperature for 12 hours. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and then purified to obtain a series of isoindolinone-propargyl alcohol compounds.

[0021] Furthermore, the synthesis reaction system process of the isoindolinone-propargyl alcohol compound is as follows:

[0022]

[0023] Furthermore, the structure of the carbazole compound is as follows:

[0024]

[0025] Wherein, R3 is halogen, alkyl or aryl.

[0026] Furthermore, when R3 is an alkyl group, the preparation method of the alkyl-substituted carbazole compound is:

[0027] 1 equivalent of 2-bromocarbazole or 3-bromocarbazole was dissolved in tetrahydrofuran. Under argon protection, 3 equivalents of alkyl Grignard reagent and 0.05 equivalents of DPPF palladium dichloride were added. The mixture was stirred at 80°C overnight. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution. The mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and then purified to obtain a series of alkyl-substituted carbazole compounds.

[0028] Furthermore, the synthesis reaction system process of the alkyl-substituted carbazole compound is as follows:

[0029]

[0030] Furthermore, when R3 is an aryl group, the preparation method of the aryl-substituted carbazole compound is:

[0031] 1 equivalent of 2-bromocarbazole or 3-bromocarbazole was dissolved in toluene. Under argon protection, 1.5 equivalents of arylboronic acid, 2.2 equivalents of potassium borate, 0.05 equivalents of 2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl and 0.02 equivalents of tris(dibenzylidene-BASE acetone)dipalladium were added. The mixture was stirred at 90°C for 24 hours. After the reaction, the reaction solution was poured into water and the mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and then purified to obtain a series of aryl-substituted carbazole compounds.

[0032] Furthermore, the synthesis reaction system process of the aromatic substituted carbazole compound is as follows:

[0033]

[0034] Compared with the prior art, the present invention has the following advantages:

[0035] 1. The compounds synthesized in the present invention have both an isoindolinone skeleton and a carbazole active fragment. Furthermore, the present invention successfully combines carbazole compounds and isoindolinone compounds for the first time through cyclization, and can produce such chiral compounds.

[0036] 2. The present invention provides a method for synthesizing chiral spiro[cyclopenta[c]carbazole-1,1'-isoindoline]-3'-one compounds, which has the advantages of mild reaction conditions, green and environmentally friendly catalysts, easy operation, few synthesis steps, easy purification and separation of products, high yield and high stereoselectivity, and easy scale-up of the reaction, and has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 This is the HPLC spectrum of the racemate of Example 1;

[0038] Figure 2 HPLC spectrum of the chiral compound in Example 1;

[0039] Figure 3 This is the HPLC spectrum of the racemate of Example 2;

[0040] Figure 4 HPLC spectrum of the chiral compound in Example 2;

[0041] Figure 5 This is the HPLC spectrum of the racemate of Example 3;

[0042] Figure 6 HPLC spectrum of the chiral compound in Example 3;

[0043] Figure 7 This is the HPLC spectrum of the racemate of Example 4;

[0044] Figure 8 HPLC spectrum of the chiral compound of Example 4;

[0045] Figure 9 This is the HPLC spectrum of the racemate of Example 5;

[0046] Figure 10 is the HPLC spectrum of the chiral compound in Example 5; DETAILED DESCRIPTION

[0047] In order to further explain the present invention, it is described below with reference to the following specific embodiments.

[0048] Example 1:

[0049] This embodiment provides a chiral preparation method of spiro[cyclopenta[c]carbazole-1,1'-isoindoline]-3'-one compounds, which comprises the following steps:

[0050] 0.1 mmol of tert-butylethynyl-substituted propargyl alcohol 1a and 0.12 mmol of 3-bromocarbazole 2a were placed in a reaction flask, 3.3 mg of chiral phosphoric acid catalyst Cat. 1 was added, and 2 ml of dry dichloromethane was added to dissolve the mixture. Stirring was continued at 20°C, and the reaction was monitored by spotting on a thin-layer chromatography plate until the reaction of the raw materials was complete. After the reaction was completed, separation and purification were performed using a silica gel column. The purified product was rotary evaporated to obtain the target product 3a (yield 72%, 95% ee), as shown in the following reaction formula:

[0051]

[0052] The structural formula of the product of Example 1 is as follows:

[0053]

[0054] The H NMR spectrum data of the obtained product are as follows:

[0055] 1 H NMR (400MHz, DMSO) δ11.53(s,1H),8.86(s,1H),7.90(d,J=7.5Hz,1H),7.79(d,J=8.5Hz,1H),7.53(dd,J=15.7 ,8.0Hz,2H),7.40(t,J=7.4Hz,1H),7.35(s,2H),7.10(s,1H),6.80(d,J=7.6Hz,1H),5.71(s,1H),1.41(s,9H).

