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Synthesis of whorl(1-tetrahydronaphthalene-4,4'-piperidine) derivative

A synthetic method and technology of tetrahydronaphthalene, applied in the field of synthesis of spiro derivatives, achieve the effects of short synthetic route, high yield and convenient reaction operation

Inactive Publication Date: 2009-07-29
上海药明康德新药开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In summary, there is currently no practical method for the synthesis of spiro(1-tetralin-4,4'-piperidin-1-one) derivatives

Method used

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  • Synthesis of whorl(1-tetrahydronaphthalene-4,4'-piperidine) derivative
  • Synthesis of whorl(1-tetrahydronaphthalene-4,4'-piperidine) derivative
  • Synthesis of whorl(1-tetrahydronaphthalene-4,4'-piperidine) derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] 1. The preparation of compound (3):

[0018]

[0019] Add 20 ml of 5% aqueous sodium hydroxide solution and 10 ml of methanol into the reaction flask, and cool in an ice-water bath. 10 grams of o-bromoacetophenone was added to the reaction flask. After the addition was complete, 10 grams of 4-pyridinecarbaldehyde was added dropwise to the reaction over 90 minutes. After the addition was complete, the reaction was carried out at this temperature for 1.5 hours. After the reaction, water and tert-butyl methyl ether were added to separate the layers. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness to obtain the product compound 3 (8.6 g, Yield 60%).

[0020] 1H (300MHz, CDCl3) δ8.71-8.6(m, 2H), 7.6(d, J=4Hz, 1H), 7.48-7.36(m, 6H), 7.31(s, 1H), 7.28(s, 1H) .

[0021] 2. Preparation of compound (4):

[0022]

[0023] Ethanol (100 ml) and compound 3 (8.6 g) were added to th...

Embodiment 2

[0037] According to the reaction formula in the technical scheme, the alkali in the first step reaction is potassium carbonate, the solvent used is water, and the reaction temperature is -20-80°C; the second step reaction solvent is dichloromethane, and the reaction temperature is from room temperature to the reflux of the solvent temperature. In the third step, the reaction solvent is tetrahydrofuran; the base is sodium carbonate; the reaction temperature is from room temperature to the reflux temperature of the solvent; the benzyl halide of the alkylating reagent is benzyl chloride. The fourth step reaction solvent is dichloromethane; the reaction temperature is from room temperature to the reflux temperature of the solvent. The fifth step reaction solvent is benzene. All the other are identical with embodiment 1.

Embodiment 3

[0039] According to the reaction formula in the technical scheme, the alkali in the first step reaction is sodium carbonate, the solvent used is methanol and water, and the reaction temperature is -20-80°C; the second step reaction solvent is tetrahydrofuran, and the reaction temperature is from room temperature to the reflux of the solvent temperature. The third step reaction solvent is toluene; the base is sodium hydroxide; the reaction temperature is from room temperature to the reflux temperature of the solvent; the alkylating reagent benzyl halide is benzyl chloride. The fourth step reaction solvent is benzene; the reaction temperature is from room temperature to the reflux temperature of the solvent. The fifth step reaction solvent is toluene. All the other are identical with embodiment 1.

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Abstract

The invention relates to a method for synthesizing spiral (1-tetralin-4, 4'-piperidine-1-ketone) derivative. The method essentially solves the technical problems of the prior synthesis method of uneasily obtained raw materials, long route, inconvenient reaction operation, difficult post treatment, low yield, etc. The technical proposal is as follows: the invention uses o-bromoacetophenone which is simple and easily obtained as a raw material to react with 4-piperidine formaldehyde in alkali solution to obtain corresponding ketene which is reduced by reducing agent to obtain saturated alcohol; then the saturated alcohol reacts with benzyl halide in the alkali solution to obtain quaternary ammonium salt which is reduced into olefin; the olefin is reduced by alkyl tin agent and cyclized to obtain a corresponding spiral (1, 2, 3, 4-tetralin-4, 4'-piperidine-1-ketone) derivative protected by phenmethyl. A product obtained by the invention is mainly used as a drug intermediate.

Description

Technical field: [0001] The present invention relates to the synthesis method of spiro(1-tetrahydronaphthalene-4,4'-piperidin-1-one) derivatives. Background technique: [0002] Spiro(1-tetrahydronaphthalene-4,4'-piperidin-1-one) is a useful drug synthesis intermediate (J.Med.Chem.1992,35,2033-2039; J.Med.Chem .1992, 35, 2033-2039; 3919-3917; J.Med.Chem.1994, 37, 2574-2582; J.Med.Chem.1999, 42, 4778-4793) [0003] At present, the synthesis of such compounds mainly contains the following types: [0004] 1. Using ketones as raw materials, Eur.J.Med.Chem.1991, 26, 4778-4793 [0005] [0006] 2. Using 2-bromo-ylbenzene as raw material through multi-step synthesis. The method has a long process and a low yield, and the post-treatment is relatively complicated. (Arch. Pharm. (Weinheim Ger.); GE; 320; 5; 1987; 385-393. [0007] [0008] 3. Using 3,4-dihydro, 2-naketone as raw material, two-step synthesis. The raw materials of this method are uncommon, the reaction yield ...

Claims

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Application Information

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IPC IPC(8): C07D221/20
Inventor 张宗华王智勇马汝建陈曙辉李革
Owner 上海药明康德新药开发有限公司
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