Process for the asymmetric synthesis of 1,1-disubstituted-tetrahydro-beta-carboline derivatives

Abstract

The application discloses an asymmetric synthesis method of 1,1-disubstituted-tetrahydro-beta-carboline derivatives and belongs to the technical field of organic synthesis. The method comprises the following steps: in a reactor, under an inert atmosphere, 1,1-diol-tetrahydro-beta-carboline compounds are reacted with benzoyl chloride under catalysis of a chiral ligand and copper chloride, and after reaction, subsequent separation and purification are carried out, so that 1,1-disubstituted-tetrahydro-beta-carboline derivatives are obtained. The method is simple in steps, safe in operation, and uses non-toxic and easily obtained raw materials, so that the whole process is simple and easy to implement, pollution is small, and the concept of green chemistry is met.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to an asymmetric synthesis method for a 1,1-disubstituted-tetrahydro-β-carbaline derivative. Background Technology

[0002] The 1,1-disubstituted-tetrahydro-β-carboline skeleton, with a chiral C1 position containing a nitrogen-containing quaternary carbon, is widely found in various biologically and pharmaceutically active natural products and is frequently used as a starting material for the synthesis of indole alkaloids (Y.Li, C.Wang, Z.Ma, K.Zhang, XTXu, Org.Lett.2020, 22, 8589-8592). Starting from these compounds, a variety of indole alkaloids with diverse biological activities can be synthesized, such as alstratine A, arbornamine, taberinggine, roemeridine, peharmaline A, peganumine A, and voacafricine. More importantly, because chiral enantiomers can exhibit drastically different pharmacological, pharmacokinetic, metabolic, and toxicological activities in vivo, the synthesis of optically pure 1,1-disubstituted-tetrahydro-β-carboline compounds is of great significance. There are few previous reports on tryptophan derivatives. Only in 2018 did Snyder's group (P. Gan; J. Pitzen; P. Qu; S. Snyder, J. Am. Chem. Soc. 2018, 140, 919-925) report the synthesis of 2-(2',2'-diol)tryptophan derivatives from benzoyl chloride catalyzed by chiral oxazoline ligands and copper chloride. However, the product synthesized by this method requires a further conversion step to obtain 1,1-disubstituted-tetrahydro-β-carboline derivatives, which greatly affects the efficiency of total synthesis of natural products.

[0003] Given the diversity of natural products and drug molecules, developing a novel asymmetric synthetic method for 1,1-disubstituted tetrahydro-β-carboline derivatives remains an important research direction. Summary of the Invention

[0004] To address the shortcomings and defects of existing technologies, the present invention aims to provide a method for the desymmetric synthesis of aza-quaternary carbon chiral centers, and more specifically, to provide an asymmetric synthesis method for 1,1-disubstituted-tetrahydro-β-carboline derivatives.

[0005] The objective of this invention is specifically achieved through the following technical solution:

[0006] An asymmetric synthetic method for a 1,1-disubstituted tetrahydro-β-carboline derivative includes the following steps:

[0007] (1) In the reactor, the chiral ligand and copper chloride were dried at room temperature to remove the water in the reaction system and then dissolved in an organic solvent; under an inert atmosphere, an organic solvent containing compound 1 was added, and after cooling, benzoyl chloride and triethylamine were added in sequence to carry out the reaction.

[0008] (2) After the reaction is completed, the reaction solution is separated and purified to obtain 1,1-disubstituted-tetrahydro-β-carboline derivative.

[0009] The structural formula of compound 1 is:

[0010] Among them, R 1 It is one of the following: methoxy, methyl, fluorine, bromine, or hydrogen atom; R 2 It is one of benzyl, 4-bromobenzyl, and 4-methoxybenzyl.

[0011] Further, the organic solvent mentioned in step (1) is one of methanol, ethanol, n-propanol, isopropanol, tert-butanol, acetonitrile, ethyl acetate, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, acetone, toluene, N,N-dimethylformamide, dimethyl sulfoxide, 2-methyltetrahydrofuran, diethyl ether, tert-butyl dimethyl ether, and 1,4-dioxane.