[0056] The carbon NMR spectrum data of the obtained product are as follows:

[0057] 13 C NMR (101MHz, DMSO) δ170.37,154.03,146.17,140.80,140.05,139.53,135.29,134.17,132.92,129.30,129. 15,128.44,126.18,123.66,122.61,121.99,121.39,118.40,113.04,111.31,110.85,72.50,33.38,29.63.

[0058] HPLC analysis:

[0059] The enantiomeric excess was determined by high performance liquid chromatography (HPLC) equipped with a Chiralpak AD column (mobile phase: a mixture of n-hexane and isopropanol in a ratio of 70:30, flow rate: 1 ml / min, detection wavelength λ = 254 nm).

[0060] The results show that:major =11.6min, t minor =8.8min.

[0061] Example 2:

[0062] The method is basically the same as that of Example 1.

[0063] 0.1 mmol of propargyl alcohol 1a and 0.12 mmol of TMS alkynyl-substituted carbazole 2b were placed in a reaction flask, 3.3 mg of chiral phosphoric acid catalyst Cat.1 was added, and 2 ml of dry dichloromethane was added to dissolve the mixture. Stirring was continued at 20°C. The reaction was monitored by spotting on a thin-layer chromatography plate until the reaction of the raw materials was complete. After the reaction was completed, separation and purification were performed using a silica gel column. The purified product was rotary evaporated to obtain the target product 3b (yield 70%, 92% ee). The reaction formula is as follows:

[0064]

[0065] The product structural formula of Example 2 is as follows:

[0066]

[0067] The H NMR spectrum data of the obtained product are as follows:

[0068] 1 H NMR (400MHz, DMSO) δ11.60(s,1H),8.81(s,1H),7.81(dd,J=17.1,8.0Hz,2H),7.58–7.47(m,2H),7.41(t,J=7.4Hz,1H) ,7.34(d,J=8.4Hz,1H),7.30–7.24(m,1H),7.04(s,1H),6.82(d,J=7.6Hz,1H),5.71(s,1H),1.42(s,9H),0.28(s,9H).

[0069] The carbon NMR spectrum data of the obtained product are as follows:

[0070] 13 C NMR (101MHz, DMSO) δ169.09,152.90,145.03,139.54,138.87,134.43,133.16,131.74,128.27,128.17,127.91,127.65 ,127.60,122.31,120.98,120.91,120.07,119.75,117.71,111.38,110.15,106.23,90.37,71.31,32.25,28.43,-0.50.

[0071] HPLC analysis:

[0072] The enantiomeric excess was determined by high performance liquid chromatography (HPLC) using a Chiralpak OD chiral column (n-hexane / isopropanol ratio of 80 / 20, flow rate of 1 ml / min, detection wavelength λ = 254 nm).

[0073] The results show that: major =4.8min, t minor =15.5min.

[0074] Example 3:

[0075] The method is basically the same as that of Example 1.

[0076] 0.1 mmol of propargyl alcohol 1a and 0.12 mmol of p-methylphenyl-substituted carbazole 2c were placed in a reaction flask, 3.3 mg of chiral phosphoric acid catalyst Cat.1 was added, and 2 ml of dry dichloromethane was added to dissolve the mixture. Stirring was continued at 20°C. The reaction was monitored by spotting on a thin-layer chromatography plate until the reaction of the raw materials was complete. After the reaction was completed, separation and purification were performed on a silica gel column. The purified product was rotary evaporated to obtain the target product 3c (yield 73%, 90% ee). The reaction formula is as follows:

[0077]

[0078] The product structural formula of Example 3 is as follows:

[0079]

[0080] The H NMR spectrum data of the obtained product are as follows:

[0081] 1 H NMR (500MHz, DMSO) δ11.42(s,1H),8.91(s,1H),7.90(d,J=7.6Hz,1H),7.76(d,J=8.4Hz,1H),7.58–7.48(m,3H),7.41(dd,J =13.5,7.9Hz,2H),7.35(d,J=8.1Hz,2H),7.31–7.17(m,3H),6.87(d,J=7.6Hz,1H),5.69(s,1H),2.36(s,3H),1.42(s,9H).

[0082] The carbon NMR spectrum data of the obtained product are as follows:

[0083] 13C NMR (126MHz, DMSO) δ170.59,154.16,146.52,140.51,140.21,140.13,138.11,135.86,135.04,134.23,132.93,130.92,129.83, 128.99,128.96,126.52,124.80,123.81,122.10,121.69,121.56,120.77,119.58,111.47,111.08,72.60,33.39,29.62,21.09.

