Preparation method of N-N axial chiral isoquinolinone derivative

Abstract

The invention discloses a preparation method of an N-N axial chiral isoquinolinone derivative, which comprises the following steps: by taking a compound with a structure as shown in a formula 1 as a substrate, carrying out decarbonylation and alkyne insertion reaction on the compound and alkyne as shown in a formula 2 in the presence of a cobalt catalyst and a Salox ligand L to generate the N-N axial chiral isoquinolinone derivative with a structure as shown in a formula 3, the reaction formula is as follows: Ar groups in # imgabs0 # formula 1 and formula 3 are phenyl, substituted phenyl or naphthyl, and the substituent group of the substituted phenyl is selected from halogen, acetamido, methyl or tertiary butyl; r2 in the formula 2 and the formula 3 is selected from methyl, ethyl, propyl or butyl; guiding groups containing R1 groups in the formula 1 and the formula 3 are selected from the following structures: # imgabs 1 #. The preparation method disclosed by the invention has the advantages of being relatively low in catalyst dosage, mild in reaction condition, simple and convenient to operate, wide in substrate practicability, good in stereoselectivity, high in yield and the like, and has relatively high application value.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing an NN-axis chiral isoquinolinone derivative. Background Art

[0002] As an important and interesting chiral system, NN atropisomers are widely present in natural products, drug lead compounds and advanced material skeletons. The anisotropic structural characteristics caused by its special axial rotation have attracted the attention of many chemists and are widely used in asymmetric synthesis catalysis, drug development and other fields. In addition, the isoquinolinone structure has unique biological activity. How to construct an isoquinolinone skeleton containing NN axial chirality has become one of the challenges that scholars have tried to overcome.

[0003] People have tried to first synthesize racemic axial chiral compounds and then use a splitting agent to split them to obtain a single axial chiral isomer, such as the 2022 Stephen team reported that tartaric acid was used to split a PI3K inhibitor with axial chirality (Acc. Chem. Res., 2022, 55 (18), 2581-2593). However, this method has low atomic utilization and serious losses. In addition, some researchers have used biological methods to synthesize axial chiral compounds, such as the 2012 Christian team reported that bacteria were used to synthesize natural products with NN axial chirality (Angew. Chem. Int. Ed., 2012, 51 (41), 10293-10297). However, biological synthesis is greatly affected by the environment and the equipment investment is high. During this period, people have also developed a variety of catalytic systems for use in a variety of reactions, such as the use of chiral amines to catalyze NH activation to construct axially chiral quinazolinone derivatives reported by Li Xin's research group in 2022 (Org. Lett., 2022, 24(1), 374-378). However, the prices of commonly used precious metal catalysts such as palladium, ruthenium, and rhodium remain high, and small molecule catalysts or additives such as chiral phosphoric acid and axially chiral ligands also have the problems of cumbersome synthesis steps and high prices. Therefore, people are also studying catalytic systems that combine cheap metals with cheap and readily available ligands to construct axially chiral compounds.

[0004] In 2021, Liu Renrong's research group reported a copper-catalyzed Friedel-Crafts alkylation method for constructing NN axial chiral compounds. The system used chiral bis-oxazoline ligands to obtain a variety of bipyrrole-type axial chiral compounds with good ee values ​​and yields (Angew. Chem. Int. Ed., 2023, 62, e202216863). Similar catalytic systems often report the construction of bipyrrole-type compounds, but there are few reports of isoquinolinone-type structures. In 2023, Niu Junlong's research group developed a method for constructing isoquinolinone-type NN axial chiral compounds by carbon-hydrogen activation using cobalt and Salox ligands (Nat. Commun., 2023, 14, 5271), but its raw material synthesis requires a large amount of relatively expensive EDCI and HOBt.

[0005] In summary, previous synthesis methods generally have problems such as difficult raw material synthesis or expensive materials used in the catalytic system. Therefore, it is necessary to develop a method to obtain NN axial chiral compounds using more readily available raw materials and a mild and inexpensive system. Summary of the invention

[0006] In view of the above problems existing in the prior art, the object of the present invention is to provide a method for preparing NN axial chiral isoquinolinone derivatives.