[0012] Further, the inert atmosphere described in step (1) is a nitrogen atmosphere.

[0013] Furthermore, the general structural formula of the chiral ligand described in step (1) is as follows:

[0014]

[0015] Among them, R 3 It is one of benzyl, phenyl, isopropyl, sec-butyl, tert-butyl, n-butyl, benzocyclopentyl, 2-(methylene)naphthyl, and 1-(methylene)naphthyl, R 4 It is one of methyl, ethyl, n-butyl, tert-butyl, phenyl, or hydrogen atom, R 5 It is methyl, or one of cyclopropyl (n=0), cyclopentyl (n=2), cyclohexyl (n=3), or cycloheptyl (n=4).

[0016] Furthermore, the cooling in step (1) is reduced to -78°C, and the reaction time at this temperature is 12 to 120 hours.

[0017] Further, the molar ratio of compound 1 to the chiral ligand in step (1) is 1:0.1 to 1:1.

[0018] Further, the molar ratio of compound 1 to copper chloride in step (1) is 1:0.1 to 1:1.

[0019] Further, the molar ratio of compound 1 to benzoyl chloride in step (1) is 1:1.1 to 1:10.

[0020] Further, the molar ratio of compound 1 to triethylamine in step (1) is 1:1.1 to 1:10.

[0021] Further, the specific steps of separation and purification in step (2) are as follows: quenching reaction with saturated ammonium chloride aqueous solution, extraction with ethyl acetate, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtration, concentration of organic phase, and separation and purification by column chromatography.

[0022] Furthermore, the product obtained from the above reaction, a 1,1-disubstituted tetrahydro-β-carbaline derivative, is one of compounds (R)-2 ((R)-(2-benzyl-1-(hydroxymethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)methyl benzoate) and (S)-2 ((S)-(2-benzyl-1-(hydroxymethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)methyl benzoate), with the following structural formulas:

[0023]

[0024] Wherein, Bn is benzyl and Bz is benzoyl.

[0025] The reaction equation for the synthesis method of this invention is as follows:

[0026]

[0027] Compared with the prior art, the present invention has the following advantages:

[0028] (1) The present invention uses tetrahydro-β-carboline derivatives as raw materials, which are non-toxic, inexpensive and readily available, and the synthesis steps are simple and safe to operate.

[0029] (2) The 1,1-disubstituted-tetrahydro-β-carboline derivative synthesized in this invention contains a nitrogen-containing quaternary carbon chiral center, which is essential in many natural products and can undergo further derivatization through various functional group transformations and cyclization reactions.

[0030] (3) Compared with the steps disclosed in the prior art, the present invention significantly improves the reaction yield, and the product yield can reach more than 90%, which significantly improves the efficiency of subsequent natural product synthesis.

[0031] (4) By adding a chiral ligand, the present invention can achieve the asymmetric synthesis of 1,1-disubstituted-tetrahydro-β-carboline derivatives, and obtain optically pure 1,1-disubstituted-tetrahydro-β-carboline derivatives, which can be applied to the synthesis of the natural product Arbornamine, which has better anti-inflammatory activity than indomethacin. Attached Figure Description

[0032] Figure 1 The hydrogen spectrum of compound 1 of the present invention is shown below;

[0033] Figure 2 This is the carbon spectrum of compound 1 of the present invention;

[0034] Figure 3 The hydrogen spectroscopy spectra of compounds (S)-2 and (R)-2 of this invention are shown below.

[0035] Figure 4 The carbon spectra of compounds (S)-2 and (R)-2 of this invention are shown. Detailed Implementation

[0036] The present invention will be further described below with reference to specific embodiments and accompanying drawings, but the implementation of the present invention is not limited thereto.

[0037] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available products. Chiral ligands L1–L8 were obtained from Daicel or Innochem reagent companies.

[0038] The products prepared in the following examples were all stored at -18°C or below.

