Method for synthesizing 3,9-diaza spiro[5.5] undecane template compounds

A technique for the synthesis of diazaspiro compounds, which is applied in the field of preparation of spiro compounds, can solve the problems of harsh reaction conditions and low yields, and achieve the effects of short reaction routes, good biological activity, and favorable scale production

Inactive Publication Date: 2008-09-03
上海药明康德新药开发有限公司
View PDF4 Cites 5 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to provide efficient, mild conditions, a synthetic method of 3,9-diazaspiro[5.5]undecane template compound with large-scale preparation value, mainly to solve the existing 3,9-diazaspiro[5.5] 5.5] The synthetic method of undecane spiro compound has the technical problems of low yield and harsh reaction conditions

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Method for synthesizing 3,9-diaza spiro[5.5] undecane template compounds
  • Method for synthesizing 3,9-diaza spiro[5.5] undecane template compounds
  • Method for synthesizing 3,9-diaza spiro[5.5] undecane template compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] 1. Synthesis of 3-benzyl-3,9-diazaspiro[5.5]undecane

[0017]

[0018] Step 1: Synthesis of 9-benzyl-3,9-diaza-2,4-dioxo-1,5-dicyanospiro[5.5]undecane

[0019] A mixture of 159.7 g (0.844 mol) of N-benzylpiperidone and 191 g (1.689 mol) of ethyl cyanoacetate was dissolved in 12% ammonia ethanol solution, stirred evenly and left to stand in a zero-degree refrigerator for eight days. The resulting solid was filtered, washed with ethanol and ether in turn, then suspended in 910 mL of water, adjusted to pH 6 with 2M hydrochloric acid, stirred for one hour, re-filtered, washed with water, and vacuum-dried to obtain 177.2 g (65%) of light yellow solid.

[0020] The second step: Synthesis of 9-benzyl-3,9-diaza-2,4-dioxo-spiro[5.5]undecane

[0021] Take 32.2 g of 9-benzyl-3,9-diaza-2,4-dioxo-1,5-dicyanospiro[5.5]undecane and suspend it in 300 mL of sulfuric acid aqueous solution (30%). The oil bath was heated to 100°C and kept at this temperature for 18 hours. The ...

Embodiment 2

[0025] 2. Synthesis of 3-benzyl-3,9-diazaspiro[5.5]undecane

[0026]

[0027] Step 1: Synthesis of 9-benzyl-3,9-diaza-2,4-dioxo-1,5-dicyanospiro[5.5]undecane

[0028] A mixture of 159.7 g (0.844 mol) of N-benzylpiperidone and 191 g (1.689 mol) of ethyl cyanoacetate was dissolved in 12% ammonia ethanol solution, stirred evenly and left to stand in a zero-degree refrigerator for eight days. The resulting solid was filtered, washed with ethanol and ether in turn, then suspended in 910 mL of water, adjusted to pH 6 with 2M hydrochloric acid, stirred for one hour, re-filtered, washed with water, and vacuum-dried to obtain 177.2 g (65%) of light yellow solid.

[0029] The second step: Synthesis of 9-benzyl-3,9-diaza-2,4-dioxo-spiro[5.5]undecane

[0030] Take 32.2 g of 9-benzyl-3,9-diaza-2,4-dioxo-1,5-dicyanospiro[5.5]undecane and suspend it in 300 mL of phosphoric acid aqueous solution (50%). The oil bath was heated to 110°C and maintained at this temperature for 30 hour...

Embodiment 3

[0034] 3. Synthesis of 3-tert-butoxycarbonyl-3,9-diazaspiro[5.5]undecane

[0035]

[0036] Step 1: Synthesis of 3-tert-butoxycarbonyl-9-benzyl-3,9-diazaspiro[5.5]undecane

[0037] 5 g of 3-benzyl-3,9-diazaspiro[5.5]undecane was dissolved in 50 mL of anhydrous dichloromethane, and 3 g of triethylamine was added. Under ice bath cooling, slowly drop 5g Boc 2 O was dissolved in 10 mL of dichloromethane solution and stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was washed with water, dried and evaporated to dryness to obtain a crude product, which was purified by column chromatography to obtain 6.8 g (96%) of a white solid.

[0038] The second step: the synthesis of 3-tert-butoxycarbonyl-3,9-diazaspiro[5.5]undecane

[0039] 5 g of 3-tert-butoxycarbonyl-9-benzyl-3,9-diazaspiro[5.5]undecane was dissolved in 50 mL of absolute ethanol, and 0.5 g of 10% palladium on carbon was added. Under 50 PSI hydrogen pressure and 50°C o...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention relates to a process for preparing spiro compounds, more particularly, relates to a synthetic process for 3, 9-diazaspiro [5. 5] undecane template compounds. The invention is mainly to solve the technical problems that the existing synthetic method for 3, 9-diazaspiro [5. 5] undecane spiro compounds has low yield and harsh reaction conditions. The process comprises using N-benzyl piperidine-4-ketone and ethyl cyanoacetate as starting material, generating dicyanocarbodiimide B in colamine solution, hydrolyzing selective decarboxylation in acid environment to obtain carbodiimide C, reducing the carbodiimide C by Lithium aluminum hydride to obtain diamine D, combining the different protecting groups to obtain the target template compounds. The invention provides a highly effective synthetic process with mild conditions and large scale preparing value for 3, 9-diazaspiro [5. 5] undecane template compounds.

Description

Technical field: [0001] The invention relates to a preparation method of a spiro compound, in particular to a synthesis method of a 3,9-diazaspiro[5.5]undecane template compound. Background technique: [0002] Containing 3, the spiro compound of 9-diaza spiro [5.5] undecane structure has been proved to have better physiological activity, literature (Bioorganic & Medicinal Chemistry Letters 11 (2001) 1289-1292; US5451578; US6291460) once reported to 3,9-diazaspiro[5.5]undecane as the core of structure 1 compounds can be used as non-peptide glycoprotein antagonists to prevent thrombosis; it has been reported in document WO2005040167 that such compounds can be used to treat CCR8 receptor-related diseases, such as asthma. [0003] [0004] Regarding the synthesis method of 3,9-diazaspiro[5.5]undecane spiro compound, the literature reports can be found in US6291469. The method takes N-benzylpiperidin-4-one and ethyl cyanoacetate as starting materials, as shown in the followi...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/10
CPCY02P20/55
Inventor 陈华祥张宗华马汝建陈曙辉李革
Owner 上海药明康德新药开发有限公司
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap