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A kind of preparation method of morpholine-3-carboxylic acid

A technology of morpholine and carboxylic acid, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of unfriendly environment and achieve the effect of simple preparation process, high yield and few steps

Active Publication Date: 2019-05-28
SHANGHAI BALMXY PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This preparation method also involves the use of sodium borohydride reduction, and chloroacetyl chloride is used in the reaction, which is not environmentally friendly

Method used

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  • A kind of preparation method of morpholine-3-carboxylic acid
  • A kind of preparation method of morpholine-3-carboxylic acid
  • A kind of preparation method of morpholine-3-carboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] (1) react with N-Boc-ethanolamine and 2-chloroacrylonitrile raw material, concrete reaction formula is as follows:

[0058]

[0059] Dissolve N-Boc-ethanolamine (161g, 1mol) in acetonitrile (1L), add 2-chloroacrylonitrile (92g, 1.05mol), replace the system with nitrogen three times, add trimethylphosphine (38g, 0.5mol) under stirring , the system was warmed up to 50° C., kept stirring for 25 hours, filtered, concentrated, added 500 mL of water, extracted twice with ethyl acetate, combined the organic phases, dried, and concentrated to obtain 206 g of a light yellow solid with a yield of 83%.

[0060] 1 H NMR (CDCl 3 ,400MHz):δ6.52(s,1H),4.65(dd,1H),4.03(ddd,2H),3.47-3.55(m,2H),3.02-3.13(m,2H),1.46(s,9H ).

[0061] (2) Use hydrochloric acid to carry out deprotection reaction, concrete reaction formula is as follows:

[0062]

[0063] Dissolve the light yellow solid (190 g, 0.76 mol) obtained in step (1) in 1,4-dioxane (200 mL), and add dropwise 3M 1,4-dioxane (...

Embodiment 2

[0073] (1) react with N-Boc-ethanolamine and 2-chloroacrylonitrile raw material, concrete reaction formula is as follows:

[0074]

[0075] N-Boc-ethanolamine (161g, 1mol) was dissolved in acetonitrile (1L), 2-chloroacrylonitrile (105g, 1.2mol) was added, the system was replaced with nitrogen three times, and sodium ethylate (27.22g, 0.4mol) was added under stirring, The system was warmed up to 40°C, kept stirring for 30 hours, filtered, concentrated, added 500 mL of water, extracted twice with ethyl acetate, combined the organic phases, dried and concentrated to obtain 200 g of light yellow solid with a yield of 80.6%.

[0076] 1 H NMR (CDCl 3 ,400MHz):δ6.52(s,1H),4.65(dd,1H),4.03(ddd,2H),3.47-3.55(m,2H),3.02-3.13(m,2H),1.46(s,9H ).

[0077] (2) Use hydrochloric acid to carry out deprotection reaction, concrete reaction formula is as follows:

[0078]

[0079] Dissolve the light yellow solid (190g, 0.76mol) obtained in step (1) in 1,4-dioxane (152mL), and add dropwi...

Embodiment 3

[0089] (1) react with N-Boc-ethanolamine and 2-chloroacrylonitrile raw material, concrete reaction formula is as follows:

[0090]

[0091] Dissolve N-Boc-ethanolamine (161g, 1mol) in acetonitrile (1L), add 2-chloroacrylonitrile (92g, 1.05mol), replace the system with nitrogen three times, add potassium tert-butoxide (89.8g, 0.8mol) under stirring ), the system was heated to 60° C., continued to stir for 20 hours, filtered, concentrated, added 500 mL of water, extracted twice with ethyl acetate, combined the organic phases, dried, and concentrated to obtain 195 g of a light yellow solid with a yield of 78.6%.

[0092] 1 H NMR (CDCl 3 ,400MHz):δ6.52(s,1H),4.65(dd,1H),4.03(ddd,2H),3.47-3.55(m,2H),3.02-3.13(m,2H),1.46(s,9H ).

[0093] (2) Use hydrochloric acid to carry out deprotection reaction, concrete reaction formula is as follows:

[0094]

[0095] Dissolve the light yellow solid (190 g, 0.76 mol) obtained in step (1) in 1,4-dioxane (380 mL), and add dropwise 3M 1,...

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Abstract

The invention provides a preparation method for morpholine-3-carboxylic acid. The preparation method comprises the following steps: taking (2-Hydroxyethyl)carbamic acid tert-butyl ester and 2-chloroacrylonitrile as raw materials, performing Michael addition reaction, performing deprotection reaction, performing ring-closure reaction, and performing hydrolysis reaction to obtain the morpholine-3-carboxylic acid. The preparation method for the morpholine-3-carboxylic acid provided by the invention is used for preparing morpholine-3-carboxylic acid through Michael addition reaction, the deprotection reaction, ring-closure reaction and hydrolysis reaction; the whole preparation process is simple, is fewer in steps, adopts cheap and easily available raw materials, is free of stimulus and easilyallergic substances, and avoids generating highly toxic products and side products; and the yield of reaction at each step can be 80% or higher, the total yield is high, large-scale production is facilitated, economic benefits are improved, and the market value is good.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical intermediates, and relates to a preparation method of morpholine-3-carboxylic acid. Background technique [0002] Morpholine-3-carboxylic acid is an important pharmaceutical intermediate and has a wide range of applications in the field of pharmaceutical synthesis. At present, the existing synthetic methods mainly contain the following two routes: [0003] The first route uses morpholine protected by tert-butoxycarbonyl (Boc) as a raw material, and finally obtains the product through etherification reaction, cyanation reaction, hydrolysis reaction and nitrogen protection. The specific reaction formula is as follows: [0004] [0005] However, in this route, the conditions of the first step reaction are relatively high, the reaction is not easy to control, and the yield is low. The second step reaction uses trimethylsilyl cyanide, which will produce highly toxic hydrocyanic acid when ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D265/30
CPCC07D265/30
Inventor 柴腾林增明
Owner SHANGHAI BALMXY PHARMA CO LTD