[0007] The technical solution adopted by the present invention is as follows:

[0008] A method for preparing an NN-axis chiral isoquinolinone derivative comprises taking a 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione derivative having a structure shown in Formula 1 as a substrate, adding an oxidant and a solvent, and carrying out a decarbonylation and acetylene insertion reaction with an alkyne shown in Formula 2 in the presence of a cobalt catalyst and a Salox ligand L to generate a (R)-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one derivative having a structure shown in Formula 3, wherein the reaction formula is as follows:

[0009]

[0010] In Formula 1 and Formula 3, the Ar group is a phenyl group, a substituted phenyl group or a naphthyl group, and the substituent of the substituted phenyl group is selected from a halogen group, an acetylamino group, a methyl group or a tert-butyl group; in Formula 2 and Formula 3, R 2 is selected from methyl, ethyl, propyl or butyl;

[0011] Formula 1 and Formula 3 contain R 1 The directing group of the group is selected from the following structures:

[0012]

[0013] Furthermore, the cobalt catalyst is one or more of cobalt iodide, cobalt bromide, cobalt chloride, cobalt acetate tetrahydrate, and cobalt acetylacetonate, preferably cobalt iodide or cobalt acetate tetrahydrate.

[0014] Furthermore, the Salox ligand L is selected from L1, L2 or L3, and the structural formulas are shown below:

[0015]

[0016] Furthermore, the oxidant is selected from one or more of silver carbonate, silver oxide, silver acetate, and manganese acetate, preferably silver carbonate.

[0017] Furthermore, the solvent is selected from one or a mixed solvent of two or more selected from dichloroethane, 1,4-dioxane, toluene, xylene, chlorobenzene, fluorobenzene, DMF, DMAc, and NMP, preferably DMF, 1,4-dioxane or toluene.

[0018] Furthermore, the molar ratio of the compound shown in Formula 1 to the alkyne is 1:1.0-1:5.0, preferably 1:1.5-1:3.0; the molar ratio of the compound shown in Formula 1 to the cobalt catalyst is 1:0.1-1:1.0, preferably 1:0.2-1:0.4; the molar ratio of the compound shown in Formula 1 to the ligand L is 1:0.2-1:2.0, preferably 1:0.4-1:0.8; the molar ratio of the compound shown in Formula 1 to the oxidant is 1:1.0-1:3.0, preferably 1:1.5-1:2.0.

[0019] Furthermore, the reaction temperature is 80-130°C, preferably 90-130°C.

[0020] Furthermore, the reaction time is 12-36 hours, preferably 24-36 hours.

[0021] By adopting the above technology, compared with the prior art, the present invention has the following advantages:

[0022] The present invention develops a method for constructing an isoquinolinone derivative with NN axial chirality by using an easily prepared 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione derivative as a raw material, and by a decarbonylation and insertion reaction catalyzed by a cheap metal cobalt and a cheap and easily synthesized Salox ligand. The present invention has the advantages of low catalyst dosage, mild reaction conditions, simple operation, wide substrate practicability, good stereoselectivity, high yield, etc., and has great application value.

[0023] When the raw materials and the catalytic system of the present invention are used for decarbonylation and acetylene insertion reaction, (R)-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one derivatives are generated with high enantioselectivity, and the ee value is generally above 90%. DETAILED DESCRIPTION

[0024] In order to better understand the technical solution of the present invention, further description is given below in conjunction with specific embodiments, but the specific implementation methods are not intended to limit the contents of the present invention.

[0025] The ligands used in the following examples are as follows:

[0026]

[0027] The reaction equation is:

[0028]

[0029] Example 1: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0030] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a, Ar group is phenyl, containing R 1 The directing group of the group is )(31.7 mg, 0.1 mmol), 3-hexyne (2a, substituent R 2 ethyl) (24.6 mg, 0.3 mmol), cobalt acetate tetrahydrate (5.0 mg, 0.02 mmol), ligand L1 (14.0 mg, 0.04 mmol), silver carbonate (41.4 mg, 0.15 mmol) were added to a pressure tube, 1,4-dioxane (1 mL) was added, and the mixture was reacted at 110°C for 36 h. After the reaction, 1,4-dioxane was removed by vacuum distillation, and column chromatography was performed with petroleum ether: ethyl acetate = 5:1 to obtain (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) with a yield of 85% and an ee value of 97%.