[0084] HPLC analysis:

[0085] The enantiomeric excess was determined by high performance liquid chromatography (HPLC) using a Chiralpak AD chiral column (mobile phase: n-hexane / isopropanol, ratio 70 / 30, flow rate 1 ml / min, detection wavelength λ = 254 nm).

[0086] The results show that: major =24.6min, t minor =12.2min.

[0087] Example 4:

[0088] The method is basically the same as that of Example 1.

[0089] 0.1 mmol of propargyl alcohol 1a and 0.12 mmol of 2-bromocarbazole 2d were placed in a reaction flask, 3.3 mg of chiral phosphoric acid catalyst Cat.1 was added, and 2 ml of dry dichloromethane was added to dissolve the mixture. Stirring was continued at 20°C. The reaction was monitored by spotting on a thin-layer chromatography plate until the reaction of the raw materials was complete. After the reaction was completed, separation and purification were performed using a silica gel column. The purified product was rotary evaporated to obtain the target product 3d (yield 72%, 98% ee). The reaction formula is as follows:

[0090]

[0091] The product structural formula of Example 4 is as follows:

[0092]

[0093] The H NMR spectrum data of the obtained product are as follows:

[0094] 1H NMR (400MHz, DMSO) δ11.49(s,1H),8.91(s,1H),7.88(d,J=7.5Hz,1H),7.80(d,J=8.5Hz,1H),7.56(dd,J=9.3,4.9Hz, 2H),7.49(t,J=7.4Hz,1H),7.39(t,J=7.4Hz,1H),6.97–6.85(m,2H),6.78(d,J=7.6Hz,1H),5.70(s,1H),1.41(s,9H).

[0095] The carbon NMR spectrum data of the obtained product are as follows:

[0096] 13 C NMR (101MHz, DMSO) δ170.51,153.93,146.18,141.87,140.58,139.86,135.44,133.99,132.85,129.44,129.34,129. 04,125.04,123.71,121.92,121.55,121.50,121.20,120.02,119.00,118.71,113.86,111.31,72.50,33.38,29.56.

[0097] HPLC analysis:

[0098] The enantiomeric excess was determined by high performance liquid chromatography (HPLC) using a Chiralpak AD70 chiral column (the mobile phase was a mixture of n-hexane and isopropanol in a ratio of 70:30, the flow rate was 1 ml / min, and the detection wavelength λ = 254 nm).

[0099] The results show that: major =9.0min,t minor =6.7min.

[0100] Example 5:

[0101] The method is basically the same as that of Example 1.

[0102] 0.1 mmol of propargyl alcohol 1a and 0.12 mmol of propyl-substituted carbazole 2e were placed in a reaction flask, 3.3 mg of chiral phosphoric acid catalyst Cat.1 was added, and 2 ml of dry dichloromethane was added to dissolve the mixture. Stirring was continued at 20°C. The reaction was monitored by spotting on a thin-layer chromatography plate until the reaction of the raw materials was complete. After the reaction was completed, separation and purification were performed using a silica gel column. The purified product was rotary evaporated to obtain the target product 3e (yield 88%, 90% ee). The reaction formula is as follows:

[0103]

[0104] The product structural formula of Example 5 is as follows:

[0105]

[0106] The H NMR spectrum data of the obtained product are as follows:

[0107] 1 H NMR (400MHz, CDCl3) δ8.22(s,1H),8.04(d,J=7.6Hz,1H),7.62(d,J=8.4Hz,1H),7.44(t,J=7.5Hz,1H),7.33(dd,J=15.1,7.8Hz,2H),7.15(d,J=8. 2Hz,1H),7.04(d,J=8.2Hz,1H),6.93–6.85(m,2H),6.05(s,1H),5.65(s, 1H), 2.51–2.40 (m, 2H), 1.77 (s, 2H), 1.43 (s, 9H), 0.79 (t, J = 7.3Hz, 3H).

[0108] The carbon NMR spectrum data of the obtained product are as follows:

[0109] 13 C NMR (126MHz, CDCl3) δ171.12,155.10,146.32,139.45,139.14,138.55,135.37,133.89,132.99,132.64,128.55,127.9 2,127.08,123.86,123.62,122.09,121.29,120.20,120.16,110.17,109.80,72.50,37.76,33.36,29.37,24.66,13.69.

[0110] HPLC analysis:

[0111] The enantiomeric excess was determined by high performance liquid chromatography (HPLC) using a Chiralpak AD column with a mobile phase of n-hexane / isopropanol (volume ratio 70 / 30) at a flow rate of 1 ml / min and a detection wavelength of λ=254 nm.