[0039] Example 1

[0040] A method for the asymmetric synthesis of 1,1-disubstituted-tetrahydro-β-carboline derivatives, comprising the following steps:

[0041] Ligand L1 (10.0 mg, 0.03 mmol) and copper chloride (4 mg, 0.03 mmol) were weighed into a 40 mL reaction flask. The flask was evacuated for 2 h using a vacuum pump, then purged with nitrogen. Anhydrous tetrahydrofuran (3 mL) was added, and the mixture was stirred at room temperature for 4 h until fully dissolved. Then, 3 mL of a tetrahydrofuran solution of compound 1 (96.6 mg, 0.3 mmol) was added to the reaction flask. The temperature was lowered to -78 °C, and benzoyl chloride (52 μL, 0.45 mmol) and triethylamine (46 μL, 0.33 mmol) were added sequentially. The reaction was maintained at -78 °C for 12 h. The reaction was quenched with saturated ammonium chloride aqueous solution at -78 °C. The mixture was extracted three times with ethyl acetate, and the combined organic phases were backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated using a rapid preparative silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound (S)-2 (white solid, 39.6 mg, yield: 31%, ee% (enantiomer excess): 30%).

[0042] The synthesis route is as follows:

[0043]

[0044] HPLC conditions: OD-H column (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min), retention time: t R =12.8min (main), t R = 22.1 min (times).

[0045] Example 2

[0046] A method for the asymmetric synthesis of 1,1-disubstituted-tetrahydro-β-carboline derivatives, comprising the following steps:

[0047] Ligand L2 (10.9 mg, 0.03 mmol) and copper chloride (4 mg, 0.03 mmol) were weighed into a 40 mL reaction flask. The flask was evacuated for 2 h using a vacuum pump, then purged with nitrogen. Anhydrous tetrahydrofuran (3 mL) was added, and the mixture was stirred at room temperature for 4 h until fully dissolved. Then, 3 mL of a tetrahydrofuran solution of compound 1 (96.6 mg, 0.3 mmol) was added to the reaction flask. The temperature was lowered to -78 °C, and benzoyl chloride (52 μL, 0.45 mmol) and triethylamine (46 μL, 0.33 mmol) were added sequentially. The reaction was maintained at -78 °C for 12 h. The reaction was quenched with saturated ammonium chloride aqueous solution at -78 °C. The mixture was extracted three times with ethyl acetate, and the combined organic phases were backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated using a rapid preparative silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound (S)-2 (white solid, 102.2 mg, yield: 80%, ee% (enantiomer excess): 76%).

[0048] The synthesis route is as follows:

[0049]

[0050] HPLC conditions: OD-H column (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min), retention time: t R =12.8min (main), t R = 22.1 min (times).

[0051] Example 3

[0052] A method for the asymmetric synthesis of 1,1-disubstituted-tetrahydro-β-carboline derivatives, comprising the following steps:

[0053] Ligand L3 (8.8 mg, 0.03 mmol) and copper chloride (4 mg, 0.03 mmol) were weighed into a 40 mL reaction flask. The flask was evacuated for 2 h using a vacuum pump, then purged with nitrogen. Anhydrous tetrahydrofuran (3 mL) was added, and the mixture was stirred at room temperature for 4 h until fully dissolved. Then, 3 mL of a tetrahydrofuran solution of compound 1 (96.6 mg, 0.3 mmol) was added to the reaction flask. The temperature was lowered to -78 °C, and benzoyl chloride (52 μL, 0.45 mmol) and triethylamine (46 μL, 0.33 mmol) were added sequentially. The reaction was maintained at -78 °C for 12 h. The reaction was quenched with saturated ammonium chloride aqueous solution at -78 °C. The mixture was extracted three times with ethyl acetate, and the combined organic phases were backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated using a rapid preparative silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound (S)-2 (white solid, 29.4 mg, yield: 23%, ee% (enantiomer excess): 4%).

[0054] The synthesis route is as follows:

[0055]

[0056] HPLC conditions: OD-H column (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min), retention time: t R =12.8min (main), t R = 22.1 min (times).

