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Resolution of 1-cyclohexyl-2-(5H-imidazole[5,1-a]isobenzazole)ethyl-1-ketone

A technology of cyclohexyl and rac-1 is applied to the chemical separation and preparation of a pair of enantiomers, and the separation technology field of imidazoisoindole compounds, which can solve the problem of high cost of chiral chromatographic columns and high separation capacity. Less problems, high cost, good industrial application prospects, less environmental pollution, and easy recycling

Active Publication Date: 2018-07-03
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But the cost of chiral chromatographic column is high, the amount of separation is small, it takes a long time and the cost is high

Method used

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  • Resolution of 1-cyclohexyl-2-(5H-imidazole[5,1-a]isobenzazole)ethyl-1-ketone
  • Resolution of 1-cyclohexyl-2-(5H-imidazole[5,1-a]isobenzazole)ethyl-1-ketone
  • Resolution of 1-cyclohexyl-2-(5H-imidazole[5,1-a]isobenzazole)ethyl-1-ketone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] (1) Salt forming process

[0033] In a 50mL round bottom flask, add 90mg rac-1 (chiral HPLC analysis results see attached figure 1 ) and 156mg of L-di-p-toluyl tartaric acid monohydrate, then add 4mL of dichloromethane and 0.3mL of petroleum ether to dissolve. Static crystallization, suction filtration, to obtain salt complex crystals. Wash with a small amount of dichloromethane and dry to obtain 36 mg of (S)-1 and L-di-p-methylbenzoyl tartrate complex.

[0034] (2), dissociation process

[0035] Suspend 36 mg of the above salt complex in 10 mL of water, add saturated sodium carbonate solution to adjust the pH to 9-10, and stir at room temperature for 10 min. After extraction with dichloromethane, the organic phase was collected and dried under reduced pressure to obtain 7 mg of (S)-1. Yield: 16%, ee=98% (t R (major) = 21.22min, t R (minor)=31.46min, chiral HPLC analysis result sees attached figure 2 ). [α] D 23 =-85.6 (c=0.9, CH 3 OH). ECD(CH 3 OH): Δε 29...

Embodiment 2

[0037] (1) Salt forming process

[0038] In a 50mL round bottom flask, add 85mg rac-1, 175mg D-di-p-methylbenzoyl tartaric acid, then add 0.5mL petroleum ether and 10mL dichloromethane to dissolve. Static crystallization, suction filtration, to obtain salt complex crystals. Wash with a small amount of dichloromethane and dry to obtain the complex of (R)-1 and D-di-p-methylbenzoyl tartrate.

[0039] (2), dissociation process

[0040] Suspend the above salt complex in 10 mL of water, add saturated sodium carbonate solution to adjust pH=9-10, and stir at room temperature for 10 min. After extraction with dichloromethane, the organic phase was collected and dried under reduced pressure to obtain 13 mg of (R)-1. Yield: 30.6%, ee>98% (t R (major) = 27.36 min, t R (minor)=20.38min, chiral HPLC analysis result sees attached image 3 ). [α] D 23 =+81.0 (c=0.5, CH 3 OH). ECD(CH 3 OH): Δε 296.5 (+2.03), 265.5 (-2.30), 226.5 (-3.81), 200 (+19.58).

[0041] (3) Absolute configur...

Embodiment 3

[0045] (1) Salt forming process

[0046] In a 50mL round bottom flask, add 30mg rac-1, 62mg L-di-p-toluoyl tartaric acid, then add 0.1mL n-hexane and 1.5mL dichloromethane to dissolve. Static crystallization, suction filtration, to obtain salt complex crystals. Wash with a small amount of dichloromethane and dry to obtain 35 mg of (S)-1 and L-di-p-methylbenzoyl tartrate complex.

[0047] (2), dissociation process

[0048] Suspend the above salt complex in 10 mL of water, add saturated sodium carbonate solution to adjust pH=9-10, and stir at room temperature for 10 min. Extract with dichloromethane, collect the organic phase, and dry under reduced pressure to obtain (S)-1, ee=85%.

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Abstract

The invention provides a method for obtaining a pair of optical isomers by resolving racemic 1-cyclohexyl-2-(5H-imidazole[5,1-a]isobenzazole)ethyl-1-ketone (rac-1) shown in a formula rac-1. The methodcomprises the following steps: by taking L-di-p-methyl benzoyl tartrate or a hydrate thereof as a resolving agent, resolving in a mixed solvent system, thus obtaining a compound of (S)-1 and L-di-p-methyl benzoyl tartrate; enabling the compound to be free in water or alcoholic solution to obtain (S)-1, and classifying absolute configuration of a sample by comparing theoretic electronic circular dichroism with the practical electronic circular dichroism; and by virtue of the same steps, taking D-di-p-methyl benzoyl tartrate or a hydrate thereof as the resolving agent, and obtaining (R)-1. Themethod provided by the invention is simple to operate and high in resolution efficiency, the resolving agent is easy to recycle, and environmental pollution is low, so that the method is applicable tolarge-scale preparation and industrial production. (The formula rac-1 is described in the specification).

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a resolution technology of imidazoisoindole compound, specifically, it relates to 1-cyclohexyl-2-(5H-imidazol[5,1-a]isoindole The chemical resolution preparation method of a pair of enantiomers of indole) ethyl-1-one. Background technique [0002] Compound 1-cyclohexyl-2-(5H-imidazo[5,1-a]isoindole)ethyl-1-one (hereinafter referred to as rac-1) is a synthetic indoleamine-2,3-dioxy Key intermediate of enzyme 1 (IDO1) inhibitor NLG919. IDO1 catalyzes the intracellular tryptophan reaction to generate kynurenine, and is the initial and rate-limiting step enzyme of the kynurenine metabolic pathway. In antigen-presenting cells and various tumor tissues, the expression level of IDO1 is abnormally increased, and tumor cells may escape the recognition of the immune system through the high expression of IDO1, resulting in immune tolerance. NLG919 rever...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07B2200/07C07D487/04
Inventor 李莉刘文强张洁杨蓓蓓
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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