Asymmetric synthesis method of carbazole axially chiral tetra-substituted allene derivative

Abstract

The invention relates to the technical field of organic chemical synthesis, in particular to a carbazole axially chiral tetra-substituted allene derivative which is a compound containing a structure shown in the formula (III), R1 is connected with a benzene ring, and R1, R2 and R3 are independently selected from H, alkyl, halogen, silicon, alkenyl, alkynyl, aryl, acyl, sulfonyl, heteroaryl and benzyl. Compared with the prior art, the carbazole axially chiral tetra-substituted allene derivative is obtained by combining the carbazole compound and the propargyl alcohol compound in an addition manner, and the carbazole axially chiral tetra-substituted allene derivative has an allene skeleton and a carbazole active fragment at the same time; the compound can be used as a potential skeleton for developing novel antibacterial and antitumor drugs.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, specifically to an asymmetric synthesis method for carbazole-based axially chiral tetrasubstituted allene derivatives. Background Technology

[0002] Nitrogen-containing aromatic ring derivatives (such as pyrrole, indole, carbazole, and benzoxazine) have become important molecular frameworks in the field of organic synthesis due to their wide applications in medicinal chemistry and materials science. For example, carbazole possesses properties that facilitate electron and charge transfer, as well as a large π-conjugated system. Various functional groups can be easily introduced into the structurally rigid carbazole ring group. These properties make carbazole widely used in medicinal chemistry fields such as antitumor, antibacterial, antioxidant, and anti-inflammatory applications. Given the significant application value of nitrogen-containing aromatic ring derivatives in medicinal chemistry, the development and acquisition of diverse nitrogen-containing aromatic ring derivatives has extremely high research value.

[0003] The synthesis strategies for chiral indole and pyrrole derivatives are relatively mature, but the synthesis methods for chiral carbazole are still in their infancy.

[0004] Existing asymmetric synthetic strategies for carbazole mainly focus on the NH asymmetric functionalization of carbazole (via asymmetric CN cross-coupling or asymmetric N-nucleophilic reaction). Direct asymmetric CH functionalization has only been reported in two cases: asymmetric alkylation at the C3 position and asymmetric arylation at the C1 position of carbazole. Both require the pre-introduction of a specific directing group (such as a hydroxyl or hydrazide group) at the 4-position of carbazole to enhance CH nucleophilicity or convert it to CH electrophilicity. However, the introduction and subsequent removal of the specific directing group increases the number of synthetic steps and reduces efficiency.

[0005] By studying existing asymmetric synthesis techniques for carbazole, the main challenges faced by CH functionalization of carbazole are: (1) the nucleophilicity of carbon atoms in carbazole is weaker than that of nitrogen atoms, which leads to the need for higher activation energy for CH functionalization; (2) the subtle differences in multiple CH bonds in carbazole make it difficult to achieve site and stereoselective control. Summary of the Invention

[0006] This invention provides an asymmetric synthesis method for carbazole-based axially chiral tetrasubstituted allene derivatives, aiming to solve the problems of cumbersome and inefficient CH functionalization steps in existing asymmetric synthesis of carbazole.

[0007] To achieve the above objective, the present invention provides a carbazole-based axially chiral tetrasubstituted allene derivative, wherein the derivative is a compound containing the structure of formula (III), wherein formula (III) is , where R 1 Connected to the benzene ring, R 1 R 2 R 3It is independently selected from: H, alkyl, halogen, silyl, alkenyl, alkynyl, aryl, acyl, sulfonyl, heteroaryl, benzyl.

[0008] Preferably, in the above technical solution, the silicon group is trimethylsilyl or tert-butyldimethylsilyl; the aryl group is monocyclic aryl (monocyclic aryl: phenyl, tolyl, xylyl), polycyclic / fused-ring aryl (polycyclic / fused-ring aryl: naphthyl, anthracene, phenanthrene), or biphenyl; and the acyl group is alkyl acyl or aromatic acyl.

[0009] To achieve the above objectives, the present invention also provides an asymmetric synthesis method for carbazole-based axially chiral tetrasubstituted allene derivatives, the asymmetric synthesis method comprising: In the presence of the small-molecule chiral phosphoric acid catalyst Cat.1, α-(4-aminophenyl)propyne compounds and carbazole compounds were added to a mixed solvent of dichloromethane and toluene in equal proportions, reacted at room temperature, and then purified to obtain the compounds. The structural formula of the small-molecule chiral phosphoric acid catalyst Cat.1 is as follows: The α-(4-aminophenyl)propyne compounds include those of formula (I). The compound, R 2 and R 3 Independently selected from: H, alkyl, halogen, silyl, alkenyl, alkynyl, aryl, acyl, sulfonyl; the carbazole compounds include formula (II). The compound, R 1 Selected from: H, alkyl, halogen, silyl, alkenyl, alkynyl, aryl, acyl, sulfonyl.

[0010] According to the above technical solution, the present invention constructs carbazole-based axially chiral tetrasubstituted allene derivatives based on precise drug structure-activity relationships. The general structural formula of the derivatives simultaneously has an allene skeleton and a carbazole active fragment. The allene skeleton helps the carbazole fragment to "localize" and promotes the formation of a specific rigid stereoconfiguration of the carbazole active fragment. As a drug skeleton, it can significantly improve the binding affinity between the drug and the target and reduce off-target effects.

[0011] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) By selecting specific α-(4-aminophenyl)propynyl alcohol as an electrophilic reagent, carbazole compounds are combined with propynyl alcohol compounds by addition. The preparation method is simple, and for the first time, the asymmetric allenylation of carbazole C3 position without the participation of the directing group was achieved, and a series of carbazole axial chiral tetrasubstituted allene derivatives were obtained with excellent yield and stereoselectivity. (2) The allene skeleton has the characteristics of three-dimensional rigidity, high reactivity and metabolic stability. The carbazole active fragment has strong DNA / RNA and protein interaction ability, diverse pharmacological activities and planar rigid structure. The structure of this type of compound synthesized in this invention has both allene skeleton and carbazole active fragment, which enhances its DNA binding ability and targeting selectivity. It can be used as a potential skeleton for developing new antibacterial and antitumor drugs. (3) The asymmetric synthesis method of the present invention has mild reaction conditions, the catalyst Cat.1 is green and environmentally friendly, the operation is easy, the synthesis steps are few, the product is easy to purify and separate, and it can obtain high yield and high stereoselectivity. At the same time, the reaction is easy to scale up and has a wide range of application prospects. Attached Figure Description