[0031] Example 2: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0032] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L1 (28.1 mg, 0.08 mmol), and silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, 1,4-dioxane (2 mL) was added, and the reaction was carried out at 110°C for 36 h. After the reaction was completed, 1,4-dioxane was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 83% and an ee value of 97%.

[0033] Example 3: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0034] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt iodide (12.5 mg, 0.04 mmol), ligand L1 (28.1 mg, 0.08 mmol), and silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, 1,4-dioxane (2 mL) was added, and the reaction was carried out at 110°C for 36 h. After the reaction was completed, 1,4-dioxane was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 78% and an ee value of 95%.

[0035] Example 4: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0036] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt bromide (8.7 mg, 0.04 mmol), ligand L1 (28.1 mg, 0.08 mmol), and silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, 1,4-dioxane (2 mL) was added, and the reaction was carried out at 110°C for 36 h. After the reaction was completed, 1,4-dioxane was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 67% and an ee value of 93%.

[0037] Example 5: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0038] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt chloride (5.2 mg, 0.04 mmol), ligand L1 (28.1 mg, 0.08 mmol), and silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, 1,4-dioxane (2 mL) was added, and the reaction was carried out at 110°C for 36 h. After the reaction was completed, 1,4-dioxane was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 35% and an ee value of 93%.

[0039] Example 6: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0040] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetylacetonate (10.4 mg, 0.04 mmol), ligand L1 (28.1 mg, 0.08 mmol), and silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, 1,4-dioxane (2 mL) was added, and the reaction was carried out at 110°C for 36 h. After the reaction was completed, 1,4-dioxane was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 57% and an ee value of 92%.

[0041] Example 7: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0042] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L2 (25.4 mg, 0.08 mmol), and silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, 1,4-dioxane (2 mL) was added, and the reaction was carried out at 110°C for 36 h. After the reaction was completed, 1,4-dioxane was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 36.4% and an ee value of 97%.

[0043] Example 8: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0044] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L3 (23.1 mg, 0.08 mmol), and silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, 1,4-dioxane (2 mL) was added, and the reaction was carried out at 110°C for 36 h. After the reaction was completed, 1,4-dioxane was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 38.8% and an ee value of 97%.

[0045] Example 9: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0046] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L4 (17.5 mg, 0.08 mmol), and silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, and 1,4-dioxane (2 mL) was added, and the reaction was carried out at 110° C. for 36 h. The target product was not obtained.

[0047] Example 10: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0048] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L5 (20.0 mg, 0.08 mmol), silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, 1,4-dioxane (2 mL) was added, and the reaction was carried out at 110° C. for 36 h. The target product was not obtained.

[0049] Example 11: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0050] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L6 (28.1 mg, 0.08 mmol), silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, 1,4-dioxane (2 mL) was added, and the reaction was carried out at 110° C. for 36 h. The target product was not obtained.

[0051] Example 12: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0052] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L1 (28.1 mg, 0.08 mmol), and silver acetate (99.7 mg, 0.6 mmol) were added to a pressure tube, 1,4-dioxane (2 mL) was added, and the reaction was carried out at 110°C for 36 h. After the reaction was completed, 1,4-dioxane was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 74% and an ee value of 97%.

[0053] Example 13: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0054] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L1 (28.1 mg, 0.08 mmol), and silver oxide (69.5 mg, 0.3 mmol) were added to a pressure tube, 1,4-dioxane (2 mL) was added, and the reaction was carried out at 110°C for 36 h. After the reaction was completed, 1,4-dioxane was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 55% and an ee value of 97%.

[0055] Example 14: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0056] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L1 (28.1 mg, 0.08 mmol), and manganese acetate (51.9 mg, 0.3 mmol) were added to a pressure tube, 1,4-dioxane (2 mL) was added, and the reaction was carried out at 110°C for 36 h. After the reaction was completed, 1,4-dioxane was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 61% and an ee value of 97%.

[0057] Example 15: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0058] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L1 (28.1 mg, 0.08 mmol), and silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, and dichloroethane (2 mL) was added, and the reaction was carried out at 110°C for 36 h. After the reaction was completed, dichloroethane was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 52% and an ee value of 97%.

