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Preparation method of trans-4-(tert-butyloxycarbonylamino) cyclohexane carboxylic acid and intermediate thereof

A technology of tert-butoxycarbonylamino and cyclohexanecarboxylic acid, which is applied in the preparation of carbamic acid derivatives, cyanide reaction preparation, organic compound preparation, etc., can solve the problems of product yield to be improved, large molecular weight of protective group, and raw material No problems such as commercialization, easy to industrial production, easy to operate, easy to control the effect of the reaction

Active Publication Date: 2021-09-17
CHONGQING MEDICAL & PHARMA COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After recrystallization and purification, deamination protection, condensation with (Boc)2O (di-tert-butyl dicarbonate) to obtain trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid, but its raw material is not commercialized, the product The yield still needs to be improved, and the molecular weight of the protecting group is large, so the carbon emission is uneconomical

Method used

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  • Preparation method of trans-4-(tert-butyloxycarbonylamino) cyclohexane carboxylic acid and intermediate thereof
  • Preparation method of trans-4-(tert-butyloxycarbonylamino) cyclohexane carboxylic acid and intermediate thereof
  • Preparation method of trans-4-(tert-butyloxycarbonylamino) cyclohexane carboxylic acid and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1 Preparation of trans-4-tert-butylsulfinamide cyclohexanecarboxylate

[0035] At room temperature, add (R)-tert-butylsulfinamide 14.5g (1.2eq) and ethyl titanate 44ml (1.2eq) to 150ml of toluene solution of 17g ethyl 4-ketocyclohexanecarboxylate, 70°C Stir under heating for 1 hour. After the reaction is completed, cool to room temperature, add 6.4g (1.5eq) of sodium borohydride in batches, and stir for 2 hours. After the reaction, add 50ml of methanol (quenched) and continue stirring for 30 minutes. The ratio of trans product to cis product is 90:10 , adding saturated brine to wash, the organic phase was filtered for insoluble matter, and then concentrated under reduced pressure to obtain 22 g of the target compound, with a yield of 80%. LC / MS: 275.

Embodiment 2

[0036] Example 2 Preparation of trans-4-tert-butylsulfinamide cyclohexanecarboxylate

[0037] At room temperature, 14.5 g (1.2 eq) of (R)-tert-butylsulfinamide and 44 ml (1.2 eq) of ethyl titanate were added to 150 ml of a toluene solution of 19.8 g of 4-ketocyclohexanecarboxylate tert-butyl, Heat and stir at 70°C for 1 hour. After the reaction is completed, cool to room temperature, add 6.4g (1.5eq) of sodium borohydride in batches, and stir for 2 hours. After the reaction, add 50ml of methanol and continue stirring for 30 minutes. The ratio of trans product to cis product is 98:2, and saturated salt is added. After washing with water, the organic phase was filtered for insoluble matter, and then concentrated under reduced pressure to obtain 28 g of the target compound, with a yield of 92.5%. LC / MS: 303.

Embodiment 3

[0038] Example 3 Preparation of trans-4-tert-butylsulfinamide cyclohexanecarboxylate

[0039] At room temperature, add (R)-tert-butylsulfinamide 14.5g (1.2eq) and ethyl titanate 44ml (1.2eq) to 150ml of toluene solution of 15.6g of methyl 4-ketocyclohexanecarboxylate, 70 It was heated and stirred at ℃ for 1 hour. After the reaction is completed, cool to room temperature, add 6.4g (1.5eq) of sodium borohydride in batches, and stir for 2 hours. After the reaction, add 50ml of methanol and continue stirring for 30 minutes. The ratio of trans product to cis product is 91:9 and add saturated saline After washing, the organic phase was filtered for insoluble matter, and then concentrated under reduced pressure to obtain 20.6 g of the target compound, with a yield of 79%. LC / MS: 261.

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Abstract

The invention provides a preparation method of trans-4-(tert-butyloxycarbonylamino) cyclohexane carboxylic acid and an intermediate thereof, which is characterized by comprising the following preparation steps of: taking 4-oxo-cyclohexane carboxylic ester and a chiral ligand reagent tert-butyl sulfinamide as raw materials; obtaining the trans-4-(tert-butyloxycarbonylamino) cyclohexane carboxylic acid throughreductive amination under catalysis of lewis acid. According to the present invention, the intermediate obtained through chiral ligand reagent tert-butyl sulfinamide and 4-oxo-cyclohexane carboxylate condensation is adopted, such that the reduction reaction has high stereoselectivity, the trans-product ratio is more than 95%, meanwhile, the tert-butyl sulfinyl group is stable under an alkaline condition and is easy to leave under an acidic condition, the reaction condition is mild, the operation is simple and convenient, the yield is high, and industrial production is easy.

Description

technical field [0001] The invention relates to a preparation method of trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid and its intermediate trans-4-tert-butylsulfinamide cyclohexanecarboxylate, which belongs to the field of organic synthesis. Background technique [0002] There are two vertical isomers of 4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid: cis-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid and trans-4-(tert-butoxycarbonylamino) ) cyclohexane carboxylic acid, among which trans-4-aminocyclohexane carboxylic acid (ACCA) and its derivatives are one of the important pharmaceutical intermediates, mainly used to synthesize short peptides, polypeptides, isoquinuclidone, etc. drugs. Trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid is a derivative of ACCA and is one of the important building blocks for constructing active drugs. [0003] European Journal al of Medicinal Chemistry, 2001, vol.36, #3, p.265-286 reported using 4-am...

Claims

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Application Information

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IPC IPC(8): C07C313/06C07C269/04C07C269/06C07C271/24C07C227/20C07C229/48
CPCC07C313/06C07C269/04C07C227/20C07C2601/14C07B2200/09C07C229/48C07C271/24Y02P20/55
Inventor 杨延音孙化富
Owner CHONGQING MEDICAL & PHARMA COLLEGE
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