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Preparation method for trans-(4-cyanomethyl)cyclohexyl tert-butyl carbamate

A technology of cyclohexyl carbamic acid and tert-butyl ester, which is applied to the preparation of carbamic acid derivatives, the preparation of organic compounds, chemical instruments and methods, etc. It can solve the problems of violent reaction, difficult control, flammability and explosion of sodium borohydride, etc. , to achieve the effect of high yield, short process route and simple operation

Inactive Publication Date: 2017-08-25
GUANGXI UNIVERSITY OF TECHNOLOGY
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0006] There are some defects in the above technical scheme: in the process of converting the compound of formula (II) into the compound of formula (III), it is necessary to use sodium borohydride to reduce, sodium borohydride is flammable and explosive, the reaction is violent, and it is difficult to control; in the process of formula (III) The highly toxic chemical methanesulfonyl chloride which is controlled by the state needs to be used in the process of converting the compound into the compound of formula (IV); the highly toxic chemical cyanide which is controlled by the state needs to be used in the reaction of the compound of formula (IV) being converted into the compound of formula (I). sodium chloride
Because the above-mentioned technical scheme needs to use flammable, highly toxic chemical raw materials, the industrial large-scale preparation of the compound of formula (I) is limited

Method used

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  • Preparation method for trans-(4-cyanomethyl)cyclohexyl tert-butyl carbamate
  • Preparation method for trans-(4-cyanomethyl)cyclohexyl tert-butyl carbamate
  • Preparation method for trans-(4-cyanomethyl)cyclohexyl tert-butyl carbamate

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Experimental program
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Effect test

Embodiment 1

[0026] Boc anhydride is reacted with trans-(4-cyanomethyl)cyclohexylcarbamate tert-butyl ester to protect the amino group to generate the compound of formula (V). The compound of formula (V) (25.7 g, 0.10 mol) was dissolved in 150 mL of tetrahydrofuran, carbonyldiimidazole (21.1 g, 0.13 mol) was added at room temperature, stirred for 3 h, then concentrated ammonia water (30 mL) was slowly added dropwise, and stirred for 3 h. After the reaction, the solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (200 mL), then washed with water (100 mL×2), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and recovered under reduced pressure to obtain the formula (VI) compound. The yield was 92%.

[0027] The compound of formula (VI) (25.6g, 0.10mol) was dissolved in 200mL of tetrahydrofuran, cooled to 0°C, triethylamine (70mL, 0.50mol) was added, stirred for 10min, and then trifluoroacetic anhydride (35mL, 0.25 mol), keep s...

Embodiment 2

[0029] Boc anhydride is reacted with trans-(4-cyanomethyl)cyclohexylcarbamate tert-butyl ester to protect the amino group to generate the compound of formula (V). Dissolve the compound of formula (V) (25.7g, 0.10mol) in 150mL of dioxane, add carbonyldiimidazole (21.1g, 0.13mol) at room temperature, stir for 2h, then slowly drop concentrated ammonia water (30mL), stir 3h. After the reaction, the solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (200 mL), then washed with water (100 mL×2), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and recovered under reduced pressure to obtain the formula (VI) compound. The yield was 90%.

[0030] Dissolve the compound of formula (VI) (25.6g, 0.10mol) in 200mL of dichloromethane, cool to 0°C, add triethylamine (70mL, 0.50mol), stir for 10min, then slowly drop trifluoroacetic anhydride (35mL , 0.25mol), insulated and stirred for 3h. After the reaction, the organic phase...

Embodiment 3

[0032]Boc anhydride is reacted with trans-(4-cyanomethyl)cyclohexylcarbamate tert-butyl ester to protect the amino group to generate the compound of formula (V). The compound of formula (V) (25.7g, 0.10mol) was dissolved in 150mL of tetrahydrofuran, Boc anhydride (26.2g, 0.12mol) and pyridine (10mL, 0.124mol) were added at room temperature, stirred for 3h, and then concentrated ammonia water ( 30mL), stirred for 3h. After the reaction, the solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate (200 mL), then washed with water (100 mL×2), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and recovered under reduced pressure to obtain the formula (VI) compound. The yield was 93%.

[0033] Dissolve the compound of formula (VI) (25.6g, 0.10mol) in 200mL of N,N-dimethylformamide, add pyridine (40mL, 0.50mol), stir at room temperature for 10min, then slowly drop phosphorus oxychloride (19mL , 0.20mol), stirred for 1h. ...

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Abstract

The invention relates to a preparation method for trans-(4-cyanomethyl)cyclohexyl tert-butyl carbamate. With trans-4-aminocyclohexylacetic acid as a starting material, amino protection is carried out, so that a compound shown as formula (V) is obtained; the carboxy group of the compound shown as formula (V) is amidated, so that a compound shown as formula (VI) is obtained; the compound shown as formula (VI) is dehydrated for elimination, so that a compound shown as formula (I), i.e. trans-(4-cyanomethyl)cyclohexyl tert-butyl carbamate, is obtained. The preparation method provided by the invention gets rid of easy burning and explosion and poisonous reagents ,such as sodium borohydride, methanesulfonyl chloride, and sodium cyanide reported in the existing literature; and moreover, the preparation method has the advantages of simple operation, short process route, high yield and the like, and is suitable for being applied to industrialized production.

Description

technical field [0001] The invention relates to the technical field of medicine synthesis, in particular to a preparation method of trans-(4-cyanomethyl)cyclohexylcarbamate tert-butyl ester. Background technique [0002] Trans-(4-cyanomethyl)cyclohexylcarbamate tert-butyl ester shown in formula (I) is an important intermediate of synthetic medicine, and the medicine synthesized by it is widely used in anti-infection, blood system disease, tumor, rheumatoid Treatment of arthritis and psoriasis. [0003] [0004] Documents WO2011157397, EP2527344, EP2397482, WO2012160030, Journal of Medicinal Chemistry, 2013, 56(11): 4764-4785, WO2013007768 and WO2013017461 respectively report technical schemes for preparing compounds represented by formula (I). The above-mentioned technical schemes all use trans-4-aminocyclohexylcarboxylic acid as the starting material, and successively undergo steps such as amino protection, carboxyl reduction, methanesulfonyl activation of hydroxyl and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/06C07C271/24
CPCC07C269/06C07C269/04C07C271/24
Inventor 蒋旭东黄晓程陈丽卢小玲廖兰王伟光
Owner GUANGXI UNIVERSITY OF TECHNOLOGY
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