Method for synthesizing 3,9-diaza-2-oxo-spiro[5.5] undecane template compounds

A synthetic method, diazepine technology, applied in the field of preparation of spirocyclic compounds, can solve the problems of harsh reaction conditions, incapable of large-scale production, low yield, etc., and achieve the effect of low cost and short reaction route

Inactive Publication Date: 2008-09-03
上海药明康德新药开发有限公司
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

[0008] The purpose of the present invention is to provide a high-efficiency, mild condition, and a synthetic method of 3,9-diaza-2-oxo-spiro[5.5]undecane template compound with large-scale preparation va...

Method used

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  • Method for synthesizing 3,9-diaza-2-oxo-spiro[5.5] undecane template compounds
  • Method for synthesizing 3,9-diaza-2-oxo-spiro[5.5] undecane template compounds
  • Method for synthesizing 3,9-diaza-2-oxo-spiro[5.5] undecane template compounds

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Embodiment 1

[0017] 1. Synthesis of 9-benzyl-3,9-diaza-2-oxo-spiro[5.5]undecane

[0018]

[0019] Step 1: Synthesis of 9-benzyl-3,9-diaza-2,4-dioxo-1,5-dicyanospiro[5.5]undecane

[0020] 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.

[0021] The second step: Synthesis of 9-benzyl-3,9-diaza-2,4-dioxo-spiro[5.5]undecane

[0022] 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...

Embodiment 2

[0026] 2. Synthesis of 9-benzyl-3,9-diaza-2-oxo-spiro[5.5]undecane

[0027]

[0028] Step 1: Synthesis of 9-benzyl-3,9-diaza-2,4-dioxo-1,5-dicyanospiro[5.5]undecane

[0029] 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.

[0030] The second step: Synthesis of 9-benzyl-3,9-diaza-2,4-dioxo-spiro[5.5]undecane

[0031] 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 ...

Embodiment 3

[0035] 3. Synthesis of 9-tert-butoxycarbonyl-3,9-diaza-2-oxo-spiro[5.5]undecane

[0036]

[0037] Step 1: Synthesis of 3,9-diaza-2-dioxo-spiro[5.5]undecane

[0038] 5 g of 9-benzyl-3,9-diaza-2-dioxo-spiro[5.5]undecane was dissolved in 80 mL of absolute ethanol, and 0.5 g of 10% palladium on carbon was added. Under 50 PSI hydrogen pressure and 50°C oil bath temperature, stir for 16 hours. The reaction was monitored by TLC. After the reaction was completed, the catalyst was filtered off and washed with ethanol. The filtrates were combined and used directly in the next reaction without treatment.

[0039] The second step: the synthesis of 9-tert-butoxycarbonyl-3,9-diaza-2-dioxo-spiro[5.5]undecane

[0040] Add 4.6g Boc dropwise to the filtrate obtained in the previous step 2 A solution of O dissolved in 10 mL of ethanol was stirred at room temperature for 3 hours. The reaction was monitored by TLC. After the reaction was completed, it was concentrated under reduced...

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Abstract

The invention relates to a process for preparing spiro compounds, more particularly, relates to a synthetic process for 3, 9-diaza-2-oxo-spiro [5. 5] undecane template compounds. The invention is mainly to solve the technical problems that the existing synthetic method for 3, 9-diaza-2-oxo-spiro [5. 5] undecane has low yield and harsh reaction conditions and is not suitable for large scale product. The process comprises using N-benzyl piperidine-4-ketone A and ethyl cyanoacetate as starting material, generating dicyanocarbodiimide B in colamine solution, hydrolyzing selective decarboxylation in acid environment to obtain carbodiimide C, selectively reducing the carbodiimide C to obtain diamine D, combining the different protecting groups to obtain the target template compounds after hydrogenating and debenzyl. The invention provides a synthetic process with a short reaction line, low cost and large scale preparing value for 3, 9-diaza-2-oxo-spiro [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-diaza-2-oxo-spiro[5.5]undecane template compound. Background technique: [0002] The spiro compound containing 3,9-diaza-2-oxo-spiro[5.5]undecane structure has been proved to have good physiological activity, and the document WO2005097795 has reported that the structure 1 compound has neurokinin Antagonistic activity, especially the antagonistic activity of N1, N1 / N2 combination, N1 / N2 / N3 combination. It can be used to treat or prevent schizophrenia, vomiting, anxiety and depression, acute bowel syndrome (IBS), circadian rhythm disturbances, preconvulsions, pain (especially visceral and neuropathic pain), pancreatitis, neurogenic inflammation, related diseases such as asthma. [0003] [0004] Regarding the synthesis method of 3,9-diaza-2-oxo-spiro[5.5]undecane, the literature reports can be found in WO2005097795. Its reaction formula ...

Claims

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Application Information

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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
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