Preparation method of polysubstituted isoindolinone

A technology of isoindolinone and multi-substitution, which is applied in the field of preparation of multi-substituted isoindolinone, can solve the problems of difficult to obtain synthetic raw materials and cumbersome steps, and achieve the application value of large drug synthesis, wide substrate range, The effect of high yield

Active Publication Date: 2017-09-12
INST OF CHEM CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The current methods for preparing polysubstituted isoindolinones in organic synthesis have disadvantages such as difficult availability of synthetic raw materials and cumbersome steps. Therefore, it is necessary to provide a low-cost and simple method for preparing polysubstituted isoindolinones

Method used

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  • Preparation method of polysubstituted isoindolinone
  • Preparation method of polysubstituted isoindolinone
  • Preparation method of polysubstituted isoindolinone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1, 3-ethyl-3-benzyl-N-methylisoindolinone (formula Ⅰ-a)

[0026]

[0027] into a 25mL Schlenk bottle under N 2 Under the protection of N-methylbenzamide (formula Ⅱ-a) (1mmol, 135.2mg), 1-phenyl-1-butyne (formula Ⅲ-a) (1mmol, 130mg), catalyst pentacarbonyl Rhenium bromide (0.025mmol, 10.2mg), base lithium tert-butoxide (0.3mmol, 24mg) and solvent anisole (4mL) were reacted at 140°C, and after 36h, saturated NaHCO 3 Solution (10 mL) was used to quench the reaction, and then extracted with dichloromethane, and the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and spin-dried. After purification by column chromatography (eluent: petroleum ether: ethyl acetate = 5 / 1, v / v), 237 mg of the target product (Formula I-a) was obtained with a yield of 89%.

[0028] The target product is characterized as follows: 1 H NMR (300MHz, CDCl 3 ):7.63(d,J=7.5Hz,1H),7.51-7.53(m,1H),7.33(t,J=7.5Hz,1H),7.28(d,J=7.8Hz,1H),7.07-6.93 (m,3H),6.71-6.6...

Embodiment 2

[0029] Example 2, 3-ethyl-3-benzyl-5-fluoro-N-methylisoindolinone (formula Ⅰ-b)

[0030]

[0031] into a 25mL Schlenk bottle under N 2 Under protection, 5-fluoro-N-methylbenzamide (formula Ⅱ-b) (1mmol, 153.1mg), 1-phenyl-1-butyne (formula Ⅲ-a) (1mmol, 130mg) were added successively , Catalyst rhenium pentacarbonyl bromide (0.025mmol, 10.2mg), base lithium tert-butoxide (0.3mmol, 24mg) and solvent anisole (4mL), react at 140 ℃, after 36h, use saturated NaHCO 3 Solution (10 mL) was used to quench the reaction, and then extracted with dichloromethane, and the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and spin-dried. After purification by column chromatography (eluent: petroleum ether: ethyl acetate = 5 / 1, v / v), 261 mg of the target product (Formula I-a) was obtained with a yield of 92%.

[0032] The target product is characterized as follows: 1 H NMR (400MHz, CDCl 3 ):7.60(m,1H)7.06-7.00(m,4H),6.96(m,1H),6.74-6.71(m,2H),δ3.14(d,J=14Hz,1H)...

Embodiment 3

[0033] Example 3, 3-ethyl-3-benzyl-5-phenyl-N-methylisoindolinone (formula Ⅰ-c)

[0034]

[0035] into a 25mL Schlenk bottle under N 2 Under protection, 5-phenyl-N-methylbenzamide (formula Ⅱ-b) (1mmol, 211.2mg), 1-phenyl-1-butyne (formula Ⅲ-a) (1mmol, 130mg) were added successively ), the catalyst rhenium pentacarbonyl bromide (0.025mmol, 10.2mg), the base lithium tert-butoxide (0.3mmol, 24mg) and the solvent anisole (4mL), react at 150°C, and after 72h, use saturated NaHCO 3 Solution (10 mL) was used to quench the reaction, and then extracted with dichloromethane, and the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and spin-dried. After purification by column chromatography (eluent: petroleum ether: ethyl acetate = 5 / 1, v / v), 292 mg of the target product (Formula I-c) was obtained with a yield of 85%.

[0036] The target product is characterized as follows: 1H NMR (300MHz, CDCl 3 ):7.71(d,J=7.8Hz,1H),7.60-7.55(m,3H),7.47(m 2H),7.40-7.36...

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Abstract

The invention discloses a preparation method of polysubstituted isoindolinone. The structural formula of the polysubstituted isoindolinone is represented by formula I. The preparation method is characterized in that amide represented by formula II and alkyne represented by formula III undergo a [4+1] cyclization reaction in the presence of a catalyst under an alkaline condition to obtain the polysubstituted isoindolinone of formula I; in the formula I, the formula II and the formula III, R<1> represents a monosubstituent or a polysubstituent in a phenyl group, and is H, a substituted or unsubstituted C1-10 alkyl group, an aryl group, halogen or an aromatic ring obtained through fusion with the phenyl ring; in the formula II, when the R<1> represents the polysubstituted in the phenyl group, H in the at least one adjacent position of two adjacent positions of the an amido group is not substituted; R<2> represents a C1-10 alkyl group; R<3> represents a C1-10 alkyl group; and in the formula I and the formula III, Ar represents an aryl group or a heteroaryl group. The synthesis of the polysubstituted isoindolinone is realized through the reaction of the amide and the alkyne in the solvent in the presence of alkali and the rhenium catalyst.

Description

technical field [0001] The invention relates to a preparation method of multi-substituted isoindolinones, belonging to the field of chemical synthesis. Background technique [0002] In organic synthesis, multi-substituted isoindolinones can be used as important intermediates, and a variety of isoindoline derivatives with complex structures can be obtained by derivatization. Therefore, multi-substituted isoindolinones are a class of compounds with important application value in industry, medicine, agriculture and other fields. The current methods for preparing polysubstituted isoindolinones in organic synthesis have disadvantages such as unavailable raw materials and cumbersome steps. Therefore, it is necessary to provide a low-cost and simple method for preparing polysubstituted isoindolinones. Contents of the invention [0003] The purpose of the present invention is to provide a kind of preparation method of polysubstituted isoindolinone. [0004] The preparation metho...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/46C07D409/06
CPCC07D209/46C07D409/06
Inventor 王从洋靳喜庆
Owner INST OF CHEM CHINESE ACAD OF SCI
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