[0057] Example 4

[0058] A method for the asymmetric synthesis of 1,1-disubstituted-tetrahydro-β-carboline derivatives, comprising the following steps:

[0059] Ligand L4 (11.7 mg, 0.03 mmol) and copper chloride (4 mg, 0.03 mmol) were weighed into a 40 mL reaction flask. The flask was evacuated for 2 h using a vacuum pump, then purged with nitrogen. Anhydrous tetrahydrofuran (3 mL) was added, and the mixture was stirred at room temperature for 4 h until fully dissolved. Then, 3 mL of a tetrahydrofuran solution of compound 1 (96.6 mg, 0.3 mmol) was added to the reaction flask. The temperature was lowered to -78 °C, and benzoyl chloride (52 μL, 0.45 mmol) and triethylamine (46 μL, 0.33 mmol) were added sequentially. The reaction was maintained at -78 °C for 12 h. The reaction was quenched with saturated ammonium chloride aqueous solution at -78 °C. The mixture was extracted three times with ethyl acetate, and the combined organic phases were backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated using a rapid preparative silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound (S)-2 (white solid, 117.8 mg, yield: 92%, ee% (enantiomer excess): 79%).

[0060] The synthesis route is as follows:

[0061]

[0062] HPLC conditions: OD-H column (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min), retention time: t R =12.8min (main), t R = 22.1 min (times).

[0063] Example 5

[0064] A method for the asymmetric synthesis of 1,1-disubstituted-tetrahydro-β-carboline derivatives, comprising the following steps:

[0065] Ligand L5 (12.5 mg, 0.03 mmol) and copper chloride (4 mg, 0.03 mmol) were weighed into a 40 mL reaction flask. The flask was evacuated for 2 h using a vacuum pump, then purged with nitrogen. Anhydrous tetrahydrofuran (3 mL) was added, and the mixture was stirred at room temperature for 4 h until fully dissolved. Then, 3 mL of a tetrahydrofuran solution of compound 1 (96.6 mg, 0.3 mmol) was added to the reaction flask. The temperature was lowered to -78 °C, and benzoyl chloride (52 μL, 0.45 mmol) and triethylamine (46 μL, 0.33 mmol) were added sequentially. The reaction was maintained at -78 °C for 12 h. The reaction was quenched with saturated ammonium chloride aqueous solution at -78 °C. The mixture was extracted three times with ethyl acetate, and the combined organic phases were backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated using a rapid preparative silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound (S)-2 (white solid, 107.4 mg, yield: 84%, ee% (enantiomer excess): 72%).

[0066] The synthesis route is as follows:

[0067]

[0068] HPLC conditions: OD-H column (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min), retention time: t R =12.8min (main), t R = 22.1 min (times).

[0069] Example 6

[0070] A method for the asymmetric synthesis of 1,1-disubstituted-tetrahydro-β-carboline derivatives, comprising the following steps:

[0071] Ligand L6 (10.8 mg, 0.03 mmol) and copper chloride (4 mg, 0.03 mmol) were weighed into a 40 mL reaction flask. The flask was evacuated for 2 h using a vacuum pump, then purged with nitrogen. Anhydrous tetrahydrofuran (3 mL) was added, and the mixture was stirred at room temperature for 4 h until fully dissolved. Then, 3 mL of a tetrahydrofuran solution of compound 1 (96.6 mg, 0.3 mmol) was added to the reaction flask. The temperature was lowered to -78 °C, and benzoyl chloride (52 μL, 0.45 mmol) and triethylamine (46 μL, 0.33 mmol) were added sequentially. The reaction was maintained at -78 °C for 12 h. The reaction was quenched with saturated ammonium chloride aqueous solution at -78 °C. The mixture was extracted three times with ethyl acetate, and the combined organic phases were backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated using a rapid preparative silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound (R)-2 (white solid, 113.7 mg, yield: 89%, ee% (enantiomer excess): 82%).