[0012] Figure 1 This is the HPLC chromatogram of the racemic mixture of the target product prepared by the preparation method in Example 1 of this invention; Figure 2 This is the HPLC chromatogram of the chiral compound of the target product obtained by the preparation method in Example 1 of this invention; Figure 3 This is the HPLC chromatogram of the racemic mixture of the target product prepared by the preparation method in Example 2 of this invention; Figure 4 This is the HPLC chromatogram of the chiral compound of the target product obtained by the preparation method in Example 2 of this invention; Figure 5 This is the HPLC chromatogram of the racemic mixture of the target product prepared by the preparation method in Example 3 of this invention; Figure 6 This is the HPLC chromatogram of the chiral compound of the target product obtained by the preparation method in Example 3 of this invention; Figure 7 This is the HPLC chromatogram of the racemic mixture of the target product prepared by the preparation method in Example 4 of this invention; Figure 8 This is the HPLC chromatogram of the chiral compound of the target product obtained by the preparation method in Example 4 of this invention; Figure 9 This is the HPLC chromatogram of the racemic mixture of the target product prepared by the preparation method in Example 5 of this invention; Figure 10 This is the HPLC chromatogram of the chiral compound of the target product obtained by the preparation method in Example 5 of this invention; Figure 11 This is the HPLC chromatogram of the racemic mixture of the target product prepared by the preparation method in Example 6 of this invention; Figure 12 This is the HPLC chromatogram of the chiral compound of the target product obtained by the preparation method in Example 6 of this invention; Figure 13 This is the HPLC chromatogram of the racemic mixture of the target product prepared by the preparation method in Example 7 of this invention; Figure 14 This is the HPLC chromatogram of the chiral compound of the target product obtained by the preparation method in Example 7 of this invention; Figure 15 This is the HPLC chromatogram of the racemic mixture of the target product prepared by the preparation method in Example 8 of this invention; Figure 16 This is the HPLC chromatogram of the chiral compound of the target product obtained by the preparation method in Example 8 of this invention; Figure 17 This is the HPLC chromatogram of the racemic mixture of the target product prepared by the preparation method in Example 9 of this invention; Figure 18 This is the HPLC chromatogram of the chiral compound of the target product obtained by the preparation method in Example 9 of this invention. Detailed Implementation

[0013] The technical solutions in the embodiments of this invention are clearly and completely described. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0014] All equivalents below are calculated based on the corresponding aminobenzophenone compounds relative to 1 equivalent.

[0015] I. An asymmetric synthetic method for carbazole-based axially chiral tetrasubstituted allene derivatives, the method comprising: Catalyzed by the small-molecule chiral phosphoric acid catalyst Cat.1, α-(4-aminophenyl)propargyl alcohol compounds and carbazole compounds were added to a mixed solvent of dichloromethane (DCM) and toluene (Tol) in equal proportions, reacted at room temperature, and then purified to obtain the compounds. The general chemical structure of the α-(4-aminophenyl)propargyl alcohol compounds is shown in Formula (I), wherein, in Formula (I), R... 3 The substituted alkyl acyl group or the substituted sulfonyl group is used; the general chemical structural formula of the carbazole compound is shown in formula (II), where R in formula (II) is... 1 It is a halogen, alkyl, alkenyl, alkynyl or various substituted aryl group; the general chemical formula of the compound is formula (Ⅲ).

[0016] The general formula for the synthesis of the carbazole-based axially chiral tetrasubstituted allene derivatives is as follows:

[0017] II. Preparation of α-(4-aminophenyl)propyne compounds: 2.5 equivalents of the corresponding alkyne were dissolved in 2 mL / mmol tetrahydrofuran, cooled to -78 °C, and 2.5 equivalents of n-butyllithium were slowly added. After stirring at -78 °C for 2 hours, 1.0 equivalent of the corresponding aminobenzophenone compound was added and dissolved in 3 mL / mmol tetrahydrofuran. After stirring at -78 °C for 15 minutes, the mixture was reacted at room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, and the mixture was extracted three times with ethyl acetate. The organic layer was dried on anhydrous sodium sulfate, filtered, and then purified to obtain a series of α-(4-aminophenyl)propyne compounds.

[0018]

[0019] III. Preparation of alkyl-substituted carbazole compounds, including the following steps: One equivalent of 2-bromocarbazole or 3-bromocarbazole was dissolved in tetrahydrofuran. Under argon protection, three equivalents of the corresponding alkyl Grignard reagent and 0.05 equivalents of DPPF palladium dichloride were slowly added, and the mixture was stirred overnight at 80°C. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution, and the mixture was extracted three times with ethyl acetate. The organic layer was dried on anhydrous sodium sulfate, filtered, and then purified to obtain a series of alkyl-substituted carbazole compounds. The chemical formula of the 3-bromocarbazole is shown in formula (IV), and the general formula of the alkyl-substituted carbazole compounds prepared from 3-bromocarbazole is shown in formula (V). In formula (V), R... 4 The 2-bromocarbazole is halogenated, alkyl, alkenyl, alkynyl, or various substituted aryl groups; the chemical formula of the 2-bromocarbazole is shown in formula (VI), and the general formula of alkyl-substituted carbazole compounds prepared from 2-bromocarbazole is shown in formula (VII), wherein R in formula (VII) 4 It can be halogen, alkyl, alkenyl, alkynyl, benzyl or various substituted aryl groups.

[0020] The synthetic reaction system of the alkyl-substituted carbazole compounds is shown below:

[0021] IV. Preparation of aryl-substituted carbazole compounds, including the following steps: One equivalent of 2-bromocarbazole or 3-bromocarbazole was dissolved in toluene. Under argon protection, 1.5 equivalents of the corresponding arylboronic acid, 2.2 equivalents of potassium borate, 0.05 equivalents of 2-bicyclohexylphosphine-2',6'-dimethoxy-1,1'-dibiphenyl, and 0.02 equivalents of tris(dibenzylene-BASEacetone)dipalladium were added, and the mixture was stirred at 80-90°C for 24 hours. After the reaction was completed, the reaction solution was poured into water, and the mixture was extracted three times with ethyl acetate. The organic layer was dried on anhydrous sodium sulfate, filtered, and then purified to obtain a series of aryl-substituted carbazole compounds. The general formula of the corresponding arylboronic acid compound is shown in formula (X), the general formula of the aryl-substituted carbazole compound synthesized from 2-bromocarbazole and formula (X) is shown in formula (XI), and the general formula of the aryl-substituted carbazole compound synthesized from 3-bromocarbazole and formula (X) is shown in formula (XII). 5 It can be halogen, alkyl, alkenyl, alkynyl, benzyl or various substituted aryl groups.

[0022] The synthetic reaction system of the aryl-substituted carbazole compounds is shown below.

[0023] Example 1 An asymmetric synthesis method for carbazole-based axially chiral tetrasubstituted allene derivatives, the method comprising: (1) 4-Trimethylacetamoxybenzophenone was generated by reacting 4-aminobenzophenone with pivaloyl chloride. 2.5 equivalents of 3,3-dimethyl-1-butyne were dissolved in 2 mL / mmol tetrahydrofuran, cooled to -78°C, and 2.5 equivalents of n-butyllithium were slowly added. After stirring at -78°C for 2 hours, 1.0 equivalent of 4-trimethylacetamoxybenzophenone was added and dissolved in 3 mL / mmol tetrahydrofuran. After stirring at -78°C for 15 minutes, the mixture was reacted at room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, and the mixture was extracted three times with ethyl acetate. The organic layer was dried on anhydrous sodium sulfate, filtered, and purified to obtain product 1a. The chemical structural formula of product 1a is: The basis for the equivalent is 1.0 equivalent of 4-trimethylacetamidobenzophenone.

[0024] (2) Take 0.05 mmol of product 1a and 0.06 mmol of 3-bromocarbazole 2a in a reaction flask, add 1.9 mg of chiral phosphoric acid catalyst Cat.1, and then add a dry 1:1 mixture of dichloromethane and toluene to dissolve it. Stir continuously at room temperature, and monitor the reaction by spotting the sample onto a thin-layer chromatography plate until the reactants have completely reacted. After the reaction is complete, separate and purify the product using a silica gel column. Rotary distillate the purified product to obtain the target product 3a (yield 92%, 94% ee). The chemical structural formula of the target product 3a is as follows: .

[0025] The reaction formula for step (1) is as follows:

[0026] The NMR analysis results of the target product 3a are as follows: 1 H NMR (500MHz, CDCl3) δ8.25 (s, 1H), 8.14 (d, J=1.8Hz, 1H), 7.89 (s, 1H), 7.52 (d, J=8.6Hz, 2H), 7.43(dd, J=8.5, 1.9Hz, 1H), 7.39–7.29(m, 9H), 7.27–7.21(m, 2H), 1.33(s, 9H), 1.25(s, 9H).

[0027] 13 C NMR (126MHz, CDCl3) δ203.43, 176.83, 139.01, 138.51, 137.79, 136.77, 133.96, 128.94, 128.86, 128.57, 128.49, 128 .23, 126.95, 125.16, 123.19, 122.13, 120.97, 120.21, 118.94, 112.20, 110.35, 108.75, 39.75, 36.19, 29.97, 27.79.

[0028] The high-performance liquid chromatography analysis results of the target product 3a are as follows: The enantiomeric excess (ee) value was determined by high-performance liquid chromatography (HPLC) under the following conditions: Chiralpak IA column, mobile phase of n-hexane / isopropanol (90 / 10), and flow rate of 1 mL / min. -1 The detection wavelength λ=254nm: the retention time of the main enantiomer is 12.4min, and the retention time of its enantiomer is 16.0min.

[0029] The peak elution pattern of the racemic mixture of target product 3a in HPLC is as follows: Figure 1 As shown in Table 1.

[0030] Table 1. Peak elution of the HPLC chromatogram of the racemic mixture. peak# Retention time / min type Peak width / min Peak area / mAU*s Peak height / mAU Peak area / % 1 12.345 MM R 0.8162 2726.29736 55.66949 50.3186 2 15.483 MM R 0.8497 2691.77832 52.79777 49.6814 The peak elution pattern of the chiral compound of target product 3a in HPLC is as follows: Figure 2 As shown in Table 2.

[0031] Table 2 Peak patterns of HPLC chromatograms of chiral compounds peak# Retention time / min type Peak width / min Peak area / mAU*s Peak height / mAU Peak area / % 1 12.399 MM R 0.7923 1.01067e4 212.60239 96.9976 2 16.008 MM R 0.6355 312.83896 8.20505 3.0024 Example 2

[0032] An asymmetric synthesis method for carbazole-based axially chiral tetrasubstituted allene derivatives, the method comprising: (1) One equivalent of 3-bromocarbazole was dissolved in toluene. Under argon protection, 1.5 equivalents of p-methylphenylboronic acid, 2.2 equivalents of potassium borate, 0.05 equivalents of 2-biscyclohexylphosphine-2',6'-dimethoxy-1,1'-diphenyl and 0.02 equivalents of tris(dibenzylene-BASEacetone)dipalladium were added, and the mixture was stirred at 90°C for 24 hours. After the reaction was completed, the reaction solution was poured into water, and the mixture was extracted three times with ethyl acetate. The organic layer was dried on anhydrous sodium sulfate, filtered, and purified to obtain product 2f. The compound structure of product 2f is as follows: The basis for the equivalent is 1.0 equivalent of 4-trimethylacetamidobenzophenone.

[0033] (2) Take 0.05 mmol of product 1a and 0.06 mmol of product 2f into a reaction flask, add 1.9 mg of chiral phosphoric acid catalyst Cat.1, and then add 2 ml of a dry, equal-ratio mixture of dichloromethane and toluene to dissolve them. Stir continuously at room temperature, and monitor the reaction by spotting the sample onto a thin-layer chromatography plate until the reactants have completely reacted. After the reaction is complete, separate and purify the product using a silica gel column. Rotary distillate the purified product to obtain the target product 3f (yield 80%, 92% ee). The chemical structural formula of the target product 3f is as follows: .

[0034] The reaction formula for step (2) is as follows:

[0035] The NMR analysis results of the target product 3f are as follows: 1 H NMR (500MHz, CDCl3) δ8.24 (s, 1H), 8.12 (s, 1H), 8.00 (s, 1H), 7.61 (dd, J=10.7, 4.5Hz, 3H), 7.51 (d, J=8.5Hz, 2H), 7.42–7.31(m, 10H), 7.27–7.24(m, 3H), 2.41(s, 3H), 1.32(s, 9H), 1.27(s, 9H).

[0036] 13C NMR (126MHz, CDCl3) δ203.43, 176.72, 139.36, 139.26, 139.13, 137.94, 1 36.76, 136.21, 134.05, 133.03, 129.58, 128.98, 128.57, 128.45, 128.27 , 127.98, 127.29, 126.87, 125.46, 123.92, 123.27, 120.93, 120.11, 119. 08, 118.76, 110.92, 110.22, 108.64, 39.74, 36.22, 30.01, 27.79, 21.21.

[0037] The high-performance liquid chromatography analysis results of the target product 3f are as follows: The enantiomeric excess (ee) value was determined by high-performance liquid chromatography (HPLC) under the following conditions: Chiralpak AD column, mobile phase of n-hexane / isopropanol (80 / 20), and flow rate of 1 mL / min. -1 The detection wavelength λ=254nm: the retention time of the main enantiomer was 28.1min, and the retention time of its enantiomer was 10.0min.

