1-trifluoromethyl-2,8-diazospiro[4.5]decane derivative and preparation method thereof

A technology of trifluoromethyl and diaza, applied in the field of 1-trifluoromethyl-2,8-diaza-spiro[4.5]decane derivatives and its preparation, can solve the problem of limited space structure, There are few types of substituents, etc., to achieve weak inhibitory effect and improve drug-like properties

Inactive Publication Date: 2013-02-27
武汉药明康德新药开发有限公司 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves the problems of few types of substituents on the spiro ring of 2,8-diaza-spiro[4.5]decane compounds, limited space structure and the like. The introduction of trifluoromethyl at the 1 position is expected to change the electronic effect and steric effect of the molecular structure to achieve the purpose of improving its drug-like properties, and provides a synthesis method for this new type of compound

Method used

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  • 1-trifluoromethyl-2,8-diazospiro[4.5]decane derivative and preparation method thereof
  • 1-trifluoromethyl-2,8-diazospiro[4.5]decane derivative and preparation method thereof
  • 1-trifluoromethyl-2,8-diazospiro[4.5]decane derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1 : 1-carbonyl-2,8-diaza-spiro[4.5]decane-2,8-dicarboxylic acid-2-benzyl ester-8-tert-butyl ester 2 preparation of

[0055]

[0056] Steps:

[0057] Under nitrogen protection, add compound 1-carbonyl-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester in a dry three-necked flask 1 (5.0 g, 19.7 mmol) and tetrahydrofuran (25 mL), slowly added n-butyllithium (7.9 mL, 19.8 mmol, 2.5 moles per liter of n-hexane solution) under a dry-ice acetone bath. The reaction solution was stirred at -78°C for 30 minutes, and then a solution of benzyl chloroformate (2.89 mL, 20.0 mmol) in THF (10 mL) was slowly added. Slowly rise to room temperature and stir overnight, quench the reaction with (100 ml) saturated aqueous ammonium chloride solution, extract the reaction solution three times with (100 ml) ethyl acetate, and dry and concentrate the organic phase to obtain the product 1-carbonyl-2,8- Diaza-spiro[4.5]decane-2,8-dicarboxylate-2-benzyl-8-tert-butyl este...

Embodiment 2

[0058] Example 2 : 1-Hydroxy-1-trifluoromethyl-2,8-diaza-spiro[4.5]decane-2,8-dicarboxylate-2-benzyl-8-tert-butyl ester 3 preparation of

[0059]

[0060] Steps:

[0061] Under nitrogen protection, 1-carbonyl-2,8-diaza-spiro[4.5]decane-2,8-dicarboxylate-2-benzyl ester-8-tert-butyl 2 (6.8 g, 17.5 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and cesium fluoride (1.32 g, 8.8 mmol) and trifluoromethyltrimethylsilyl (7.5 g, 52.8 mmol) were added rapidly. After the reaction solution was stirred at room temperature for 2-3 hours, tetrabutylammonium fluoride (9.0 g, 34.5 mmol) was added, and the reaction solution was stirred at room temperature for 10 minutes. Concentration under reduced pressure, the crude product was subjected to silica gel column chromatography (petroleum ether / ethyl acetate=20:1) to obtain 1-hydroxy-1-trifluoromethyl-2,8-diaza-spiro[4.5]decane- 2,8-Dicarboxylic acid-2-benzyl ester-8-tert-butyl ester 3 , 3.6 grams, yield 45%.

[0062] 1 (...

Embodiment 3

[0063] Example 3 : tert-butyl 1-trifluoromethyl-2,8-diaza-spiro[4.5]decane-8-carboxylate 4 preparation of

[0064]

[0065] Steps:

[0066] 1-Hydroxy-1-trifluoromethyl-2,8-diaza-spiro[4.5]decane-2,8-dicarboxylate-2-benzyl-8-tert-butyl ester 3 (3.6 g, 7.9 mmol) was dissolved in methanol (150 ml), and wet palladium on carbon (0.45 g, palladium content was 10%) was added, and the reaction was stirred under 1 atmosphere of hydrogen pressure overnight. The reaction solution was filtered to remove palladium carbon, the mother liquor was concentrated, and silica gel column chromatography was used to obtain tert-butyl 1-trifluoromethyl-2,8-diaza-spiro[4.5]decane-8-carboxylate 4 , 0.44 grams, yield 18%.

[0067] 1 (400MHz, CDCl 3 ): 3.77 (s, 2H), 2.89-3.19 (m, 5H), 1.70-1.81 (m, 5H), 1.57-1.62 (m, 2H), 1.39 (s, 9H). Anal. Calcd. for C14H23F3N2O2 ( MS [M+H] + : 309.1784), Measured Mass: 309.1784. error: -0.2 ppm.

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Abstract

The invention relates to a novel 1-trifluoromethyl-2,8-diazospiro[4.5]decane derivative and a preparation method thereof, and mainly solves the problems of few types of substituent groups on the spiro ring system of a 2,8-diazospiro[4.5]decane compound, limited space structure and the like. The chemical structural formula is shown in the specification, wherein R1 is a substituent functional group or amino protective group and is one of H and C1-10 straight-chain or substituent-side-chain-containing benzyl, acyl, sulfonyl, urea or thiourea; and R2 is hydrogen or alkoxycarbonyl.

Description

technical field [0001] The invention relates to a preparation method of tert-butyl 1-trifluoromethyl-2,8-diaza-spiro[4.5]decane-8-carboxylate. Background technique [0002] 2,8-diaza-spiro[4.5]decane compounds are a class of molecules with special structures, which can effectively link key pharmacophore units into their rigid structures to form special spatial configurations / conformations Molecules, which can match the spatial structure of different biomacromolecules in the organism, produce different biological activities or effects, and have broad application value, especially as template compounds in the process of drug research. The present invention introduces a trifluoromethyl group at the 1-position of 2,8-diaza-spiro[4.5]decane, in order to change the electronic effect and steric effect of the molecular structure to improve its drug-like properties, and provides this Synthetic methods of novel compounds. The following are some examples that have been disclosed in s...

Claims

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Application Information

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IPC IPC(8): C07D471/10A61P35/00
CPCY02P20/55
Inventor 肖琳霞刘德军喻婷婷孙玮丽沈余红董径超吴颢马汝建陈曙辉林寿忠
Owner 武汉药明康德新药开发有限公司
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