A method for preparing N-N axially chiral isoquinolinone derivatives
The decarbonylation and acetylene insertion reaction catalyzed by a cobalt catalyst and a Salox ligand solves the problem of high synthesis cost of NN axial chiral isoquinolinone derivatives in the prior art, realizes an efficient and low-cost preparation method, and generates isoquinolinone derivatives with high enantioselectivity.
Patent Information
- Application Number
- CN202510046972.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-13
- Publication Date
- 2025-10-10
- Estimated Expiration
- 2045-01-13
AI Technical Summary
The existing methods for synthesizing NN axial chiral isoquinolinone derivatives have the problems of difficult raw material synthesis or expensive catalytic system materials, making it difficult to achieve efficient and low-cost preparation.
Using 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione derivatives as substrates, a decarbonylation and acetylene insertion reaction catalyzed by a cobalt catalyst and Salox ligand L was performed to generate isoquinolinone derivatives with NN axial chirality. Cheap oxidants and solvents were used, and the reaction conditions were optimized.
The method achieves high enantioselectivity to generate (R)-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one derivatives with an ee value above 90%, low catalyst dosage, mild reaction conditions, simple operation, wide substrate applicability, and high yield.
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Figure CN119751453B_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing an NN axial chiral isoquinolinone derivative. Background Art
[0002] As an important and intriguing chiral system, NN atropisomers are widely present in natural products, drug leads, and advanced material frameworks. Their unique anisotropic structural properties, caused by their unique axial rotation, have attracted the attention of numerous chemists and are widely used in asymmetric synthesis, catalysis, and drug development. Furthermore, given the unique biological activity of isoquinolinone structures, constructing isoquinolinone frameworks that incorporate NN axial chirality has become a challenging task for researchers.
[0003] People have tried to first synthesize racemic axial chiral compounds and then use a resolving agent to split them to obtain a single axial chiral isomer. For example, in 2022, Stephen's group reported that a PI3K inhibitor with axial chirality was obtained by splitting with tartaric acid (Acc. Chem. Res., 2022, 55 (18), 2581-2593). However, this method has low atom utilization and serious losses. In addition, some researchers have used biological methods to synthesize axial chiral compounds, such as the use of bacteria to synthesize natural products with NN axial chirality reported by Christian's group in 2012 (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 various 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 N-N axial chiral compounds. This system uses a chiral bisoxazoline ligand to obtain various axially chiral compounds with good ee value and yield (Angew. Chem. Int. Ed., 2023, 62, e202216863). Similar catalytic systems are commonly reported for the construction of axially chiral compounds, but there are few reports on isoquinolinone-type structures. In 2023, the research group of Niu Junlong developed a method for constructing isoquinolinone-type N-N axial chiral compounds by carbon-hydrogen activation using a cobalt-Salox ligand (Nat. Commun., 2023, 14, 5271), but the synthesis of the raw material requires the use of a large amount of expensive EDCI and HOBt.
[0005] In summary, the previous synthesis methods generally have problems such as difficulty in synthesizing raw materials or expensive materials used in the catalytic system, so there is a need to develop a method for obtaining N-N axial chiral compounds using more readily available raw materials and a mild and inexpensive system. SUMMARY
[0006] In view of the above problems existing in the prior art, the purpose of the present application is to provide a preparation method of N-N axial chiral isoquinolinone derivatives.
[0007] The technical solution adopted by the present application is as follows:
[0008] A preparation method of N-N axial chiral isoquinolinone derivatives, using 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione derivatives with the structure shown in formula 1 as the substrate, adding an oxidizing agent and a solvent, in the presence of a cobalt catalyst and a Salox ligand L, and reacting with an alkyne shown in formula 2 to generate (R)-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one derivatives with the structure shown in formula 3, and 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 halogen, acetylamino, methyl or tert-butyl; in formula 2 and formula 3, R 2 is selected from methyl, ethyl, propyl or butyl;
[0011] In formula 1 and formula 3, the directing group containing the R 1 group is selected from the following structures:
[0012]
[0013] Further, the cobalt catalyst is one or more of cobalt iodide, cobalt bromide, cobalt chloride, cobalt acetate tetrahydrate, cobalt acetylacetonate, preferably cobalt iodide or cobalt acetate tetrahydrate.