[0072] The synthesis route is as follows:

[0073]

[0074] HPLC conditions: OD-H column (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min), retention time: t R = 12.8 min (times), t R =22.1min (main).

[0075] Example 7

[0076] A method for the asymmetric synthesis of 1,1-disubstituted-tetrahydro-β-carboline derivatives, comprising the following steps:

[0077] Ligand L7 (12.1 mg, 0.03 mmol) and copper chloride (4 mg, 0.03 mmol) were weighed into a 40 mL reaction flask. The flask was evacuated for 2 h using a vacuum pump, then purged with nitrogen. Anhydrous tetrahydrofuran (3 mL) was added, and the mixture was stirred at room temperature for 4 h until fully dissolved. Then, 3 mL of a tetrahydrofuran solution of compound 1 (96.6 mg, 0.3 mmol) was added to the reaction flask. The temperature was lowered to -78 °C, and benzoyl chloride (52 μL, 0.45 mmol) and triethylamine (46 μL, 0.33 mmol) were added sequentially. The reaction was maintained at -78 °C for 12 h. The reaction was quenched with saturated ammonium chloride aqueous solution at -78 °C. The mixture was extracted three times with ethyl acetate, and the combined organic phases were backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated using a rapid preparative silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound (R)-2 (white solid, 55.0 mg, yield: 43%, ee% (enantiomer excess): -47%).

[0078] The synthesis route is as follows:

[0079]

[0080] HPLC conditions: OD-H column (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min), retention time: t R = 12.8 min (times), t R =22.1min (main).

[0081] Example 8

[0082] A method for the asymmetric synthesis of 1,1-disubstituted-tetrahydro-β-carboline derivatives, comprising the following steps:

[0083] Ligand L7 (24.2 mg, 0.06 mmol) and copper chloride (8 mg, 0.06 mmol) were weighed into a 40 mL reaction flask. The flask was evacuated for 2 h using a vacuum pump, then purged with nitrogen. Anhydrous tetrahydrofuran (3 mL) was added, and the mixture was stirred at room temperature for 6 h until fully dissolved. Then, 3 mL of a tetrahydrofuran solution of compound 1 (96.6 mg, 0.3 mmol) was added to the reaction flask. The temperature was lowered to -78 °C, and benzoyl chloride (104 μL, 0.9 mmol) and triethylamine (92 μL, 0.66 mmol) were added sequentially. The reaction was maintained at -78 °C for 24 h. The reaction was quenched with saturated ammonium chloride aqueous solution at -78 °C. The mixture was extracted three times with ethyl acetate, and the combined organic phases were backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated using a rapid preparative silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound (R)-2 (white solid, 72.8 mg, yield: 57%, ee% (enantiomer excess): -49%).

[0084] The synthesis route is as follows:

[0085]

[0086] HPLC conditions: OD-H column (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min), retention time: t R = 12.8 min (times), t R =22.1min (main).

[0087] Example 9

[0088] A method for the asymmetric synthesis of 1,1-disubstituted-tetrahydro-β-carboline derivatives, comprising the following steps:

[0089] Ligand L8 (14.6 mg, 0.03 mmol) and copper chloride (4 mg, 0.03 mmol) were weighed into a 40 mL reaction flask. The flask was evacuated for 2 h using a vacuum pump, then purged with nitrogen. Anhydrous tetrahydrofuran (3 mL) was added, and the mixture was stirred at room temperature for 6 h until fully dissolved. Subsequently, 3 mL of a tetrahydrofuran solution of compound 1 (96.6 mg, 0.3 mmol) was added to the reaction flask. The temperature was lowered to -78 °C, and benzoyl chloride (52 μL, 0.45 mmol) and triethylamine (46 μL, 0.33 mmol) were added sequentially. The reaction was maintained at -78 °C for 24 h. The reaction was quenched with saturated ammonium chloride aqueous solution at -78 °C. The mixture was extracted three times with ethyl acetate, and the combined organic phases were backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated using a rapid preparative silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound (S)-2 (white solid, 29.4 mg, yield: 23%, ee% (enantiomer excess): 5%).

