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Preparation method of 3-amino-4-piperidone and corresponding derivative thereof

A technology for piperidone and its derivatives, which is applied in the field of preparation of 3-amino-4-piperidone and its corresponding derivatives, and can solve the problem of low yield of synthetic routes, difficulties in separation and purification, poor selectivity of epoxy ring opening, etc. problems, to achieve the effect of ensuring reproducibility and stability, choosing a reasonable reaction process, and reducing synthesis costs

Inactive Publication Date: 2010-10-13
上海药明康德新药开发有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] 3-amino-4-piperidone and its corresponding derivatives are relatively important synthetic intermediates, but so far there is no very effective synthetic method to prepare this product. Two preparation methods have been reported in the literature
[0007] In literature synthesis routes 1 and 2, there is the same problem, that is, the selectivity of the key step epoxy ring opening is very poor, the yield is extremely low, and the separation and purification are extremely difficult, resulting in low yield of the whole synthesis route, which is difficult to scale Preparation
And in the document synthetic route 2, the raw material sodium azide used belongs to highly poisonous, explosive, unfavorable for expanding production

Method used

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  • Preparation method of 3-amino-4-piperidone and corresponding derivative thereof
  • Preparation method of 3-amino-4-piperidone and corresponding derivative thereof
  • Preparation method of 3-amino-4-piperidone and corresponding derivative thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] 1. Synthesis of 1-benzyloxycarbonyl-3-amino-4-piperidone hydrochloride

[0021] Step 1: Synthesis of 1-benzyloxycarbonyl-4-hydroxyiminopiperidine

[0022] The 1-benzyloxycarbonyl-4-piperidone (480 g, 2.1 mol), hydroxylamine hydrochloride (288.4 g, 4.12 mol), potassium carbonate (569 g, 4.12 mol) and ethanol (2000 mL) were heated to 50° C. to react for 0.5 h. The solvent was evaporated under reduced pressure, water (1000 mL) and ethyl acetate (2000 mL) were added to the residue, the phases were separated, the organic phase was washed with saturated brine and dried over sodium sulfate. After filtration, the filtrate was spin-dried under reduced pressure to obtain a pale yellow liquid, which was 1-benzyloxycarbonyl-4-hydroxyiminopiperidine (470 g, 1.88 mol, yield: 92%). 1 H NMR(400MHz, CDCl 3 ): δ7.1189(m, J=60.8Hz, 5H), δ5.082(d, J=120Hz 2H), δ3.513(m, J=28.0Hz, 4H), δ2.568(m, J= 30.4Hz, 2H); δ2.284 (m, J=67.4Hz, 2H).

[0023] Step 2: Synthesis of 1-benzyloxycarbonyl-4-hydr...

Embodiment 2

[0028] 1. Synthesis of 1-benzyloxycarbonyl-3-amino-4-piperidone hydrochloride

[0029] Step 1: Synthesis of 1-benzyloxycarbonyl-4-hydroxyiminopiperidine

[0030] Heat 1-benzyloxycarbonyl-4-piperidone (480g, 2.1mol), hydroxylamine hydrochloride (288.4g, 4.12mol), triethylamine (416.1g, 4.12mol) and dichloromethane (2000mL) to reflux for reaction 0.5h. After the reaction solution was cooled, it was washed with water (1000 mL) three times, and the organic phase was washed with saturated brine and dried over sodium sulfate. After filtration, the filtrate was spin-dried under reduced pressure to obtain a pale yellow liquid, which is 1-benzyloxycarbonyl-4-hydroxyiminopiperidine (450 g, 1.8 mol, yield: 88%).

Embodiment 3

[0032] 1. Synthesis of 1-benzyloxycarbonyl-3-amino-4-piperidone hydrochloride

[0033] Step 1: Synthesis of 1-benzyloxycarbonyl-4-hydroxyiminopiperidine

[0034] Heat 1-benzyloxycarbonyl-4-piperidone (480g, 2.1mol), hydroxylamine hydrochloride (288.4g, 4.12mol), sodium carbonate (436.7g, 4.12mol) and methanol (2000mL) to 50°C and react for 0.5h . The solvent was evaporated under reduced pressure, water (1000 mL) and ethyl acetate (2000 mL) were added to the residue, the phases were separated, the organic phase was washed with saturated brine and dried over sodium sulfate. After filtering, the filtrate was spin-dried under reduced pressure to obtain a pale yellow liquid, which was 1-benzyloxycarbonyl-4-hydroxyiminopiperidine (455 g, 1.82 mol, yield: 89%).

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Abstract

The invention relates to a preparation method of 3-amino-4-piperidone and a corresponding derivative thereof, aiming to solve the technical problems of complicated steps and lower yield in the original preparation process. The preparation method comprises the following steps of: reacting 1-R1-4-piperidone used as a raw material with hydroxylamine hydrochloride to generate 1-R1-4-hydroximino piperidine in the presence of akali; reacting the 1-R1-4-hydroximino piperidine with paratoluensulfonylchloride or methylsulfonylchloride to generate corresponding 1-R1-4-hydroximino piperidine tosylate or morphine methylsulfonate; carrying out Neber rearrangement on the 1-R1-4-hydroximino piperidine tosylate or the morphine methylsulfonate in the presence of sodium alkoxide, and carrying out acid treatment to obtain the halogen acid salts or sulfate and the like of 1-R1-3-amino-4-piperidone. The invention provides the method for effectively synthesizing the 3-amino-4-piperidone and the derivative intermediate thereof.

Description

Technical field: [0001] The invention relates to a preparation method of 3-amino-4-piperidone and its corresponding derivatives. Background technique: [0002] 3Amino-4-piperidone and its corresponding derivatives are important synthetic intermediates, but so far there is no very effective synthetic method to prepare this product. Two preparation methods have been reported in the literature. One method is to use Boc protected 1,2,3,6-tetrahydropyridine as the raw material, and then react with m-CPBA to generate the corresponding epoxy compound (Tetrahedron Lett. 2004, 45, 6841), and then with dimethyl ammonia The reaction obtains the ring-opened product (Chem. Commun.; 1962, 27, 2907), and the hydroxyl group is oxidized by sulfonylpyridine to obtain 3-amino-4-piperidone derivative. Another method is to use Cbz-protected 1,2,3,6-tetrahydropyridine as a raw material, react with m-CPBA to generate an epoxy compound, open the ring with sodium azide, and then reduce the azide with tr...

Claims

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Application Information

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IPC IPC(8): C07D211/74
Inventor 龚万本朱晨江郑宝江尹云星施一峰马汝建陈曙辉
Owner 上海药明康德新药开发有限公司
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