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Preparation method according to D-serine through splitting method

A technology of serine and resolving agent, applied in chemical instruments and methods, preparation of cyanide reaction, preparation of organic compounds, etc., can solve crystal data without diastereomeric salts, research without energy difference of diastereomeric salts , no assumptions and other issues, to achieve the effect of simple operation, effective utilization rate improvement and consumption reduction

Active Publication Date: 2014-04-30
HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite many trials and attempts, there are now neither computer-aided models of the resolution process, no detailed examination of crystallographic data for diastereomeric salts, no energy difference studies of diastereomeric salts, nor assumptions about empirically related formations, let alone formulate a theory to predict a splitting technique

Method used

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  • Preparation method according to D-serine through splitting method
  • Preparation method according to D-serine through splitting method
  • Preparation method according to D-serine through splitting method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Step a: Add 34.6g (0.3mol) of phosphoric acid to 400mL of isopropanol water (volume ratio is 9 / 1), add 105.1g (1mol) of hydroserine and (-)-4-(2- Chlorophenyl)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane resolving agent 138.3g (0.5mol), heating to reflux until the solution is clear , stirred for 1h, cooled and crystallized, filtered, and washed the filter cake with 50mL of isopropanol to obtain 201.7g of a white solid. The molecular structural formula is shown in compound (1). The crystal was tested as a monohydrate, see the attached figure 1 :

[0038]

[0039] Compound (1) 。

[0040]

[0041] Step b: Dissolve the above filter cake in 200mL isopropanol / water solution (volume ratio: 20 / 1), adjust pH=5.68 with NaOH solution, filter, wash with 20mL isopropanol, and dry to obtain 48.7g of D-serine , yield 93%, -14.75°(c=10 2N HCl), ChemicalBook value: -14.75° (c=10 2N HCl). After the filtrate was concentrated, 300 mL of water was added, the pH was adj...

Embodiment 2

[0044] Step a: Add 608 g (6 mol) of 36% hydrochloric acid to 400 mL of methanol water (volume ratio 1 / 1), add 105.1 g (1 mol) of hydrochloric acid to the solution and (-)-4-(2- Chlorophenyl)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane resolving agent 138.3 g (0.5mol), heated to reflux until the solution is clear , stirred for 1 h, cooled and crystallized, filtered, and washed the filter cake with 50 mL of methanol to obtain 202.1 g of a white solid, the molecular structure of which was D-serine (-)-4-(2-chlorophenyl)-2-hydroxyl-5, 5-Dimethyl-2-oxo-1,3,2-dioxaphosphorinane double salt monohydrate.

[0045] Step b: Dissolve the above filter cake in 300mL of water, adjust the pH to strong acidity with hydrochloric acid, stir at room temperature for 3 hours, a large amount of solid precipitates, filter, and recover (-)-4-(2-chlorophenyl)-2-hydroxy-5 , 133.8 g of 5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane, the recovery rate was 97%, and the recovered resolving agent was ...

Embodiment 3

[0048] Step a: Add 98 g (0.5 mol) of 50% sulfuric acid to 400 mL of ethanol, add 105.1 g (1 mol) of cycloserine and (-)-4-(2-chlorophenyl)-2-hydroxyl-5 ,5-Dimethyl-2-oxo-1,3,2-dioxaphosphorinane resolving agent 138.3g (0.5mol), heated to reflux until the solution was clear, stirred for 1h, cooled and crystallized, filtered, Wash the filter cake with 50 mL of ethanol to obtain 192.5 g of double salt filter cake white solid, the molecular structure is D-serine (-)-4-(2-chlorophenyl)-2-hydroxyl-5,5-dimethyl- 2-Oxo-1,3,2-dioxaphosphorinane double salt anhydrous.

[0049] Step b: Dissolve the above filter cake in 200mL ethanol / water solution (volume ratio is 20 / 1), adjust pH=5.68 with NaOH solution, filter, wash with 20mL ethanol, and dry to obtain 49.5g of D-serine, yield 94%. -14.73°(c=10 2N HCl), ChemicalBook value: -14.75° (c=10 2N HCl). After the filtrate is concentrated, add 300mL of water, adjust the pH to strong acidity with hydrochloric acid, stir at room temperature...

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Abstract

The invention discloses a preparation method according to D-serine through a splitting method. The preparation method takes levo-cyclic phosphoric acid as a splitting agent, adopts a half-quantity splitting method to split dl-serine, and comprises the following steps: heating and reflowing the dl-serine and half equivalent of the levo-cyclic phosphoric acid splitting agent in an inorganic proton acid alcohol and aqueous solution; reducing temperature and devitrifying; carrying out separating and dissociating to obtain the D-serine and L-serine respectivelt; recycling the L-serine after racemization. The preparation method is simple to operate; effective utilization rate of the chiral splitting agent is increased; dosage of the chiral splitting agent is decreased; the cost is relatively low; the yield is high; products are good in purity; the preparation method belongs to the field of racemoid splitting.

Description

technical field [0001] The invention relates to a resolution method for racemic compounds, in particular to a new method for preparing D-serine by resolution of racemic serine. Background technique [0002] D-serine is an important chiral intermediate, which is widely used in the fields of organic synthesis, new drug research and peptide synthesis. D-serine is not only an important glial cell transmitter, but also acts on N-methyl-D-aspartate receptors for the treatment of schizophrenia. In addition, D-serine is also an important intermediate of some chiral drugs such as cycloserine and lacosamide. [0003] D-serine is difficult to obtain from nature. At present, the preparation methods of D-serine mainly include asymmetric synthesis, biological method and chemical resolution method. [0004] Asymmetric synthesis methods such as Saghyan et al. (Tetrahedron: Asymmetry 2010, 21, 2956-2965) use a complex of fluorine-containing chiral ligands and glycine or alanine Schiff base...

Claims

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Application Information

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IPC IPC(8): C07C229/22C07C227/34
Inventor 孙凤霞毛春丽王玉春贾琳茹孔飞飞
Owner HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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