[0059] Example 16: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0060] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L1 (28.1 mg, 0.08 mmol), and silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, toluene (2 mL) was added, and the reaction was carried out at 110°C for 36 h. After the reaction was completed, toluene was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 56% and an ee value of 97%.

[0061] Example 17: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0062] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L1 (28.1 mg, 0.08 mmol), and silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, and xylene (2 mL) was added, and the reaction was carried out at 110°C for 36 h. After the reaction was completed, xylene was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 53% and an ee value of 97%.

[0063] Example 18: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0064] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L1 (28.1 mg, 0.08 mmol), and silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, chlorobenzene (2 mL) was added, and the reaction was carried out at 110°C for 36 h. After the reaction was completed, chlorobenzene was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 55% and an ee value of 96%.

[0065] Example 19: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0066] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L1 (28.1 mg, 0.08 mmol), and silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, fluorobenzene (2 mL) was added, and the reaction was carried out at 110°C for 36 h. After the reaction was completed, fluorobenzene was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 45% and an ee value of 95%.

[0067] Example 20: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0068] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L1 (28.1 mg, 0.08 mmol), and silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, and DMF (2 mL) was added, and the reaction was carried out at 110°C for 36 h. After the reaction was completed, DMF was removed by distillation under reduced pressure and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 66% and an ee value of 97%.

[0069] Example 21: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0070] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L1 (28.1 mg, 0.08 mmol), and silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, DMAc (2 mL) was added, and the reaction was carried out at 110°C for 36 h. After the reaction was completed, DMAc was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 51% and an ee value of 95%.

[0071] Example 22: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0072] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L1 (28.1 mg, 0.08 mmol), and silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, NMP (2 mL) was added, and the reaction was carried out at 110°C for 36 h. After the reaction was completed, NMP was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 53% and an ee value of 94%.

[0073] Example 23: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0074] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L1 (28.1 mg, 0.08 mmol), and silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, 1,4-dioxane (2 mL) was added, and the reaction was carried out at 90°C for 36 h. After the reaction was completed, 1,4-dioxane was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 65% and an ee value of 97%.

[0075] Example 24: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0076] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L1 (28.1 mg, 0.08 mmol), and silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, 1,4-dioxane (2 mL) was added, and the reaction was carried out at 130°C for 36 h. After the reaction was completed, 1,4-dioxane was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 82% and an ee value of 94%.

[0077] Example 25: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0078] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L1 (28.1 mg, 0.08 mmol), and silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, 1,4-dioxane (2 mL) was added, and the reaction was carried out at 110°C for 24 h. After the reaction was completed, 1,4-dioxane was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 61% and an ee value of 97%.

[0079] Example 26: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0080] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (24.6 mg, 0.3 mmol), cobalt acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L1 (28.1 mg, 0.08 mmol), and silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, 1,4-dioxane (2 mL) was added, and the reaction was carried out at 110°C for 36 h. After the reaction was completed, 1,4-dioxane was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 75% and an ee value of 97%.

[0081] Example 27: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0082] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetate tetrahydrate (5.0 mg, 0.02 mmol), ligand L1 (14.0 mg, 0.04 mmol), and silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, 1,4-dioxane (2 mL) was added, and the reaction was carried out at 110°C for 36 h. After the reaction was completed, 1,4-dioxane was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 62% and an ee value of 97%.

[0083] Example 28: Preparation of (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a)

[0084] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione (1a) (63.4 mg, 0.2 mmol), 3-hexyne (2a) (49.3 mg, 0.6 mmol), cobalt acetate tetrahydrate (5.0 mg, 0.02 mmol), ligand L1 (14.0 mg, 0.04 mmol), and silver carbonate (110.3 mg, 0.4 mmol) were added to a pressure tube, 1,4-dioxane (2 mL) was added, and the reaction was carried out at 110°C for 36 h. After the reaction was completed, 1,4-dioxane was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 5:1 to give (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) in a yield of 82% and an ee value of 97%.

[0085] Example 29: Substrate derivatization, preparation of (R)-3,4-dibutyl-2-(9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one

[0086] (R)-3,4-dibutyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3d) (85.5 mg, 0.2 mmol) and DDQ (109.0 mg, 0.48 mmol) were added to a pressure tube, and 2 mL of toluene was added, and the reaction was carried out at 120°C for 2 h. After the reaction was completed, toluene was removed by vacuum distillation, and (R)-3,4-dibutyl-2-(9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one was obtained by column chromatography with elution of petroleum ether:ethyl acetate=5:1, with a yield of 88% and an ee value of 97%.

