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Preparation method of homopiperazine and derivative thereof

A technology for homopiperazine and derivatives, which is applied in the field of compound preparation, can solve the problems of high consumption of raw materials, many by-products, serious equipment corrosion, etc., and achieves the effects of reducing production costs, mild reaction conditions and easy control.

Active Publication Date: 2012-12-12
CHENGDU XINJIE HIGH TECH DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The raw material consumption of this process is high, the yield is low, the finished product is high, there are many by-products, and the equipment is severely corroded.

Method used

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  • Preparation method of homopiperazine and derivative thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1 Preparation of 1-benzyloxycarbonyl-4-piperidone, refer to literature ("PROTECTIVE GROUPS IN ORGANIC SYNTHESIS" written by GREENE T.W., translated by the Organic Teaching and Research Group of East China University of Science and Technology, first edition in October 2004 by East China University of Science and Technology Press Chapter 7 pp. 494-653)

[0029] Combine 4-piperidone hydrochloride hydrate (7.68 kg) and potassium carbonate (20.7 kg), at 0°C, add water (50 liters), stir well, add dichloromethane (40 liters), and then dropwise add benzene A solution of methoxycarbonylsuccinimide (12.4 kg) in dichloromethane (80 liters) was reacted at room temperature for two hours. The reaction solution was separated, and the aqueous layer was extracted with dichloromethane (2×15 L). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain 11.5 kg of 1-benzyloxycarbonyl-4-piperidone as a colorless oil.

Embodiment 2

[0030] Embodiment 2 prepares 1-benzyloxycarbonyl-4-piperidone oxime

[0031] Dissolve the 1-benzyloxycarbonyl-4-piperidone oxime (7.2 kg) prepared in Example 1 with about ethanol (40 liters), add potassium carbonate (6.4 kg) and water (20 liters) solution, drop at 0°C Add a solution of hydroxylamine hydrochloride (2.57 kg) in water (20 L), and stir at room temperature for 3 hours. Concentrate ethanol under reduced pressure, add ethyl acetate to extract (4×15 L), combine organic phases, dry and concentrate to obtain white solid 1-benzyloxycarbonyl-4-piperidone oxime.

Embodiment 3

[0032] Embodiment 3 prepares 1-benzyloxycarbonyl-5-carbonyl homopiperazine

[0033] Dissolve 1-benzyloxycarbonyl-4-piperidone oxime (4.2 kg) and p-toluenesulfonyl chloride (3.55 kg) in 50 liters of acetone prepared in Example 2, and slowly add aqueous sodium hydroxide solution (7.4 kg) dropwise at 0°C. liters, 2.5 equivalents), reacted at 65°C for 3 hours. Concentrate the acetone under reduced pressure, add 20 liters of water, extract with ethyl acetate (4×15 liters), combine the organic layers, dry and concentrate to obtain 1-benzyloxycarbonyl-5-carbonylhomopiperazine as a white solid.

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Abstract

The invention discloses a preparation method of a homopiperazine derivative. The preparation method comprises the following steps of: (1) reacting 4-piperidone hydrochloride hydrate with an amino protective agent to prepare amino-protected 4-piperidone; (2) performing oximation reaction on the amino-protected 4-piperidone to prepare amino-protected 4-oxime piperidone; (3) performing molecular rearrangement on the amino-protected 4-oxime piperidone to prepare amino-protected 5-carbonyl homopiperazine; and (4) performing reduction reaction on the amino-protected 5-carbonyl homopiperazine to prepare amino-protected homopiperazine. The 4-piperidone hydrochloride hydrate is taken as a raw material, and is subjected to amino protection, oximation, rearrangement, reduction and deprotection to prepare the homopiperazine, and the amino-protected homopiperazine is reduced by sodium borohydride in the presence of an adjuvant to prepare the homopiperazine, so that lithium aluminum hydride which has high safety risk and cost in a preparation process of the conventional method is avoided. The whole process is easy to control, reaction conditions of each step are mild, the method is suitable forindustrial production, the yield is 75 percent, the raw material with low cost is used, and production cost is effectively reduced.

Description

technical field [0001] The invention relates to a method for preparing a compound, in particular to a method for preparing homopiperazine (or a derivative thereof) by an organic synthesis method. Background technique [0002] Homopiperazine, also known as 1,4-diazepane, molecular formula C 5 h 12 N 2 , relative molecular mass 100.16, white to light yellow crystal; melting point 42-45°C, boiling point 167°C, flash point 64°C; easily soluble in water, ethanol, benzene. The instrument detection parameters are: 1 H-NMR (400MHz, CDCl 3 ): δ2.71-2.66 (m, 8H, NCH 2 ), 1.99 (bs, 2H, NH), 1.52 (m, 2H, CH 2 ) ppm; 13 C-NMR (50MHz, CDCl 3 ): δ51.4, 47.8, 33.3ppm. [0003] Homopiperazine and its derivatives are important pharmaceutical intermediates and fine chemical raw materials with a wide range of applications. [0004] 1. As a pharmaceutical intermediate, homopiperazine can be used to synthesize homopiperazine hydrochloride, cyclizine, carbamazepine, quinolones and chlorc...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D243/08
Inventor 高建王晓玲李有章叶丁谢成莲
Owner CHENGDU XINJIE HIGH TECH DEV CO LTD
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