[0038] The peak elution of the target product 3f in the racemic HPLC chromatogram is shown in Table 3 and Figure 3 As shown.

[0039] Table 3 Peak elution of the HPLC chromatogram of the racemic mixture peak# Retention time / min type Peak width / min Peak area / mAU*s Peak height / mAU Peak area / % 1 10.101 MM R 0.8947 8196.48242 152.69258 49.9930 2 28.432 MM R 3.1938 8198.78516 42.78503 50.0070 The peak elution pattern of the HPLC chromatogram of the target product 3f chiral compound is as follows: Figure 4 As shown in Table 4.

[0040] Table 4 Peak patterns of HPLC chromatograms of chiral compounds peak# Retention time / min type Peak width / min Peak area / mAU*s Peak height / mAU Peak area / % 1 10.035 MM R 0.8107 894.79352 18.39662 3.9787 2 28.084 MM R 3.1464 2.15950e4 114.39114 96.0213 Example 3

[0041] An asymmetric synthesis method for carbazole-based axially chiral tetrasubstituted allene derivatives, the method comprising: (1) One equivalent of 3-bromocarbazole was dissolved in toluene. Under argon protection, 1.5 equivalents of 1-naphthoic acid, 2.2 equivalents of potassium borate, 0.05 equivalents of 2-biscyclohexylphosphine-2',6'-dimethoxy-1,1'-diphenyl and 0.02 equivalents of tris(dibenzylene-BASEacetone)dipalladium were added, and the mixture was stirred at 90°C for 24 hours. After the reaction was completed, the reaction solution was poured into water, and the mixture was extracted three times with ethyl acetate. The organic layer was dried on anhydrous sodium sulfate, filtered, and purified to obtain product 2i. The compound structure of product 2i is as follows: The basis for the equivalent is 1.0 equivalent of 4-trimethylacetamidobenzophenone.

[0042] (2) Take 0.05 mmol of product 1a and 0.06 mmol of product 2i into a reaction flask, add 1.9 mg of chiral phosphoric acid catalyst Cat.1, and then add 1 ml of a dry 1:1 mixture of dichloromethane and toluene to dissolve them. Stir continuously at room temperature and monitor the reaction by spotting the sample onto a thin-layer chromatography plate until the reactants have completely reacted. After the reaction is complete, separate and purify the product using a silica gel column. Rotary distillate the purified product to obtain the target product 3i (yield 90%, 94% ee). The chemical structure of the target product 3i is as follows: .

[0043] The reaction formula for step (2) is as follows:

[0044] The NMR analysis results of the target product 3i are as follows: 1 H NMR (400MHz, CDCl3) δ8.25 (s, 1H), 8.19 (s, 1H), 8.00 (t, J=3.9Hz, 2H), 7.95 (d, J=8.0Hz, 1H), 7.89 (dd, J=7.3, 1.9Hz, 1H), 7.59–7.48 (m, 7H), 7.46–7.29 (m, 10H), 7.27–7.22 (m, 1H), 1.33 (s, 9H), 1.28 (s, 9H).

[0045] 13 C NMR (101MHz, CDCl3) δ203.47, 176.71, 141.19, 139.24, 139.11, 137.87, 136.73, 134 .00, 133.98, 132.38, 132.17, 128.95, 128.64, 128.44, 128.33, 128.25, 128.22, 128 .02, 127.53, 127.32, 126.86, 126.58, 126.03, 125.77, 125.55, 123.49, 123.11, 121.85, 120.96, 120.13, 119.08, 110.40, 110.26, 108.65, 39.72, 36.21, 30.00, 27.77.

[0046] The high-performance liquid chromatography analysis results of the target product 3i are as follows: The enantiomeric excess (ee) value was determined by high-performance liquid chromatography (HPLC) under the following conditions: Chiralpak AD column, mobile phase of n-hexane / isopropanol (90 / 10), and flow rate of 1 mL / min. -1 The detection wavelength λ=254nm: the retention time of the main enantiomer was 15.7min, and the retention time of its enantiomer was 18.3min.

[0047] The peak elution pattern of the racemic mixture of target product 3i is as follows: Figure 5 As shown in Table 5.

[0048] Table 5. Peak elution of the HPLC chromatograms of the racemic mixture. peak# Retention time / min type Peak width / min Peak area / mAU*s Peak height / mAU Peak area / % 1 15.714 MM R 1.0022 8046.00586 133.80852 50.1954 2 18.231 MM R 1.1546 7983.36865 115.24272 49.8046 The peak elution pattern of the chiral compound of target product 3i in HPLC is as follows: Figure 6 As shown in Table 6.

[0049] Table 6 Peak patterns of HPLC chromatograms of chiral compounds peak# Retention time / min type Peak width / min Peak area / mAU*s Peak height / mAU Peak area / % 1 15.727 BB 0.9155 9071.80371 149.17780 97.3699 2 18.298 BBA 0.6428 245.03918 4.51755 2.6301 Example 4

[0050] An asymmetric synthesis method for carbazole-based axially chiral tetrasubstituted allene derivatives, the method comprising: (1) One equivalent of 3-bromocarbazole was dissolved in tetrahydrofuran. Under argon protection, three equivalents of propane and 0.05 equivalents of DPPF palladium dichloride were slowly added, and the mixture was stirred overnight at 80°C. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, and the mixture was extracted three times with ethyl acetate. The organic layer was dried on anhydrous sodium sulfate, filtered, and purified to obtain product 2l. The compound structure of product 2l is as follows: The basis for the equivalent is 1.0 equivalent of 4-trimethylacetamidobenzophenone.

[0051] (2) Take 0.05 mmol of product 1a and 0.06 mmol of product 2l in a reaction flask, add 1.9 mg of chiral phosphoric acid catalyst Cat.1, and then add 1 ml of a dry, equal-ratio mixture of dichloromethane and toluene to dissolve them. Stir continuously at room temperature, and monitor the reaction by spotting the sample onto a thin-layer chromatography plate until the reactants have completely reacted. After the reaction is complete, separate and purify the product using a silica gel column. Rotary distillation of the purified product yields the target product 3l (yield 89%, 94% ee). The compound structure of the target product 3l is as follows: .

