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Preparation method of 1-aryl-2-amidogen-1,3-propylene glycol hydrochloride derivative

A technology of propylene glycol hydrochloride and derivatives, which is applied in the preparation of amino hydroxyl compounds, the preparation of organic compounds, chemical instruments and methods, etc., can solve the problems of low product purity and conversion rate, increased production cost, and cumbersome process routes, etc. Achieve the effects of easy storage and transportation, reduced preparation cost, and simple synthesis process route

Inactive Publication Date: 2018-05-11
NANTONG CHANGYOO PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The structure of this product contains two active chiral centers, which are prone to reactions and lead to impurities. The traditional preparation method of this product is N -Boc-D-serine methyl ester is the starting material, which is prepared by first reducing the ester group to alcoholic hydroxyl group and then oxidizing it to aldehyde group. This preparation method has many side reactions, cumbersome process routes, low product purity and conversion rate, etc. Defects, and because the process route is more cumbersome, the production cost also increases

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] a, the preparation of oxazole ring compound IM-1: add 44g in the reaction flask N -Boc-D-serine methyl ester (0.2mol, 1.0eq), 62.4g 2,2-dimethoxypropane (0.6mol, 3.0eq), 300mL acetone, stir to dissolve, then add 3.8g p-toluenesulfonic acid (0.02mol, 0.1eq), and then react at 35°C; after the reaction is complete, add saturated sodium bicarbonate solution to the reaction solution to adjust the pH of the reaction solution to about 7; evaporate the solvent under reduced pressure, and then add 500mL of water and 300mL of dichloro Methane, stirred and separated, separated the organic phase, extracted the aqueous phase with dichloromethane (200mL×2), combined the organic phase; washed the organic phase with 300mL saturated brine, dried over anhydrous sodium sulfate, suction filtered, evaporated to dryness, Obtained 45.3g of IM-1 product, yield: 87%.

[0023] b. Preparation of aldehyde compound IM-2: Add 45.3g IM-1 (0.17mol, 1.0eq) and 300mL toluene into a reaction flask under...

Embodiment 2

[0027] a, the preparation of oxazole ring compound IM-1: add 44g in the reaction bottle N -Boc-D-serine methyl ester (0.2mol, 1.0eq), 52.1g 2,2-dimethoxypropane (0.5mol, 2.5eq), 300mL acetone, stir to dissolve, then add 6.9g p-toluenesulfonic acid (0.04mol, 0.2eq), and then react at 35°C; after the reaction is complete, add saturated sodium bicarbonate solution to the reaction solution to adjust the pH of the reaction solution to about 7; evaporate the solvent under reduced pressure, and then add 500mL of water and 300mL of dichloro Methane, stirred and separated, separated the organic phase, extracted the aqueous phase with dichloromethane (200mL×2), combined the organic phase; washed the organic phase with 300mL saturated brine, dried over anhydrous sodium sulfate, suction filtered, evaporated to dryness, Obtained 45.3g of IM-1 product, yield: 87%.

[0028] b. Preparation of aldehyde compound IM-2: Add 45.3g IM-1 (0.17mol, 1.0eq) and 300mL toluene into a reaction flask unde...

Embodiment 3

[0032] a, the preparation of oxazole ring compound IM-1: add 44g in the reaction bottle N -Boc-D-serine methyl ester (0.2mol, 1.0eq), 72.9g 2,2-dimethoxypropane (0.7mol, 3.5eq), 300mL acetone, stir to dissolve, then add 3.8g p-toluenesulfonic acid (0.02mol, 0.1eq), and then react at 35°C; after the reaction is complete, add saturated sodium bicarbonate solution to the reaction solution to adjust the pH of the reaction solution to about 7; evaporate the solvent under reduced pressure, and then add 500mL of water and 300mL of dichloro Methane, stirred and separated, separated the organic phase, extracted the aqueous phase with dichloromethane (200mL×2), combined the organic phase; washed the organic phase with 300mL saturated brine, dried over anhydrous sodium sulfate, suction filtered, evaporated to dryness, Obtained 45.3g of IM-1 product, yield: 87%.

[0033] b. Preparation of aldehyde compound IM-2: Add 45.3g IM-1 (0.17mol, 1.0eq) and 300mL toluene into a reaction flask unde...

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PUM

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Abstract

The invention discloses a preparation method of a 1-aryl-2-amidogen-1,3-propylene glycol hydrochloride derivative. The method comprises the steps that N-Boc-D-serine methyl ester is used as an initialraw material and prepared through amidogen fixation, reduction reaction, Grignard reaction, Grignard butt joint, acetonylidene removal and salinization reaction. The preparation method has the advantages that the source of the initial raw material N-Boc-D-serine methyl ester is wide, easy to obtain and moderate in cost, the synthesis process is simple in route, and the preparation cost of products is lowered; acetonylidene is applied to protection of amidogen and aliphatic hydroxyl groups, the side reaction caused by active amidogen and aliphatic hydroxyl groups is effectively avoided, impurities are reduced, and the product purity and reaction yield are increased; the target products exist in a hydrochloride compound mode, the stability of the products is improved, the products are easily stored and conveyed, and the preparation method is suitable for large-scale industrialized production.

Description

technical field [0001] The invention relates to the field of medicine preparation, in particular to a preparation method of 1-aryl-2-amino-1,3-propanediol hydrochloride derivatives. Background technique [0002] The 1-aryl-2-amino-1,3-propanediol hydrochloride derivative is an important drug synthesis intermediate and a key intermediate for the production of Eliglustat. The structure of this product contains two active chiral centers, which are prone to reactions and lead to impurities. The traditional preparation method of this product is N -Boc-D-serine methyl ester is the starting material, which is prepared by first reducing the ester group to alcoholic hydroxyl group and then oxidizing it to aldehyde group. This preparation method has many side reactions, cumbersome process routes, low product purity and conversion rate, etc. Defects, and because the process route is relatively cumbersome, the production cost also increases. Contents of the invention [0003] In ord...

Claims

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Application Information

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IPC IPC(8): C07C213/00C07C215/36C07D263/06C07D263/04C07D319/18
CPCC07C213/00C07D263/04C07D263/06C07D319/18C07C215/36
Inventor 严军李泽标黄虎祁晓庆丁海明马甜甜
Owner NANTONG CHANGYOO PHARMATECH CO LTD
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