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A kind of chiral isoquinolinone compound and preparation method thereof

A technology for isoquinolinones and compounds, which is applied in the field of chiral isoquinolinone compounds and their asymmetric catalysis preparation, can solve the problems of high enantioselectivity of products, complex structures of chiral ligands or chiral catalysts, and poor operation. complex problems, to achieve the effect of easy separation and purification, novel and diverse structures, and high enantioselectivity

Active Publication Date: 2020-12-11
HANGZHOU NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In order to solve the problem of complex structures of chiral ligands or chiral catalysts in the current synthesis of chiral isoquinolinone compounds, and the complex operation of these methods, the present invention proposes a chiral isoquinolinone compound and a preparation method thereof , the reaction conditions are mild, the obtained product is stable in the air, the yield is high, the enantioselectivity of the product is high, and the product is easy to separate and purify

Method used

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  • A kind of chiral isoquinolinone compound and preparation method thereof
  • A kind of chiral isoquinolinone compound and preparation method thereof
  • A kind of chiral isoquinolinone compound and preparation method thereof

Examples

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Effect test

preparation example 1

[0045] Preparation example 1: the compound shown in structural formula (IIc)

[0046]

[0047] Dissolve 476mg of compound 1 and 924mg of ammonium acetate in 5mL of methanol, add 188mg of sodium cyanoborohydride to the resulting solution, heat at 70°C for 8 hours, and after cooling to room temperature, add 0.5mL of hydrogen with a concentration of 5mol / L Aqueous sodium oxide solution was stirred for 2 hours. After the reaction, 20 mL of water was added, the reaction solution was extracted with ethyl acetate for 3 times, the organic phase was washed with saturated brine for 3 times, and the organic phase was dried and concentrated to obtain the crude product shown in formula S-Ic, which was dissolved in 10 mL of dichloro Methane, then add 3mmol triethylamine and cool to 0°C, then add 381.2mg p-toluenesulfonyl chloride, react at room temperature for 3 hours, add 20mL water to the reaction system, extract the reaction solution three times with ethyl acetate, and combine the org...

Embodiment 1

[0048] Embodiment 1: prepare the chiral isoquinolinone of structure shown in formula Ia

[0049] The reaction formula is as follows:

[0050]

[0051] In a 30mL reaction tube, 109.6mg (0.3mmol) of the compound shown in IIa, 6.9mg (0.03mmol) of palladium acetate, 4.2mg (0.03mmol) of copper chloride, 6.5mg (0.09mmol) of L-Boc-Val-OH (chiral amino acid ligand shown in IIIa), 29.3mg (0.09mmol) of cesium carbonate dissolved in 3mL of isopropanol, successively fill the airbag with 60mL of carbon monoxide (2.7mmol), and 300mL of oxygen (12.4mmol), and combine the airbag with After the reaction tube was connected, the reaction system was heated to reflux at 80° C. for 48 hours. After cooling to room temperature, the reaction solution was filtered through a short silica gel column and fully eluted with ethyl acetate. After the eluent was concentrated, the resulting residue was separated and purified by flash silica gel column chromatography to obtain 73.9 mg of the compound represe...

Embodiment 2

[0053] Embodiment 2: prepare the chiral isoquinolinone compound of structure shown in formula Ib

[0054] The reaction formula is as follows:

[0055]

[0056] Using the same method as in Example 1, using 118.1 mg of the compound represented by IId as a raw material, 84.3 mg of the compound represented by the formula Ib was obtained with a yield of 67%. Utilize Waters 2695 high-performance liquid chromatography to test the compound shown in the Ib structure, the chromatographic column is a Dale AD-H column, and the mobile phase is n-hexane with a volume ratio of 95:5: isopropanol mixed solution, and the flow rate is 1mL / min, detection wavelength 254nm, major enantiomer retention time tr=28.1min, minor enantiomer retention time tr=23.0min. The result shows that the ee value of the compound shown in Ib is 75%, and this compound is a white solid, 1H NMR (400MHz, CDCl3) δ8.04(d, J=8.3Hz, 2H), 7.91(d, J=7.7Hz, 1H), 7.37(d, J=7.4Hz, 1H), 7.31(d, J =8.1Hz, 2H), 7.24(t, J=7.7Hz...

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Abstract

The invention provides a chiral isoquinolinone compound and a preparation method thereof to overcome the problems of complex structures of chiral ligands or chiral catalysts and complex operation in conventional methods for synthesis of chiral isoquinolinone compounds. According to the invention, a chiral amino acid ligand is used as a chiral induction source, and raw materials are allowed to undergo an intramolecular C-H / N-H carbonylation reaction in the presence of a palladium catalyst and a cocatalyst to form chiral lactam, so the chiral isoquinolinone compound is efficiently prepared in one step; reaction conditions are mild; the obtained chiral isoquinolinone compound is stable in air, high in yield, high in enantioselectivity, and easy to separate and purify.

Description

technical field [0001] The invention relates to the field of organic chemistry, in particular to a chiral isoquinolinone compound and an asymmetric catalytic preparation method thereof. Background technique [0002] The isoquinoline skeleton exists in many natural products and compounds with biological activity. For example, Tetrahydropalmatine (E.L.Sutin, D.M.Jacobowitz, Prog. Brain Res. 1991, 88, 3.), which has analgesic, sedative, hypnotic and stable effects, and Dichlorofensine (Ulin, J.; Gee, A.D.; Malmborg, P.; Tedroff, J.; B. Appl. Radiat. Isot. 1989, 40, 171; Kaczián, E.Z.; L.; Deák, G.; Seregi, A.; Dóda, M.J.Med.Chem.1986, 29, 1189.), compound 3 with antagonistic effect on protein-coupled receptors (P.S.Humphries et al, Bioorg.Med. Chem.Lett.2009,19,2400.), anti-tumor active substance Pancratistatin (T.Hudlicky; U.Rinner; D.Gonzalez; H.Akgun; S.Schilling; P.Siengalewicz; T.A.Martinot; G.R.Pettit; J. Org. Chem. 2002, 67, 8726.), etc. [0003] [0004] There...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D217/24
CPCC07B2200/07C07D217/24
Inventor 徐利文柏惺峰郑战江杨科芳郭彬徐征尹官武叶飞崔玉明曹建
Owner HANGZHOU NORMAL UNIVERSITY