[0014] Further, the Salox ligand L is selected from L1, L2 or L3, and the structural formulae are as follows:
[0015]
[0016] Further, the oxidant is selected from one or more of silver carbonate, silver oxide, silver acetate, manganese acetate, preferably silver carbonate.
[0017] Further, the solvent is selected from one or more of dichloroethane, 1,4-dioxane, toluene, xylene, chlorobenzene, fluorobenzene, DMF, DMAc, NMP, preferably DMF, 1,4-dioxane or toluene.
[0018] Further, the molar ratio of the compound of 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 of 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 of formula 1 to the ligand L is 1:0.2-1:2.0, preferably 1:0.4-1:0.8; and the molar ratio of the compound of formula 1 to the oxidant is 1:1.0-1:3.0, preferably 1:1.5-1:2.0.
[0019] Further, the reaction temperature is 80-130℃, preferably 90-130℃.
[0020] Further, the reaction time is 12-36h, preferably 24-36h.
[0021] By using the above-mentioned technology, compared with the prior art, the present application has the following advantages:
[0022] The present application develops a method for constructing isoquinolinone derivatives with N-N axial chirality by using 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoindole-1,3-dione derivatives as raw materials, and by using a cheap metal cobalt and a cheap and easy-to-synthesize Salox ligand to catalyze decarbonylation and alkyne insertion reaction. The present application has the advantages of low catalyst consumption, mild reaction conditions, simple operation, wide applicability of substrates, good stereoselectivity and high yield, and has great application value.
[0023] When the raw materials and catalytic system of the present invention are used to carry out a decarbonylation-alkyne 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 The following were added into a pressure tube: 1,4-dioxane (1 mL), 2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a). The yield was 85% and the ee value was 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), silver carbonate (82.7 mg, 0.3 mmol) were added into a pressure tube, 1,4-dioxane (2 mL) was added, and the mixture was stirred 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 using petroleum ether: ethyl acetate = 5:1 as the eluent 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) in a yield of 83% and with 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 acetate tetrahydrate (10.0 mg, 0.04 mmol), ligand L1 (28.1 mg, 0.08 mmol), silver carbonate (82.7 mg, 0.3 mmol) were added into a pressure tube, 1,4-dioxane (2 mL) was added, and the mixture was stirred 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 using petroleum ether: ethyl acetate = 5:1 as the eluent 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) in a yield of 83% and with an ee value of 97%.
[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, 1,4-dioxane was removed by distillation under reduced pressure, and the product was purified by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent to afford (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, 1,4-dioxane was removed by distillation under reduced pressure, and the product was purified by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent to afford (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, 1,4-dioxane was removed by distillation under reduced pressure, and the product was purified by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent to afford (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, 1,4-dioxane was removed by distillation under reduced pressure, and the product was purified by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent to afford (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, 1,4-dioxane was removed by distillation under reduced pressure, and the product was purified by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent to afford (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 placed in a pressure tube. 1,4-dioxane (2 mL) was added, and the mixture was reacted at 110°C for 36 h. No target product was 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), and silver carbonate (82.7 mg, 0.3 mmol) were placed in a pressure tube. 1,4-dioxane (2 mL) was added, and the mixture was reacted at 110°C for 36 h. No target product was 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), and silver carbonate (82.7 mg, 0.3 mmol) were placed in a pressure tube. 1,4-dioxane (2 mL) was added, and the mixture was reacted at 110°C for 36 h. No target product was 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, 1,4-dioxane was removed by distillation under reduced pressure, and the product was purified by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent to afford (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] (R)-3,4-Diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) was prepared according to the procedure described in Example 14, using 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), manganese acetate (51.9 mg, 0.3 mmol). The reaction was carried out in 1,4-dioxane (2 mL) at 110 °C for 36 h. After the reaction was completed, the 1,4-dioxane was removed by distillation under reduced pressure. The residue was purified by column chromatography, eluting 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 61% yield with 97% ee.
[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] (R)-3,4-Diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) was prepared according to the procedure described in Example 14, using 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), manganese acetate (51.9 mg, 0.3 mmol). The reaction was carried out in 1,4-dioxane (2 mL) at 110 °C for 36 h. After the reaction was completed, the 1,4-dioxane was removed by distillation under reduced pressure. The residue was purified by column chromatography, eluting 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 61% yield with 97% ee.
