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O-fluorine o-imidogen benzoic acid intermediate compound as well as preparation method and application thereof

A technology of o-iminobenzoic acid and compounds, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of high ee% value and high purity of intermediates, increase the difficulty of product separation, increase the complexity of reactions, etc., and achieve easy formation of final product, avoid reaction by-products, high reactivity effect

Active Publication Date: 2019-03-22
浙江东亚药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The combination of pyridine and triphenyl phosphite is a common method for activating carboxyl groups. However, since the two materials in the first step reaction contain carboxyl groups, if the materials are not added in an orderly manner, it is difficult to form a master due to the problem of activation activity. The one-pot method seems to simplify the operation, but actually increases the complexity of the reaction and the difficulty of separating the product
That is to say, most of the raw materials used in the existing preparation methods are difficult to purify, and cannot meet the requirements of high ee% value and high purity of the intermediate, and need to be improved.

Method used

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  • O-fluorine o-imidogen benzoic acid intermediate compound as well as preparation method and application thereof
  • O-fluorine o-imidogen benzoic acid intermediate compound as well as preparation method and application thereof
  • O-fluorine o-imidogen benzoic acid intermediate compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] In this example, the corresponding chirality is the compound of formula I of S (S)-2-((2-((tert-butoxycarbonyl)amino)-1-phenoxybutenyl)amino)-6-fluoro The concrete preparation of benzoic acid is as follows:

[0050]

[0051] Dissolve 10g (0.05mol) N-Boc-L-2-aminobutyric acid in an appropriate amount of 100mL toluene solvent, add 4g pyridine and 17g P(OPh) 3 Stir and mix evenly, continue to stir to activate the carboxylic acid completely, then add 8.5g of 2-amino-6-fluorobenzoic acid, heat up to 55°C to conduct the condensation reaction for 1.5 hours, and follow up to confirm that the reaction is complete; after the reaction, Add 1M hydrochloric acid to acidify the reaction solution, let it stand, separate layers, collect the organic layer, concentrate and remove the solvent to obtain 15.2 g of oil, which is (S)-2-((2-((tert-butoxycarbonyl)amino) -1-phenoxybutenyl)amino)-6-fluorobenzoic acid, the oil can be further purified by flash column separation to obtain pure p...

Embodiment 2

[0053] Dissolve 10g (0.05mol) N-Boc-L-2-aminobutyric acid in an appropriate amount of 150mL toluene solvent, add 6g pyridine and 16g P(OPh) 3 Stir and mix evenly, continue to stir to fully activate the carboxylic acid, then add 9.0 g of 2-amino-6-fluorobenzoic acid, raise the temperature to 60°C, and control the temperature at 60°C-65°C to carry out the condensation reaction for 1.0 hour, Follow up to confirm that the reaction is complete; after the reaction, add 1M hydrochloric acid to acidify the reaction solution, leave it to stand, separate layers, collect the organic layer and concentrate to remove the solvent to obtain an oil, which is (S)-2-((2-(( tert-butoxycarbonyl)amino)-1-phenoxybutenyl)amino)-6-fluorobenzoic acid, and the oil can be separated and purified by flash column to obtain pure product. The obtained (S)-2-((2-((tert-butoxycarbonyl)amino)-1-phenoxybutenyl)amino)-6-fluorobenzoic acid is carried out to corresponding structural analysis, the results show Its 1...

Embodiment 3

[0055] Dissolve 10g (0.05mol) N-Boc-L-2-aminobutyric acid in an appropriate amount of 150mL toluene solvent, add 7g pyridine and 18g P(OPh) 3 Stir and mix evenly, continue to stir to fully activate the carboxylic acid, then add 8.5 g of 2-amino-6-fluorobenzoic acid, raise the temperature to 75°C, and control the temperature at 75°C-80°C to carry out the condensation reaction for 1.0 hour, Follow up to confirm that the reaction is complete; after the reaction, add 1M hydrochloric acid to acidify the reaction solution, leave it to stand, separate layers, collect the organic layer and concentrate to remove the solvent to obtain an oil, which is (S)-2-((2-(( tert-butoxycarbonyl)amino)-1-phenoxybutenyl)amino)-6-fluorobenzoic acid, and the oil can be separated and purified by flash column to obtain pure product. The obtained (S)-2-((2-((tert-butoxycarbonyl)amino)-1-phenoxybutenyl)amino)-6-fluorobenzoic acid was subjected to structural analysis, and its 1H-NMR , 31 The P-NMR spectr...

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Abstract

The invention relates to an o-fluorine o-imidogen benzoic acid intermediate compound as well as a preparation method and application thereof, and belongs to the technical field of medicine intermediate synthesis. To solve the problems of hard separation and poor activity, the invention provides the o-fluorine o-imidogen benzoic acid intermediate compound as well as the preparation method and application thereof. The preparation method comprises the following steps: dissolving a compound shown by a formula II as shown in the specification with an organic solvent, then adding pyridine and triphenyl phosphate, stirring to activate carboxyl, and adding 2-amino-6-fluorobenzoic acid for a condensation reaction to obtain the corresponding o-fluorine o-imidogen benzoic acid intermediate compound.The intermediate compound provided by the invention is high in reaction activity and easy to activate, can be effectively applicable to synthesis of key intermediate raw materials of Idelalisib, and is relatively high in reaction stability, and an obtained corresponding intermediate product has the effects of high quality and high purity.

Description

technical field [0001] The invention relates to an o-fluoro-o-iminobenzoic acid intermediate compound and a preparation method and application thereof, belonging to the technical field of pharmaceutical intermediate synthesis. Background technique [0002] The chemical name of Idelalisib is 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]-(3H)-quinazolin-4-one, which The structural formula is shown in the following formula. [0003] [0004] There are many reports on the preparation methods of Idelalisib, and a key intermediate 2-[(1S)-1-aminopropyl]-5-fluoro-3-phenyl-4(3H )-quinazolone. [0005] [0006] For example, in WO2005 / 113556A, the earliest route to prepare the above-mentioned intermediate is to use 2-fluoro-6-nitrobenzoic acid as the initial raw material, react with an acyl chloride reagent to form an acid chloride, then condense with aniline, and react the obtained intermediate with an acyl chloride reagent Acyl chloride is obtained, and the obtain...

Claims

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Application Information

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IPC IPC(8): C07C269/06C07C271/22C07D239/91
CPCC07B2200/07C07C269/06C07C271/22C07D239/91Y02P20/55
Inventor 王海平池骋
Owner 浙江东亚药业股份有限公司
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