[0052] The reaction formula for step (2) is as follows:

[0053] The NMR analysis results of the target product 3l are as follows: 1 H NMR (500MHz, CDCl3) δ7.98 (s, 1H), 7.95 (s, 1H), 7.87 (s, 1H), 7.54–7.50 (m, 2H), 7.42–7.30 (m, 10H), 7.27–7.25 (m, 1H) ), 7.23 (dd, J=8.2, 1.6Hz, 1H), 2.80–2.72 (m, 2H), 1.78–1.70 (m, 2H), 1.34 (s, 9H), 1.28 (s, 9H), 0.99 (t, J=7.3Hz, 3H).

[0054] 13 C NMR (126MHz, CDCl3) δ203.46, 176.68, 138.98, 138.36, 138.01, 136.75, 134.09, 133.98, 129.00, 128.43, 128.28, 128.25, 127.64, 1 26.84, 123.50, 123.11, 120.83, 120.04, 119.90, 119.15, 110.37, 110.01, 108.56, 39.75, 38.30, 36.23, 30.03, 27.80, 25.54, 14.05.

[0055] The high-performance liquid chromatography analysis of the target product 3l is as follows: Enantiomeric excess (ee) was determined by high-performance liquid chromatography (HPLC) under the following conditions: Chiralpak AD column, mobile phase of n-hexane / isopropanol (85 / 15), and flow rate of 1 mL / min. -1 The detection wavelength λ=254nm: the retention time of the main enantiomer is 8.1min, and the retention time of its enantiomer is 13.4min.

[0056] The peak elution of the target product 3l in the racemic HPLC chromatogram is shown in Table 7 and... Figure 7 As shown.

[0057] Table 7 Peak elution of the HPLC chromatogram of the racemic mixture peak# Retention time / min type Peak width / min Peak area / mAU*s Peak height / mAU Peak area / % 1 8.081 BB 0.3824 8527.17480 322.61490 50.6091 2 13.229 MM R 0.7651 8321.91992 181.27296 49.3909 The peak elution pattern of the chiral compound of target product 3l in HPLC is as follows: Figure 8 As shown in Table 8.

[0058] Table 8 Peak patterns of HPLC chromatograms of chiral compounds peak# Retention time / min type Peak width / min Peak area / mAU*s Peak height / mAU Peak area / % 1 8.069 MM R 0.4159 1.85389e4 742.87463 97.2351 2 13.350 MM R 0.6677 527.16162 13.15801 2.7649 Example 5

[0059] An asymmetric synthesis method for carbazole-based axially chiral tetrasubstituted allene derivatives, the method comprising: (1) One equivalent of 3-bromocarbazole was dissolved in triethylamine. Under argon protection, 1.2 equivalents of phenylacetylene, 0.03 equivalents of cuprous iodide, 0.05 equivalents of 2-biscyclohexylphosphine-2',6'-dimethoxy-1,1'-diphenylene and 0.02 equivalents of tris(dibenzylene-BASEacetone)dipalladium were added, and the mixture was stirred at 80°C for 24 hours. After the reaction was completed, the reaction solution was poured into water, and the mixture was extracted three times with ethyl acetate. The organic layer was dried on anhydrous sodium sulfate, filtered, and purified to obtain product 2n. The compound structure of product 2n is as follows: The basis for the equivalent is 1.0 equivalent of 4-trimethylacetamidobenzophenone.

[0060] (2) Take 0.05 mmol of product 1a and 0.06 mmol of product 2n in a reaction flask, add 1.9 mg of chiral phosphoric acid catalyst Cat.1, and then add 1 ml of a dry, equal-ratio mixture of dichloromethane and toluene to dissolve them. Stir continuously at room temperature, and monitor the reaction by spotting the sample onto a thin-layer chromatography plate until the reactants have completely reacted. After the reaction is complete, separate and purify the product using a silica gel column. Rotary distillate the purified product to obtain the target product 3n (yield 86%, 95% ee). The compound structure of the target product 3n is as follows: .

[0061]

[0062] The NMR analysis results of the target product 3n are as follows: 1 H NMR (500MHz, CDCl3) δ 8.30 (s, 1H), 8.30 (s, 1H), 7.99 (s, 1H), 7.61–7.53 (m, 5H), 7.43–7.33 (m, 13H), 7.29–7.25 (m, 1H), 1.34 (s, 9H), 1.28 (s, 9H).

[0063] 13C NMR (126MHz, CDCl3) δ203.45, 176.79, 139.61, 138.98, 137.83, 136.77, 13 3.98, 131.60, 129.58, 128.97, 128.95, 128.48, 128.46, 128.28, 128.24, 12 7.91, 126.93, 124.19, 124.02, 123.45, 122.68, 121.02, 120.18, 118.99, 1 13.97, 110.85, 110.33, 108.75, 90.93, 87.71, 39.74, 36.21, 29.98, 27.79.

[0064] The high-performance liquid chromatography analysis results of the target product 3n are as follows: Enantiomeric excess (ee) was determined by high-performance liquid chromatography (HPLC) under the following conditions: Chiralpak AD column, mobile phase of n-hexane / isopropanol (85 / 15), and flow rate of 1 mL / min. -1 The detection wavelength λ=254nm: the retention time of the main enantiomer is 15.6min, and the retention time of its enantiomer is 8.1min.

[0065] The peak elution patterns of the target product 3n in the racemic HPLC chromatogram are shown in Table 9 and... Figure 9 As shown.

[0066] Table 9 Peak elution of the HPLC chromatogram of the racemic mixture peak# Retention time / min type Peak width / min Peak area / mAU*s Peak height / mAU Peak area / % 1 8.036 MM R 0.5655 6125.90674 180.54611 50.1726 2 15.568 MM R 1.3001 6083.75635 77.99060 49.8274 The peak elution pattern of the HPLC chromatogram of the target product 3n chiral compound is as follows: Figure 10 As shown in Table 10.

[0067] Table 10 Peak patterns of HPLC chromatograms of chiral compounds peak# Retention time / min type Peak width / min Peak area / mAU*s Peak height / mAU Peak area / % 1 8.096 MM R 0.4449 171.90125 6.43991 2.4545 2 15.570 MM R 1.3666 6831.61133 83.31934 97.5455 Example 6

[0068] An asymmetric synthesis method for carbazole-based axially chiral tetrasubstituted allene derivatives, the method comprising: (1) 11H-benzo(C)carbazole (CAS No. 239-01-0) is product 2p, and the compound structural formula of product 2p is as follows: .

[0069] (2) Take 0.05 mmol of product 1a and 0.06 mmol of product 2p in a reaction flask, add 1.9 mg of chiral phosphoric acid catalyst Cat.1, and then add 1 ml of a dry, equal-ratio mixture of dichloromethane and toluene to dissolve them. Stir continuously at room temperature, and monitor the reaction by spotting the sample onto a thin-layer chromatography plate until the reactants have completely reacted. After the reaction is complete, separate and purify the product using a silica gel column. Rotary distillation of the purified product yields the target product 3p (yield 56%, 92% ee). The chemical structural formula of the target product 3p is as follows: .