[0090] The synthesis route is as follows:

[0091]

[0092] HPLC conditions: OD-H column (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min), retention time: t R =12.8min (main), t R = 22.1 min (times).

[0093] Example 10

[0094] A method for the asymmetric synthesis of 1,1-disubstituted-tetrahydro-β-carboline derivatives, comprising the following steps:

[0095] Ligand L8 (146 mg, 0.3 mmol) and copper chloride (40 mg, 0.3 mmol) were weighed into a 40 mL reaction flask. The flask was evacuated for 2 h, then purged with nitrogen. Anhydrous tetrahydrofuran (3 mL) was added, and the mixture was stirred at room temperature for 6 h until fully dissolved. Then, 3 mL of a tetrahydrofuran solution of compound 1 (96.6 mg, 0.3 mmol) was added to the reaction flask. The temperature was lowered to -78 °C, and benzoyl chloride (347 μL, 3 mmol) and triethylamine (414 μL, 3 mmol) were added sequentially. The reaction was maintained at -78 °C for 24 h. The reaction was quenched with saturated ammonium chloride solution at -78 °C. The mixture was extracted three times with ethyl acetate, and the combined organic phases were backwashed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated using a rapid preparative silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound (S)-2 (white solid, 37 mg, yield: 29%, ee% (enantiomer excess): 10%).

[0096] The synthesis route is as follows:

[0097]

[0098] HPLC conditions: OD-H column (n-hexane / isopropanol = 90 / 10, flow rate 1.0 ml / min), retention time: t R =12.8min (main), t R = 22.1 min (times).

[0099] The yields of compounds (S)-2 and (R)-2 synthesized in Examples 1-10 above varied considerably due to the coordination effect of the ligand with copper chloride and the influence of steric hindrance. Analysis of the above results indicates that using cyclopropyl-derived bisoxazoline ligands, due to their smaller steric hindrance, allows the catalyst to participate more easily in coordination, resulting in better yields and ee values.

[0100] The structures of all compounds in Examples 1-10 above were confirmed by nuclear magnetic resonance spectroscopy. Figure 1 The hydrogen spectrum of compound 1 is shown below. Figure 2 The carbon spectrum of compound 1 is shown below. Figure 3 The proton NMR spectra of compounds (S)-2 and (R)-2 are shown. Figure 4 The carbon spectra of compounds (S)-2 and (R)-2 are shown below; the identification data are as follows:

[0101] Compound 1:

[0102] 1H NMR (500MHz, DMSO-d6) δ10.55(s,1H),7.43(d,J=7.5Hz,2H),7.31-7.38(m,4H),7.24(t,J=7.3Hz,1H),7.03(t,J=7.6Hz,1 H),6.94(t,J=7.4Hz,1H),4.50-4.41(m,2H),4.03(s,2H),3.98-3.82(m,4H),2.96(t,J=5.6Hz,2H),2.55(t,J=5.6Hz,2H).

[0103] 13 C NMR (125MHz, DMSO-d6) δ141.4,136.1,136.0,128.2,128.1,126.5,126.4,120.3,117.9,117.3,111.1,109.2,62.9,62.6,52.6,44.6,21.2.

[0104] Compounds (S)-2 and (R)-2 (enantiomers of each other, NMR spectra) Figure 1 To:

[0105] 1 H NMR(500MHz, CDCl3)δ8.62(s,1H),8.09-7.99(m,2H),7.65-7.58(m,1H),7.53-7.45(m,3H),7.42-7.37( m,2H),7.36-7.31(m,3H),7.30-7.27(m,1H),7.18(ddd,J=8.2,7.1,1.2Hz,1H),7.10(ddd,J=8.0,7.1,1 .1Hz,1H),4.96(d,J=12.1Hz,1H),4.81(d,J=12.1Hz,1H),4.27(d,J=14.0Hz,1H),4.13(d,J=11.1Hz,1H ),4.02(d,J=11.1Hz,1H),3.74(d,J=14.0Hz,1H),3.18(brs,1H),3.16-2.97(m,2H),2.82-2.64(m,2H).

