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Preparation method for trans-4-alkoxycyclohexylamine

A technology of alkoxycyclohexylamine and hydroxycyclohexylamine, which is applied in the field of pharmaceutical intermediates, can solve the problems of high product loss, low product yield, and difficult operation, and achieve high total yield, environmental friendliness, and easy measurement produced effect

Active Publication Date: 2018-01-12
SHANGHAI BALMXY PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] However, in this route, the tert-butoxycarbonyl group causes more product loss during the protection and deprotection process, and at the same time, due to its own melting point problem, it is not conducive to the operation in industrial production, and in the process of methyl etherification in this route Often intramolecular ring closure generates by-products of oxazol-2 ketones, resulting in low product yields in this route
[0012] This shows, all there is certain defective in the existing route, is not easy to operate, and yield is low, easy to pollute etc.

Method used

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  • Preparation method for trans-4-alkoxycyclohexylamine
  • Preparation method for trans-4-alkoxycyclohexylamine
  • Preparation method for trans-4-alkoxycyclohexylamine

Examples

Experimental program
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Effect test

Embodiment 1

[0059] In this embodiment, trans-4-methoxycyclohexylamine is prepared by the following preparation method, which method includes the following steps:

[0060] (1) Preparation of the trans-4-hydroxycyclohexylamine of trityl protection:

[0061]

[0062] Trans-4-hydroxycyclohexylamine (115 g, 1 mol) was dissolved in dichloromethane (2 L), and triethylamine (121 g, 1.2 mol) was added with stirring, and the reaction system dropped to zero. Then trityl chloride (284g, 1.02mol) was added portion by portion, the reaction was slowly warmed up to room temperature and stirred for 5 hours, the reaction solution was washed with 10% citric acid, washed with saturated brine, dried over anhydrous sodium sulfate, and off-white Powder, crystallized with ethyl acetate petroleum ether to obtain 332g of pure product, yield 93%.

[0063] (2) Preparation of trans 4-methoxycyclohexylamine protected by trityl group:

[0064]

[0065] The compound obtained in step (1) (250 g, 0.7 mol) was diss...

Embodiment 2

[0071] In the present embodiment, trans-4-isopropoxycyclohexylamine is prepared by the following steps, the method comprising the following steps:

[0072] (1) Preparation of the trans-4-hydroxycyclohexylamine of trityl protection:

[0073]

[0074] Trans-4-hydroxycyclohexylamine (115 g, 1 mol) was dissolved in dichloromethane (2 L), and triethylamine (151.25 g, 1.5 mol) was added with stirring, and the reaction system dropped to zero. Then trityl chloride (278g, 1mol) was added portion by portion, the reaction was slowly warmed up to room temperature and stirred for 10 hours, the reaction solution was washed with 10% citric acid, washed with saturated brine, and dried over anhydrous sodium sulfate to obtain off-white powder , crystallized with ethyl acetate petroleum ether to obtain 327g of pure product, yield 91.6%.

[0075] (2) Preparation of trans 4-isopropoxycyclohexylamine protected by trityl group:

[0076]

[0077] The compound obtained in step (1) (250 g, 0.7 ...

Embodiment 3

[0083] In the present embodiment, trans-4-butoxycyclohexylamine is prepared through the following steps, the method comprising the following steps:

[0084] (1) Preparation of the trans-4-hydroxycyclohexylamine of trityl protection:

[0085]

[0086] Trans-4-hydroxycyclohexylamine (115 g, 1 mol) was dissolved in dichloromethane (2 L), and triethylamine (101 g, 1 mol) was added with stirring, and the reaction system dropped to zero. Then trityl bromide (505g, 1.5mol) was added portion by portion, the reaction was slowly warmed up to room temperature and stirred for 1 hour, the reaction solution was washed with 10% citric acid, washed with saturated brine, dried over anhydrous sodium sulfate, and off-white Powder, crystallized with ethyl acetate petroleum ether to obtain 306g of pure product, yield 85.7%.

[0087] (2) Preparation of the trans-4-butoxycyclohexylamine of trityl protection:

[0088]

[0089] The compound obtained in step (1) (250 g, 0.7 mol) was dissolved i...

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Abstract

The invention provides a preparation method for trans-4-alkoxycyclohexylamine. The method includes the following steps: (1) trans-4-hydroxycyclohexylamine reacts with triphenylmethyl halide, so that triphenylmethyl-protected trans-4-hydroxycyclohexylamine shown as formula I is obtained; (2) the solution of triphenylmethyl-protected trans-4-hydroxycyclohexylamine shown as formula I is added with sodium hydride, and is then added with halogenated alkane to react, so that triphenylmethyl-protected trans-4-alkoxycyclohexylamine shown as formula II is obtained; (3) triphenylmethyl-protected trans-4-alkoxycyclohexylamine shown as formula II undergoes deprotection reaction, so that trans-4-alkoxycyclohexylamine is obtained. By utilizing the preparation method, the flow of the preparation processfor trans-4-alkoxycyclohexylamine is simpler and environmentally friendly, irritation and allergens do not exist, industrial production is easy to operate, total yield is high, and mass production iseasy.

Description

technical field [0001] The invention relates to the field of pharmaceutical intermediates, in particular to a preparation method of trans-type 4-alkoxycyclohexylamine. Background technique [0002] Trans-4-alkoxycyclohexylamine is a pharmaceutical intermediate, which can be used to produce the antidiabetic drug glimepiride. The synthetic technique of trans 4-alkoxycyclohexylamine mainly contains following 3 kinds of methods at present: [0003] The first method starts from the trans 4-hydroxycyclohexylamine, by connecting the amino group with a bisbenzyl group, then reacting with an alkyl halide to convert the hydroxyl group into an alkoxy group, and then hydrogenating to remove the bisbenzyl group to obtain the trans 4-hydroxycyclohexylamine. 4-hydroxycyclohexylamine, the reaction process is as follows: [0004] [0005] But in this route, the first step of double benzylation needs to use benzyl bromide or benzyl chloride, these two substances have great irritation and...

Claims

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Application Information

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IPC IPC(8): C07C213/08C07C213/06C07C215/44C07C217/52
Inventor 吴天俊
Owner SHANGHAI BALMXY PHARMA CO LTD
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