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Preparation method of 3-carbonyl-2,8-diazepine helix[4.5]decane-8-carboxylic acid tert-butyl ester

A technology of tert-butyl carboxylate and diazepam is applied in the field of preparation of 3-carbonyl-2,8-diazaspiro[4.5]decane-8-carboxylate tert-butyl ester, and can solve the problem that the reaction product is difficult to Purification, single synthetic route and other problems, to achieve the effect of novel selection, high overall yield, cheap and easy to obtain reaction raw materials

Active Publication Date: 2010-11-03
SHANGHAI SYNTHEALL PHARM CO LTD
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Problems solved by technology

[0004] The purpose of the present invention is to provide a new route to effectively prepare 3-carbonyl-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester, which mainly solves the difficult purification of the reaction product of the existing synthetic method and the synthetic route A single technical problem, in addition to providing a method for the synthesis of an important intermediate 8-(tert-butoxycarbonyl)-3-carbonyl-2,8-diazaspiro[4.5]decane-4-carboxylic acid

Method used

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  • Preparation method of 3-carbonyl-2,8-diazepine helix[4.5]decane-8-carboxylic acid tert-butyl ester
  • Preparation method of 3-carbonyl-2,8-diazepine helix[4.5]decane-8-carboxylic acid tert-butyl ester
  • Preparation method of 3-carbonyl-2,8-diazepine helix[4.5]decane-8-carboxylic acid tert-butyl ester

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Embodiment 1

[0013] Synthesis of tert-butyl 3-carbonyl-2,8-diazaspiro[4.5]decane-8-carboxylate

[0014] Preparation of raw material tert-butyl-4-(2,2-dimethyl-4,6-dicarbonyl-1,3-dioxane-5-ylidene)piperidine-1-carboxylate: N- tert-butoxycarbonyl-4-piperidone (50g, 0.25mol), isopropylidene malonate (47g, 0.33mol), and triisopropyl borate (115mL, 0.5mol) were added to ethyl acetate (500mL) After stirring, aqueous ammonia solution (4.2 mL) and acetic acid (2.9 mL) were added in sequence, and stirred at room temperature for 24 hours. After the reaction, the reaction solution was directly filtered, and the filter cake was washed twice with ethyl acetate solution, 60 mL each time, to obtain the compound tert-butyl-4-(2,2-dimethyl-4,6-dicarbonyl-1 ,3-dioxan-5-ylidene)piperidine-1-carboxylate (81 g, 90.6% yield, 97% purity) as a white solid.

[0015] The first step (Micheal addition): Nitromethane (89.84g, 1.47mol) and sodium methoxide (79.41g, 1.47mol) were added to 1,4-dioxane (2.4L), heated to...

Embodiment 2

[0018] Synthesis of tert-butyl 3-carbonyl-2,8-diazaspiro[4.5]decane-8-carboxylate

[0019] Step 1 (Micheal addition): Nitromethane (4.01 g, 65.7 mmol) and sodium methoxide (3.55 g, 65.7 mmol) were added to 1,4-dioxane (100 mL), heated to 40° C., stirred 24 hours. Then the raw material tert-butyl-4-(2,2-dimethyl-4,6-dicarbonyl-1,3-dioxane-5-ylidene)piperidine-1-carboxylate (10.69g, 32.9mmol) was added into the reaction system and stirred for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was slurried with 10 mL of ethanol for 16 hours, filtered, and the filter cake was washed once with 8 mL of ethanol. The pale yellow solid was directly used in the next reaction.

[0020] The second step: replace the air in the hydrogenation bottle with argon, add Raney Ni (0.3g, 3%wt / wt), add 200ml of ethanol, add the solid obtained in the first step, adjust the hydrogen pressure to 55psi, and adjust the temperature to 60°C, stirring for 3 hou...

Embodiment 3

[0023]Synthesis of tert-butyl 3-carbonyl-2,8-diazaspiro[4.5]decane-8-carboxylate

[0024] Step 1 (Micheal addition): Nitromethane (4.01g, 65.7mmol) and sodium methoxide (3.55g, 65.7mmol) were added to 1,4-dioxane (100mL), heated to 30°C and stirred 10 hours. Then the raw material tert-butyl-4-(2,2-dimethyl-4,6-dicarbonyl-1,3-dioxane-5-ylidene)piperidine-1-carboxylate (10.69g, 32.9mmol) was added into the reaction system and stirred for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was slurried with 10 mL of ethanol for 16 hours, filtered, and the filter cake was washed once with 8 mL of ethanol. The pale yellow solid was directly used in the next reaction.

[0025] The second step: replace the air in the hydrogenation bottle with argon, add Raney Ni (0.7g, 7%wt / wt), add ethanol 200ml, add the solid obtained in the first step reaction, adjust the hydrogen pressure to 50psi, and adjust the temperature to 35°C, stirring for 3 ho...

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Abstract

The invention relates to a synthesis method of 3-carbonyl-2,8-diazepine helix[4.5]decane-8-carboxylic acid tert-butyl ester, mainly solving the technical problems of difficult reactant purification and the like in the traditional synthesis method and additionally providing a route for synthesizing an important intermediate, i.e. 8-(tert-butoxycarbonyl)-3-carbonyl-2,8-diazepine helix[4.5]decane-4-carboxylic acid. The synthesis method comprises the steps of: carrying out Micheal addition on an intermediate, i.e. tertiary butyl-4-(2,2-dimethyl-4,6-dicarbonyl-1,3-dioxan-5-ylene)piperidine-1-carboxylic ester and nitromethane to obtain a compound, i.e. tertiary butyl-4-(2,2-dimethyl-4,6-dicarbonyl-1,3-dioxan-5-group)-4-(nitromethyl)piperidine-1-carboxylic ester, then carrying out catalytic hydrogenation and lactamization to obtain a compound, i.e. 8-(butylcarbonyl)-3-carbonyl-2,8-diazepine helix[4.5]decane-4-carboxylic acid, and finally carrying out decarboxylation to obtain the final product, i.e. 3-carbonyl-2,8-diazepine helix[4.5]decane--8-carboxylic acid tert-butyl ester. The product of the invention is used as a template micromolecule for synthesizing various compound libraries.

Description

Technical field: [0001] The invention relates to a method for synthesizing tert-butyl 3-carbonyl-2,8-diazaspiro[4.5]decane-8-carboxylate. Background technique: [0002] tert-butyl 3-carbonyl-2,8-diazaspiro[4.5]decane-8-carboxylate, which can be used as a template small molecule to synthesize a variety of compound libraries, may be a future leader in the pharmaceutical industry The compound provides a new pharmacophore. For the preparation of tert-butyl 3-carbonyl-2,8-diazaspiro[4.5]decane-8-carboxylate, there are few reports in the literature. Paul W.Smith reported in March 1995 that tert-butyl-4-(2,2-dimethyl-4,6-dicarbonyl-1,3-dioxane-5-ylidene)piperidine- 1-Carboxylate was used as raw material, and 3-carbonyl-2,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl was prepared by two-step reaction. The reported synthetic route is short, but each step uses column chromatography purification. Wherein the first step is to complete under nitrogen protection, do solvent (10...

Claims

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Application Information

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IPC IPC(8): C07D471/10B01J25/02
Inventor 张赛丹张欣黄平周盛峰马汝建郭劲松陈民章唐苏翰
Owner SHANGHAI SYNTHEALL PHARM CO LTD
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