[0087] Examples 30-49: Preparation of (R)-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one derivatives (3b-3r)

[0088] 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione derivative (1b-1n) (0.2 mmol), alkyne (2a-2d) (0.6 mmol), cobalt acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L1 (28.1 mg, 0.08 mmol), and silver carbonate (82.7 mg, 0.3 mmol) were added to a pressure tube, 1,4-dioxane (2 mL) was added, and the reaction was carried out at 110°C for 36 h. After the reaction, 1,4-dioxane was removed by distillation under reduced pressure, and column chromatography was performed with petroleum ether:ethyl acetate = 10:1-3:1 as the eluent to obtain (R)-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one derivatives (3b-3r). The yields and ee values ​​are shown in Table 1.

[0089] Table 1: Experimental results of Examples 30 to 48

[0090]

[0091]

[0092]

[0093]

[0094]

[0095] The contents described in this specification are merely an enumeration of implementation forms of the inventive concept, and the protection scope of the present invention should not be regarded as being limited to the specific forms described in the embodiments.

Claims

1. A method for preparing a NN-axis chiral isoquinolinone derivative, characterized in that: A 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione derivative having a structure shown in Formula 1 is used as a substrate, an oxidant and a solvent are added, and in the presence of a cobalt catalyst and a Salox ligand L, a decarbonylation reaction is carried out with the alkyne shown in Formula 2 to generate a (R)-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one derivative having a structure shown in Formula 3. The reaction formula is as follows: In Formula 1 and Formula 3, the Ar group is a phenyl group, a substituted phenyl group or a naphthyl group, and the substituent of the substituted phenyl group is selected from a halogen group, an acetylamino group, a methyl group or a tert-butyl group; in Formula 2 and Formula 3, R 2 is selected from methyl, ethyl, propyl or butyl; Formula 1 and Formula 3 contain R 1 The directing group of the group is selected from the following structures:

2. The method for preparing a NN-axis chiral isoquinolinone derivative according to claim 1, characterized in that: The cobalt catalyst is one or more of cobalt iodide, cobalt bromide, cobalt chloride, cobalt acetate tetrahydrate, and cobalt acetylacetonate, preferably cobalt iodide or cobalt acetate tetrahydrate.

3. The method for preparing a NN-axis chiral isoquinolinone derivative according to claim 1, characterized in that: The Salox ligand L is selected from L1, L2 or L3, and the structural formulas are shown below:

4. The method for preparing a NN-axis chiral isoquinolinone derivative according to claim 1, characterized in that: The oxidant is selected from one or more of silver carbonate, silver oxide, silver acetate, and manganese acetate, preferably silver carbonate.

5. The method for preparing a NN-axis chiral isoquinolinone derivative according to claim 1, characterized in that: The solvent is selected from one or a mixed solvent of dichloroethane, 1,4-dioxane, toluene, xylene, chlorobenzene, fluorobenzene, DMF, DMAc, and NMP, preferably DMF, 1,4-dioxane or toluene.

6. The method for preparing a NN-axis chiral isoquinolinone derivative according to claim 1, characterized in that: The molar ratio of the compound shown in Formula 1 to the alkyne is 1:1.0-1:5.0, preferably 1:1.5-1:3.0; the molar ratio of the compound shown in Formula 1 to the cobalt catalyst is 1:0.1-1:1.0, preferably 1:0.2-1:0.4; the molar ratio of the compound shown in Formula 1 to the ligand L is 1:0.2-1:2.0, preferably 1:0.4-1:0.8; the molar ratio of the compound shown in Formula 1 to the oxidant is 1:1.0-1:3.0, preferably 1:1.5-1:2.

0.

7. The method for preparing a NN-axis chiral isoquinolinone derivative according to claim 1, characterized in that: The reaction temperature is 80-130°C, preferably 90-130°C.

8. The method for preparing a NN-axis chiral isoquinolinone derivative according to claim 1, characterized in that: The reaction time is 12-36 hours, preferably 24-36 hours.

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