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Process for production of bicyclo[2.2.2]octylamine derivative

A production method and compound technology, which are applied in the field of production of bicyclo[2.2.2]octylamine derivatives, and can solve the problems of undisclosed methods and the like

Inactive Publication Date: 2011-07-06
KYORIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is no disclosure at all about the method of producing bicyclo[2.2.2]octylamine derivatives by combining primary amine compounds
[0011] Non-Patent Document 4 also discloses a method for forming a bicyclo[2.2.2]octyl skeleton, but for the formation of a bicyclo[2.2.2]octane skeleton while combining an amine compound to produce a bicyclo[2.2.2] Methods for octylamine derivatives are not disclosed at all

Method used

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  • Process for production of bicyclo[2.2.2]octylamine derivative
  • Process for production of bicyclo[2.2.2]octylamine derivative
  • Process for production of bicyclo[2.2.2]octylamine derivative

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0171] Embodiment 1 (operation 1 and 2)

[0172] 4-(Benzylamino)-2-oxobicyclo[2.2.2]octane-1-carboxylic acid ethyl ester

[0173] Toluene (100 mL) was added to ethyl 1-acetyl-4-oxocyclohexylcarboxylate (8.0 g, 38 mmol) and stirred. Benzylamine (5.3 mL, 49 mmol), p-toluenesulfonic acid monohydrate (76 mg, 0.40 mmol) were added thereto. Install a Dean-Stark apparatus, and stir under reflux for 8 hours under dehydration conditions. After cooling to room temperature, it was concentrated under reduced pressure to obtain a crude product. The obtained crude product was subjected to silica gel column chromatography (hexane-ethyl acetate) to obtain a mixture of the target product and an imine. This mixture was dissolved in chloroform (200 mL), and treated with 0.5 mol / L hydrochloric acid (100 mL). The suspended organic layer was collected, treated with 5% aqueous sodium bicarbonate solution, and separated. The organic layer was dried over anhydrous magnesium sulfate, the desiccant...

Embodiment 2

[0181] Embodiment 2 (operation 1 and 2)

[0182]4-(Benzylamino)-2-oxobicyclo[2.2.2]octane-1-carboxylic acid ethyl ester

[0183] Toluene (130 mL) was added to ethyl 1-acetyl-4-oxocyclohexylcarboxylate (12.9 g, 60.6 mmol) and stirred. Benzylamine (13.3 mL, 121 mmol), p-toluenesulfonic acid monohydrate (124 mg, 0.65 mmol) were added thereto. Install a Dean-Stark apparatus, and stir under reflux for 7 hours under dehydration conditions. After cooling to room temperature, 1 mol / L hydrochloric acid (130 mL) was added and stirred for 0.5 hours. Adjust to be alkaline with 2mol / L sodium hydroxide aqueous solution, separate organic layer, carry out quantitative analysis (LC), the yield of result target object is 75% (internal standard substance is 1,2,4-trimethylbenzene) .

Embodiment 3

[0184] Embodiment 3 (operation 1 and 2)

[0185] 4-(Benzylamino)-2-oxobicyclo[2.2.2]octane-1-carboxylic acid ethyl ester

[0186] Toluene (310 mL) was added to ethyl 1-acetyl-4-oxocyclohexylcarboxylate (31.0 g, 146 mmol) and stirred. Benzylamine (48.0 mL, 438 mmol), p-toluenesulfonic acid monohydrate (251 mg, 1.32 mmol) were added thereto. Install a Dean-Stark apparatus, and stir under reflux for 7 hours under dehydration conditions. After cooling to 20° C., 3 mol / L hydrochloric acid (155 g) was added dropwise, followed by stirring for 0.5 hours. A 6 mol / L aqueous sodium hydroxide solution was added dropwise thereto, followed by stirring for 10 minutes and performing liquid separation. The organic layer was washed twice with 155 g of an 18% aqueous ammonium chloride solution, and then washed with 62 g of water. Quantitative analysis (LC) of the organic layer revealed that the yield of the target substance was 95% (internal standard substance was m-xylene).

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Abstract

Disclosed is a production process which can synthesize a bicyclo[2.2.2]octylamine derivative (which can be used as an intermediate for the production of a pharmaceutical agent) efficiently under mild conditions in a large quantity. The bicyclo[2.2.2]octylamine derivative can be produced by cyclizing a compound represented by general formula (1) [wherein R1 represents an alkyl group having 1 to 6 carbon atoms which may have a substituent, an arylmethyl group which may have a substituent, or an arylethyl group which may have a substituent] with a compound represented by general formula (2): R2-NH2 [wherein R2 represents an alkyl group having 1 to 6 carbon atoms which may have a substituent, an aralkyl group which may have a substituent, a hydroxy group, an alkyloxy group having 1 to 6 carbon atoms which may have a substituent, or an aralkyloxy group which may have a substituent] and reducing the resulting product.

Description

technical field [0001] The present invention relates to the preparation method of bicyclo[2.2.2]octylamine derivatives. Background technique [0002] Bicyclo[2.2.2]octylamine derivatives represented by the general formula (8) are important as raw materials for medicines such as diabetes medicines (Patent Documents 1 to 3). [0003] [0004] [where, R 1 Represents an alkyl group with 1 to 6 carbon atoms that may have a substituent, an arylmethyl group that may have a substituent, or an arylethyl group that may have a substituent; [0005] R 3 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent, or an aralkyl group which may have a substituent]. [0006] In Patent Documents 1 to 3, bicyclo[2.2.2]octylamine derivatives can be produced, for example, from bicyclo[2.2.2]octyldicarboxylic acid derivatives. However, these Patent Documents 1 to 3 do not disclose at all a method of forming a bicyclo[2.2.2]octane skeleton by combini...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/16C07C229/50C07C251/20C07C251/44C07C309/66
CPCC07C2102/44C07C309/66C07C227/22C07C229/50C07C249/02C07C303/28C07C251/20C07C227/16C07C2602/44
Inventor 明星知宏入山友辅川浪弘贵
Owner KYORIN PHARMA CO LTD
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