[0106] 13C NMR(125MHz,DMSO-d6)δ165.7,141.2,136.2,134.5,133.3,129.7,129.1,128.7,128.1,12 7.9,126.5,126.2,120.6,118.1,117.5,111.2,109.6,65.3,63.4,61.4,52.7,44.8,21.2.

[0107] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. An asymmetric synthetic method for a 1,1-disubstituted tetrahydro-β-carbaline derivative, characterized in that, Includes the following steps: (1) In the reactor, the chiral ligand and copper chloride were dried at room temperature to remove the water in the reaction system and then dissolved in an organic solvent; under an inert atmosphere, an organic solvent containing compound 1 was added, and after cooling, benzoyl chloride and triethylamine were added in sequence to carry out the reaction. (2) After the reaction is completed, the reaction solution is separated and purified to obtain 1,1-disubstituted-tetrahydro-β-carbaline derivative; The structural formula of compound 1 is as follows: Among them, R 1 For hydrogen atoms, R 2 It is benzyl; The general structural formula of the chiral ligand described in step (1) is as follows: Among them, R 3 It is one of benzyl, phenyl, isopropyl, sec-butyl, tert-butyl, and n-butyl, R 4 It is one of methyl, ethyl, n-butyl, tert-butyl, phenyl, or hydrogen atom, R 5 It is methyl; The structural formula of the 1,1-disubstituted tetrahydro-β-carbaline derivative is as follows: or Wherein, Bn is benzyl and Bz is benzoyl.

2. The asymmetric synthesis method of the 1,1-disubstituted-tetrahydro-β-carbaline derivative according to claim 1, characterized in that, The organic solvent mentioned in step (1) is methanol, ethanol, n-propanol, isopropanol, tert-butanol, acetonitrile, ethyl acetate, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, acetone, toluene, etc. N , N - One of dimethylformamide, dimethyl sulfoxide, 2-methyltetrahydrofuran, diethyl ether, tert-butyl dimethyl ether, and 1,4-dioxane.

3. The asymmetric synthesis method of the 1,1-disubstituted-tetrahydro-β-carbaline derivative according to claim 1, characterized in that, The inert atmosphere mentioned in step (1) is a nitrogen atmosphere.

4. The asymmetric synthesis method of the 1,1-disubstituted-tetrahydro-β-carbaline derivative according to claim 1, characterized in that, The molar ratio of compound 1 to the chiral ligand in step (1) is 1:0.1 to 1:

1.

5. The asymmetric synthesis method of the 1,1-disubstituted-tetrahydro-β-carbaline derivative according to claim 1, characterized in that, The molar ratio of compound 1 to copper chloride in step (1) is 1:0.1 to 1:

1.

6. The asymmetric synthesis method of the 1,1-disubstituted-tetrahydro-β-carbaline derivative according to claim 1, characterized in that, The cooling in step (1) is to reduce the temperature to -78°C, and the reaction time at this temperature is 12~120 h.

7. The asymmetric synthesis method of the 1,1-disubstituted-tetrahydro-β-carbaline derivative according to claim 1, characterized in that, The molar ratio of compound 1 to benzoyl chloride in step (1) is 1:1.1 to 1:

10.

8. The asymmetric synthesis method of the 1,1-disubstituted-tetrahydro-β-carbaline derivative according to claim 1, characterized in that, The molar ratio of compound 1 to triethylamine in step (1) is 1:1.1 to 1:

10.

9. The asymmetric synthesis method of the 1,1-disubstituted-tetrahydro-β-carbaline derivative according to any one of claims 1-8, characterized in that, The specific steps for separation and purification in step (2) are as follows: quenching reaction with saturated ammonium chloride aqueous solution, extraction with ethyl acetate, backwashing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtration, concentration of organic phase, and separation and purification by column chromatography.

Images