[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, dichloroethane was removed by distillation under reduced pressure, and the product was purified by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent to afford (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, toluene was removed by distillation under reduced pressure, and the product was purified by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent to afford (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, xylene was removed by distillation under reduced pressure, and the product was purified by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent to afford (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, chlorobenzene was removed by distillation under reduced pressure, and the product was purified by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent to afford (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, fluorobenzene was removed by distillation under reduced pressure, and the product was purified by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent to afford (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, DMF was removed by distillation under reduced pressure, and the product was purified by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent to afford (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, DMAc was removed by distillation under reduced pressure, and the product was purified by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent to afford (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, NMP was removed by distillation under reduced pressure, and the product was purified by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent to afford (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, 1,4-dioxane was removed by distillation under reduced pressure, and the product was purified by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent to afford (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, 1,4-dioxane was removed by distillation under reduced pressure, and the product was purified by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent to afford (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] (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) was prepared according to the procedure described in Example 26, using 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), silver carbonate (82.7 mg, 0.3 mmol) and 1,4-dioxane (2 mL) as the solvent. The reaction was stirred at 110 °C for 24 h. After the reaction was completed, the 1,4-dioxane was removed by distillation under reduced pressure. The residue was purified by column chromatography using petroleum ether: ethyl acetate = 5:1 as the eluent 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 61% yield with 97% ee value.
[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] (R)-3,4-diethyl-2-(5,6,7,8-tetrahydro-9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one (3a) was prepared according to the procedure described in Example 26, using 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), silver carbonate (82.7 mg, 0.3 mmol) and 1,4-dioxane (2 mL) as the solvent. The reaction was stirred at 110 °C for 36 h. After the reaction was completed, the 1,4-dioxane was removed by distillation under reduced pressure. The residue was purified by column chromatography using petroleum ether: ethyl acetate = 5:1 as the eluent 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 75% yield with 97% ee value.
[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, 1,4-dioxane was removed by distillation under reduced pressure, and the product was purified by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent to afford (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, 1,4-dioxane was removed by distillation under reduced pressure, and the product was purified by column chromatography using petroleum ether:ethyl acetate = 5:1 as the eluent to afford (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, followed by 2 mL of toluene. The mixture was reacted at 120°C for 2 h. After completion of the reaction, the toluene was removed by vacuum distillation, and the product was purified by column chromatography using a 5:1 ratio of petroleum ether to ethyl acetate to afford (R)-3,4-dibutyl-2-(9H-pyrido[2,3-b]indol-9-yl)isoquinolin-1(2H)-one in an 88% yield and 97% ee.
[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 derivatives (1b-1n) (0.2 mmol), alkynes (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 the mixture was eluted by column chromatography with petroleum ether:ethyl acetate = 10:1-3:1 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 the implementation forms of the inventive concept, and the scope of protection 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 an NN axial 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. 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 phenyl, substituted phenyl or naphthyl, and the substituent of the substituted phenyl is selected from halogen, acetylamino, methyl or tert-butyl; in formula 2 and formula 3, R 2 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: ； The cobalt catalyst is one or more of cobalt iodide, cobalt bromide, cobalt chloride, cobalt acetate tetrahydrate, and cobalt acetylacetonate; The Salox ligand L is selected from L1, L2 or L3, and the structural formulas are shown below: ； The oxidizing agent is selected from one or more of silver carbonate, silver oxide, silver acetate, and manganese acetate; The solvent is selected from one of dichloroethane, 1,4-dioxane, toluene, xylene, chlorobenzene, fluorobenzene, DMF, DMAc, and NMP, or a mixture of two or more solvents.
2. The method for preparing an NN axial chiral isoquinolinone derivative according to claim 1, wherein: The molar ratio of the compound represented by Formula 1 to alkyne is 1:1.0-1:5.0; the molar ratio of the compound represented by Formula 1 to the cobalt catalyst is 1:0.1-1:1.0; the molar ratio of the compound represented by Formula 1 to the ligand L is 1:0.2-1:2.0; and the molar ratio of the compound represented by Formula 1 to the oxidant is 1:1.0-1:3.
0.
3. The method for preparing a NN axial chiral isoquinolinone derivative according to claim 1, wherein: The reaction temperature is 80-130 ℃.
4. The method for preparing an NN axial chiral isoquinolinone derivative according to claim 1, wherein: The reaction time is 12-36 h.
Citation Information
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