[0112] The results show that: major =15.5min, t minor =10.8min.

[0113] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent replacements or changes based on the technical solution and inventive concept of the present invention, should be covered by the scope of protection of the present invention.

Claims

1. A chiral synthesis method of spiro[cyclopenta[c]carbazole-1,1'-isoindoline]-3'-one compounds, characterized in that: The synthesis method comprises the following steps: adding an isoindolinone-propargyl alcohol compound and a carbazole compound to a solvent of dichloromethane under the catalysis of a chiral phosphoric acid catalyst, reacting at 20°C, and purifying to obtain a chiral spiro[cyclopenta[c]carbazole-1,1'-isoindoline]-3'-one compound; The synthesis reaction system process is as follows: Wherein, R1 is an alkyl group, a trimethylsilyl group or an aryl group; R2 is hydrogen, alkyl, alkoxy, hydroxy, cyano, amino, nitro, halo or phenyl; R3 is halogen, alkyl or aryl.

2. The chiral synthesis method of a spiro[cyclopenta[c]carbazole-1,1'-isoindoline]-3'-one compound according to claim 1, characterized in that: The chiral phosphoric acid catalyst is chiral phosphoric acid catalyst Cat.1, and its structure is as follows:

3. The chiral synthesis method of a spiro[cyclopenta[c]carbazole-1,1'-isoindoline]-3'-one compound according to claim 1, characterized in that: The structural formula of the isoindolinone-propargyl alcohol compound is as follows: The preparation method of the isoindolinone-propargyl alcohol compound is as follows: 2.5 equivalents of alkyne were dissolved in 2 mL / mmol of tetrahydrofuran, cooled to -78°C, and then 2.5 equivalents of n-butyl lithium were added. After stirring at -78°C for 30 minutes, 1.0 equivalents of a phthalimide compound was added and dissolved in 3 mL / mmol of tetrahydrofuran. After stirring at -78°C for 15 minutes, the mixture was reacted at room temperature for 12 hours. After the reaction was completed, the reaction was quenched with a saturated ammonium chloride solution, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and then purified to obtain a series of isoindolinone-propargyl alcohol compounds.

4. The chiral synthesis method of spiro[cyclopenta[c]carbazole-1,1'-isoindoline]-3'-one compounds according to claim 3, characterized in that: The synthesis reaction system process of the isoindolinone-propargyl alcohol compound is as follows:

5. The chiral synthesis method of spiro[cyclopenta[c]carbazole-1,1'-isoindoline]-3'-one compounds according to claim 1, characterized in that: The structure of the carbazole compound is as follows: Wherein, R3 is halogen, alkyl or aryl.

6. The chiral synthesis method of spiro[cyclopenta[c]carbazole-1,1'-isoindoline]-3'-one compounds according to claim 5, characterized in that: When R3 is an alkyl group, the preparation method of the alkyl-substituted carbazole compound is: 1 equivalent of 2-bromocarbazole or 3-bromocarbazole was dissolved in tetrahydrofuran. Under argon protection, 3 equivalents of alkyl Grignard reagent and 0.05 equivalents of DPPF palladium dichloride were added. The mixture was stirred at 80°C overnight. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution. The mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and then purified to obtain a series of alkyl-substituted carbazole compounds.

7. The chiral synthesis method of spiro[cyclopenta[c]carbazole-1,1'-isoindoline]-3'-one compounds according to claim 6, characterized in that: The synthesis reaction system process of the alkyl-substituted carbazole compound is as follows:

8. The chiral synthesis method of spiro[cyclopenta[c]carbazole-1,1'-isoindoline]-3'-one compounds according to claim 5, characterized in that: When R3 is an aryl group, the preparation method of the aryl-substituted carbazole compound is as follows: 1 equivalent of 2-bromocarbazole or 3-bromocarbazole was dissolved in toluene. Under argon protection, 1.5 equivalents of arylboronic acid, 2.2 equivalents of potassium borate, 0.05 equivalents of 2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-biphenyl and 0.02 equivalents of tris(dibenzylidene-BASE acetone)dipalladium were added. The mixture was stirred at 90°C for 24 hours. After the reaction, the reaction solution was poured into water and the mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and then purified to obtain a series of aryl-substituted carbazole compounds.

9. The chiral synthesis method of spiro[cyclopenta[c]carbazole-1,1'-isoindoline]-3'-one compounds according to claim 8, characterized in that: The synthesis reaction system process of the aromatic substituted carbazole compound is as follows:

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