[0070] The reaction formula for step (2) is as follows:

[0071] The NMR analysis results of the target product 3p are as follows: 1 H NMR (500MHz, CDCl3) δ8.65 (d, J=8.3Hz, 1H), 8.51 (s, 1H), 8.46 (s, 1H), 7.98 (d, J=8.0Hz, 1H), 7.83 (d, J=8.7Hz, 1H), 7.71 (t, J= 7.6Hz, 1H), 7.58(d, J=8.7Hz, 1H), 7.54(d, J=8.6Hz, 2H), 7.49–7.35(m, 10H), 7.28(t, J=7.3Hz, 1H), 1.35(s, 9H), 1.34(s, 9H).

[0072] 13 C NMR (126MHz, CDCl3) δ203.92, 176.73, 138.02, 137.63, 137.56, 136.80, 134.07, 130.03, 129.41, 129.35, 129.32, 129.00, 128.49, 128.33, 127 .55, 127.06, 126.91, 126.08, 123.88, 123.25, 123.06, 122.86, 120.11 , 119.53, 115.46, 112.76, 110.54, 108.66, 39.76, 36.22, 30.21, 27.80.

[0073] The high-performance liquid chromatography analysis results of the target product 3p are as follows: Enantiomeric excess (ee) was determined by high-performance liquid chromatography (HPLC) under the following conditions: Chiralpak AD column, mobile phase of n-hexane / isopropanol (85 / 15), and flow rate of 1 mL / min. -1The detection wavelength λ=254nm: the retention time of the main enantiomer was 10.4min, and the retention time of its enantiomer was 9.3min.

[0074] The peak elution of the target product 3p in the racemic HPLC chromatogram is shown in Table 11 and... Figure 11 As shown.

[0075] Table 11 Peak patterns of the HPLC chromatograms of the racemic mixture peak# Retention time / min type Peak width / min Peak area / mAU*s Peak height / mAU Peak area / % 1 9.182 MM R 0.4817 6853.86377 237.15517 49.8190 2 10.396 MM R 0.5274 6903.67139 218.15767 50.1810 The peak elution pattern of the HPLC chromatogram of the target product, a 3p chiral compound, is as follows: Figure 12 As shown in Table 12.

[0076] Table 12 Peak patterns of HPLC chromatograms of chiral compounds peak# Retention time / min type Peak width / min Peak area / mAU*s Peak height / mAU Peak area / % 1 9.262 MM R 0.3931 511.28040 22.14271 3.7794 2 10.379 MF R 0.5511 1.32970e4 402.15225 96.2206 Example 7

[0077] An asymmetric synthesis method for carbazole-based axially chiral tetrasubstituted allene derivatives, the method comprising: (1) 2.5 equivalents of trimethylsilylacetylene were dissolved in 2 mL / mmol tetrahydrofuran, cooled to -78°C, and 2.5 equivalents of n-butyllithium were slowly added. After stirring at -78°C for 2 hours, 1.0 equivalent of 4-pentaventamidobenzophenone (also known as 4-trimethylacetamidobenzophenone) was dissolved in 3 mL / mmol tetrahydrofuran. After stirring at -78°C for 15 minutes, the mixture was allowed to react at room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, and the mixture was extracted three times with ethyl acetate. The organic layer was dried on anhydrous sodium sulfate, filtered, and purified to obtain product 1b. The chemical structural formula of product 1b is as follows: The equivalent is based on 1.0 equivalent of 4-pentafenamidobenzophenone.

[0078] (2) Take 0.05 mmol of product 1b and 0.06 mmol of 3-bromocarbazole 2a in a reaction flask, add 1.9 mg of chiral phosphoric acid catalyst Cat.1, and then add 1 ml of a dry, equal-ratio mixture of dichloromethane and toluene to dissolve it. Stir continuously at room temperature, and monitor the reaction by spotting the sample onto a thin-layer chromatography plate until the reactants have completely reacted. After the reaction is complete, separate and purify the product using a silica gel column. Rotary distillate the purified product to obtain the target product 3r (yield 93%, 90% ee). The chemical structural formula of the target product 3r is as follows: .

[0079] The reaction formula for step (2) is as follows:

[0080] The NMR analysis results of the target product 3r are as follows: 1 H NMR (500MHz, CDCl3) δ8.37 (s, 1H), 8.12 (s, 1H), 7.97 (s, 1H), 7.52 (d, J=7.3Hz, 2H), 7.48 (d, J= 8.4Hz, 1H), 7.44–7.35(m, 6H), 7.35–7.27(m, 3H), 7.26–7.19(m, 2H), 1.31(s, 9H), 0.34(s, 9H).

[0081] 13 C NMR (126MHz, CDCl3) δ209.37, 176.90, 138.99, 138.57, 137.04, 136.70, 133.22, 128.71, 128.64, 128.59, 128.10, 128.00 , 127.06, 126.91, 125.06, 123.03, 122.75, 120.46, 119.29, 112.31, 112.19, 111.28, 106.21, 104.10, 39.72, 27.77, 0.22.

[0082] The high-performance liquid chromatography analysis of the target product 3r is as follows: The enantiomeric excess (ee) value was determined by high-performance liquid chromatography (HPLC) under the following conditions: Chiralpak IA column, mobile phase of n-hexane / isopropanol (90 / 10), and flow rate of 1 mL / min. -1 The detection wavelength λ=254nm: the retention time of the main enantiomer was 11.2min, and the retention time of its enantiomer was 17.4min.

[0083] The peak elution patterns of the target product 3r in the racemic HPLC chromatogram are shown in Table 13 and... Figure 13 As shown.

[0084] Table 13 Peak elution of the HPLC chromatogram of the racemic mixture peak# Retention time / min type Peak width / min Peak area / mAU*s Peak height / mAU Peak area / % 1 11.378 MM R 0.6378 1.49779e4 391.41553 49.8456 2 17.409 MM R 1.0638 1.50706e4 236.11235 50.1544 The peak elution pattern of the chiral compound of the target product 3r is as follows: Figure 14 As shown in Table 14.

[0085] Table 14 Peak patterns of HPLC chromatograms of chiral compounds peak# Retention time / min type Peak width / min Peak area / mAU*s Peak height / mAU Peak area / % 1 11.175 MM R 0.6555 1.59427e4 405.33401 95.3087 2 17.392 MM R 0.6182 784.73370 21.15584 4.6913 Example 8

[0086] An asymmetric synthesis method for carbazole-based axially chiral tetrasubstituted allene derivatives, the method comprising: (1) 2.5 equivalents of 3,3-dimethyl-1-butyne were dissolved in 2 mL / mmol tetrahydrofuran, cooled to -78°C, and 2.5 equivalents of n-butyllithium were slowly added. After stirring at -78°C for 2 hours, 1.0 equivalent of N-(4-benzoylphenyl)benzamide (CAS No.: 19617-84-6) was dissolved in 3 mL / mmol tetrahydrofuran. After stirring at -78°C for 15 minutes, the mixture was reacted at room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, and the mixture was extracted three times with ethyl acetate. The organic layer was dried on anhydrous sodium sulfate, filtered, and purified to obtain product 1c. The chemical structural formula of 1c is as follows: The equivalent is based on 1.0 equivalent of N-(4-benzoylphenyl)benzamide.

[0087] (2) Take 0.05 mmol of product 1c and 0.06 mmol of product 2n in a reaction flask, add 1.9 mg of chiral phosphoric acid catalyst Cat.1, and then add 1 ml of a dry, equal-ratio mixture of dichloromethane and toluene to dissolve them. Stir continuously at room temperature, and monitor the reaction by spotting the sample onto a thin-layer chromatography plate until the reactants have completely reacted. After the reaction is complete, separate and purify the product using a silica gel column. Rotary distillate the purified product to obtain the target product 3s (yield 80%, 96% ee). The chemical structure of the target product 3s is as follows: .

[0088] The reaction formula for step (2) is as follows:

[0089] The NMR analysis results of the target product 3s are as follows: 1 H NMR (500MHz, CDCl3) δ8.30 (s, 1H), 8.25 (s, 1H), 8.00 (s, 1H), 7.93 (s, 1H), 7.88 (d, J=7.4Hz, 2H), 7.65 (d, J=8.5Hz, 2H), 7.59–7.52 (m, 4H), 7.48 (t, J=7.6Hz, 2H), 7.43 (d, J=7.5Hz, 4H), 7.40–7.31 (m, 8H), 7.28 (t, J=7.3Hz, 1H), 1.30 (s, 9H).

[0090] 13C NMR (126MHz, CDCl3) δ203.51, 165.97, 139.59, 138.98, 137.79, 136.67, 135 .10, 134.32, 131.99, 131.59, 129.59, 129.00, 128.94, 128.51, 128.45, 128 .31, 127.91, 127.15, 126.98, 124.20, 124.00, 123.46, 122.70, 121.02, 120.39, 119.08, 114.00, 110.84, 110.35, 108.77, 90.91, 87.74, 36.23, 30.01.

[0091] The high-performance liquid chromatography analysis results of the target product 3s are as follows: Enantiomeric excess (ee) was determined by high-performance liquid chromatography (HPLC) under the following conditions: Chiralpak IG column, mobile phase of hexane / isopropanol (80 / 20), and flow rate of 1 mL / min. -1 The detection wavelength λ=254nm: the retention time of the main enantiomer was 15.9min, and the retention time of its enantiomer was 11.6min.

[0092] The peak elution of the target product 3s in the racemic HPLC chromatogram is shown in Table 15 and... Figure 15 As shown.

[0093] Table 15 Peak elution of the HPLC chromatogram of the racemic mixture peak# Retention time / min type Peak width / min Peak area / mAU*s Peak height / mAU Peak area / % 1 11.674 BB 1.2583 446.56543 50.94206 50.8206 2 16.359 MM R 6.3079 4302.96533 11.36920 49.1794 The peak elution pattern of the HPLC chromatogram of the target product, a chiral compound of 3s, is as follows: Figure 16 As shown in Table 16.

[0094] Table 16 Peak patterns of HPLC chromatograms of chiral compounds peak# Retention time / min type Peak width / min Peak area / mAU*s Peak height / mAU Peak area / % 1 11.607 MM R 1.2758 308.58264 4.03111 1.9134 2 15.863 MM R 6.6298 1.58191e4 39.76742 98.0866 Example 9

[0095] An asymmetric synthesis method for carbazole-based axially chiral tetrasubstituted allene derivatives, the method comprising: (1) 2.5 equivalents of 3,3-dimethyl-1-butyne were dissolved in 2 mL / mmol tetrahydrofuran, cooled to -78°C, and 2.5 equivalents of n-butyllithium were slowly added. After stirring at -78°C for 2 hours, 1.0 equivalent of 4-p-toluenesulfonamide benzophenone was added and dissolved in 3 mL / mmol tetrahydrofuran. After stirring at -78°C for 15 minutes, the mixture was reacted at room temperature for 24 hours. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, and the mixture was extracted three times with ethyl acetate. The organic layer was dried on anhydrous sodium sulfate, filtered, and purified to obtain product 1f. The chemical structural formula of product 1f is as follows: The structural formula of the 4-p-toluenesulfonamide benzophenone is as follows: The equivalent is based on 1.0 equivalent of 4-p-toluenesulfonamide benzophenone.

[0096] (2) Take 0.05 mmol of product 1f and 0.06 mmol of product 2n into a reaction flask, add 1.9 mg of chiral phosphoric acid catalyst Cat.1, and then add 1 ml of a dry, equal-ratio mixture of dichloromethane and toluene to dissolve them. Stir continuously at room temperature, and monitor the reaction by spotting the sample onto a thin-layer chromatography plate until the reactants have completely reacted. After the reaction is complete, separate and purify the product using a silica gel column. Rotary distillate the purified product to obtain the target product 3v (yield 65%, 70% ee). The chemical structural formula of the target product 3v is as follows: .

[0097] The reaction formula is as follows:

[0098] The NMR analysis results of the target product 3V are as follows: 1 H NMR (500MHz, CDCl3) δ8.31 (s, 1H), 8.19 (s, 1H), 7.98 (s, 1H), 7.72 (d, J=8.3Hz, 2H), 7.64–7.56 (m, 3H), 7.42–7.33 (m, 10H), 7.31–7.28 (m, 3H), 7.24 (d, J=8.2Hz, 2H), 7.07 (d, J=8.5Hz, 2H), 6.88 (s, 1H), 2.36 (s, 3H), 1.29 (s, 9H).

[0099] 13C NMR (126MHz, CDCl3) δ203.32, 143.94, 139.44, 138.84, 137.45, 136.19, 135.05 ,134.96,131.47,129.69,129.56,128.94,128.74,128.40,128.37,128.21,12 8.11, 127.86, 127.28, 126.94, 124.05, 123.83, 123.33, 122.61, 121.60, 120.89, 119.07, 114.02, 110.75, 110.22, 108.40, 90.69, 87.72, 36.11, 29.86, 21.53.

[0100] The high-performance liquid chromatography analysis results of the target product 3v are as follows: The enantiomeric excess (ee) value was determined by high-performance liquid chromatography (HPLC) under the following conditions: Chiralpak AD column, mobile phase of n-hexane / isopropanol (80 / 20), and flow rate of 1 mL / min. -1 The detection wavelength λ=254nm: the retention time of the main enantiomer was 17.4min, and the retention time of its enantiomer was 14.2min.

[0101] The peak elution of the target product 3v in the racemic HPLC chromatogram is shown in Table 17 and... Figure 17 As shown.

[0102] Table 17 Peak elution of the HPLC chromatogram of the racemic mixture peak# Retention time / min type Peak width / min Peak area / mAU*s Peak height / mAU Peak area / % 1 14.144 MM R 1.2607 3893.13623 51.46910 49.9664 2 17.340 BB 1.2626 3898.37598 45.45398 50.0336 The peak elution pattern of the HPLC chromatogram of the target product 3v chiral compound is as follows: Figure 18 As shown in Table 18.

[0103] Table 18 Peak patterns of HPLC chromatograms of chiral compounds peak# Retention time / min type Peak width / min Peak area / mAU*s Peak height / mAU Peak area / % 1 14.206 MM R 1.1596 1184.48694 17.02378 15.4339 2 17.393 MM R 1.7580 6490.08691 61.53027 84.5661 This invention can be implemented in various ways and is not limited to the embodiments described. Those skilled in the art will understand that the invention can be implemented in other specific ways without changing the technical concept or essential features. Therefore, it should be understood that the embodiments described above are exemplary and not intended to limit the invention.

Claims

1. A carbazole-based axially chiral tetrasubstituted allene derivative, characterized in that, The derivative is a compound containing the structure of formula (III), wherein formula (III) is , where R 1 Connected to the benzene ring, R 1 R 2 R 3 It is independently selected from: H, alkyl, halogen, silyl, alkenyl, alkynyl, aryl, acyl, sulfonyl, heteroaryl, benzyl.

2. The carbazole-based axially chiral tetrasubstituted allene derivative as described in claim 1, characterized in that, R 2 It is alkyl or trimethylsilyl, R 3 R is a substituted alkyl acyl group or a substituted sulfonyl group. 1 It can be halogen, alkyl, alkenyl, alkynyl or various substituted aryl groups.

3. The carbazole-based axially chiral tetrasubstituted allene derivative as described in claim 2, characterized in that, The derivatives include , , , , , , , , .

4. An asymmetric synthetic method for carbazole-based axially chiral tetrasubstituted allene derivatives, characterized in that, The asymmetric synthesis method includes: In the presence of the small-molecule chiral phosphoric acid catalyst Cat.1, α-(4-aminophenyl)propyne compounds and carbazole compounds were added to a mixed solvent of dichloromethane and toluene in equal proportions, reacted at room temperature, and then purified to obtain the compounds. The structural formula of the small-molecule chiral phosphoric acid catalyst Cat.1 is as follows: The α-(4-aminophenyl)propyne compounds include those of formula (I). The compound, R 2 and R 3 Independently selected from: H, alkyl, halogen, silyl, alkenyl, alkynyl, aryl, acyl, sulfonyl; the carbazole compounds include formula (II). The compound, R 1 Selected from: H, alkyl, halogen, silyl, alkenyl, alkynyl, aryl, acyl, sulfonyl.

5. The asymmetric synthesis method of carbazole-based axially chiral tetrasubstituted allene derivatives as described in claim 4, characterized in that, The preparation method of the α-(4-aminophenyl)propyne compounds is as follows: the corresponding alkyne is dissolved in tetrahydrofuran, cooled to -78°C, n-butyllithium is slowly added, and stirred at -78°C for 2 hours. Then, the corresponding p-aminobenzophenone compound is added and dissolved in tetrahydrofuran, stirred at -78°C for 15 minutes, and reacted at room temperature for 24 hours. After the reaction is completed, the reaction is quenched with saturated ammonium chloride solution, the mixture is extracted with ethyl acetate, the organic layer is dried, filtered, and purified to obtain the α-(4-aminophenyl)propyne compounds.

6. The asymmetric synthesis method of carbazole-based axially chiral tetrasubstituted allene derivatives as described in claim 5, characterized in that, α-(4-aminophenyl)propyne compounds are or or or .

7. The asymmetric synthesis method of carbazole-based axially chiral tetrasubstituted allene derivatives as described in claim 4, characterized in that, The preparation method of the carbazole compounds is as follows: 2-bromocarbazole or 3-bromocarbazole is dissolved in tetrahydrofuran. Under argon protection, the corresponding alkyl Grignard reagent and DPPF palladium dichloride are slowly added. The mixture is stirred overnight at 80°C. After the reaction is complete, the reaction is quenched with saturated ammonium chloride solution, extracted with ethyl acetate, the organic layer is dried, filtered, and purified to obtain alkyl-substituted carbazole compounds. The alkyl-substituted carbazole compounds are compounds containing formula (V) or formula (VII), where formula (V) is... Equation (VII) is , where R 4 It can be halogen, alkyl, alkenyl, alkynyl, benzyl or various substituted aryl groups.

8. The asymmetric synthesis method of carbazole-based axially chiral tetrasubstituted allene derivatives as described in claim 7, characterized in that, The alkyl-substituted carbazole compound is or .

9. The asymmetric synthesis method of carbazole-based axially chiral tetrasubstituted allene derivatives as described in claim 4, characterized in that, The preparation method of the carbazole compounds is as follows: 1 equivalent of 2-bromocarbazole or 3-bromocarbazole is dissolved in toluene. Under argon protection, a compound containing formula (X), potassium borate, 2-dicyclohexylphosphine-2',6'-dimethoxy-1,1'-dibiphenyl, and tris(dibenzylene-BASEacetone)dipalladium are added. The mixture is stirred at 80-90°C for 24 hours. After the reaction is complete, the reaction solution is poured into water, extracted with ethyl acetate, the organic layer is dried, filtered, and purified to obtain aryl-substituted carbazole compounds. The aryl-substituted carbazole compounds include compounds containing formula (XI) or formula (XII), where formula (XI) is... Equation (XII) is The aforementioned formula (X) is R in equation (XI) or equation (XII) or equation (X) 5 It can be halogen, alkyl, alkenyl, alkynyl, benzyl or various substituted aryl groups.

10. The asymmetric synthesis method of carbazole-based axially chiral tetrasubstituted allene derivatives as described in claim 1, characterized in that, The aryl-substituted carbazole compounds are or or .

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