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Novel preparation method of (5R, 6S)-5,6-dephenyl -2-morpholinone

A technology of diphenylmorpholine and a new method, applied in the field of preparation-5, can solve the problems of harmfulness to human body and the environment, many steps, increased cost and the like

Inactive Publication Date: 2014-11-19
SHANGHAI AOBO PHARMTECH INC LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are following defects in this route: at first, in order to promote the smooth progress of the ring-closing reaction, the amine group must be protected
However, deprotection must be carried out in the end, which is not only cumbersome to operate, but also greatly increases the cost
Secondly, a large amount of strong carcinogenic benzene and chloroform are used as solvents in the reaction process, which is very harmful to the human body and the environment
In addition, this route has many steps and the total yield is low
These defects show that this method is not conducive to industrial production
[0008] Therefore, according to various defects existing in the prior art, the preparation of (5R, 6S)-5,6-diphenylmorpholin-2-ketone (I) on an industrial scale has been limited.

Method used

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  • Novel preparation method of (5R, 6S)-5,6-dephenyl -2-morpholinone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1 Synthesis of 2-[(1R, 2S)-2-hydroxyl-1,2-diphenylethylamino]acetic acid (III)

[0034] At room temperature, 1860 g of (1S,2S)-2-chloro-1,2-diphenylethanol (II), 258 g of tetrabutylammonium bromide, 890 g of triethylamine and 5 L of tetrahydrofuran were mixed together. Cool down to 0°C, and slowly add 660g of glycine dissolved in 5L of water dropwise under sufficient stirring. After the dropwise addition, tetrahydrofuran was removed under reduced pressure, and 1N hydrochloric acid was added dropwise to the remaining aqueous phase until the Ph of the system was neutral, and solids were precipitated. Filter and dry to obtain 1600g of 2-[(1R,2S)-2-hydroxy-1,2-diphenylethylamino]acetic acid (III), which is directly carried out to the next reaction.

Embodiment 2

[0035] Example Two Synthesis of 2-[(1R, 2S)-2-hydroxyl-1,2-diphenylethylamino]acetic acid hydrochloride (IVa)

[0036] At room temperature, 200 g of 2-[(1R,2S)-2-hydroxy-1,2-diphenylethylamino]acetic acid (III) obtained in Example 1 and 400 mL of ethanol were mixed with each other. Then slowly add 360 mL of 35% hydrogen chloride ethanol solution. The mixture was fully stirred at 40°C for 12h, cooled and filtered. After the solid was fully washed with ethanol, it was filtered and dried to obtain 210 g of 2-[(1R,2S)-2-hydroxy-1,2-diphenylethylamino]acetic acid hydrochloride (IVa) as a white solid.

Embodiment 3

[0037] Embodiment three (5R, 6S)-5, the synthesis of 6-diphenylmorpholin-2-ketone (I)

[0038]Stir 400g of thionyl chloride with 10mL of N,N-dimethylformamide and 2L of dichloromethane. Then add 210 g of 2-[(1R,2S)-2-hydroxy-1,2-diphenylethylamino]acetic acid hydrochloride (IVa) obtained in Example 2, raise the temperature to 40°C, and react for 24 hours . Thionyl chloride and dichloromethane were distilled off under reduced pressure, and the residue was added to 2L of ethyl acetate, washed with saturated sodium bicarbonate solution, and separated to obtain an organic phase. After the organic phase was washed with water and dried over anhydrous sodium sulfate, the ethyl acetate was removed under reduced pressure, and when 60% of the ethyl acetate was removed, the reduced pressure was stopped and left to stand at room temperature. After sufficient crystallization, 135 g of (5R,6S)-5,6-diphenylmorpholin-2-one (I) was obtained by filtration as a white solid with a purity of 99....

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Abstract

The invention discloses a novel preparation method of (5R, 6S)-5,6-dephenyl -2-morpholinone (I). The novel preparation method comprises the following reaction steps: enabling (1S, 2S)-2-chloro-1, 2-diphenylethanol (II) to react with glycine to generate 2-[(1R, 2S)-2-hydroxyl-1,2-diphenylethylamino] acetic acid (III); salifying the compound (III) and acid to form 2-[(1R, 2S)-2-hydroxyl-1,2-diphenylethylamino] ethanoic acid salt (IV); and enabling the compound (IV) to be subjected to ring closing reaction under the action of a ring closing reagent to obtain (5R,6S)-5,6-dephenyl -2-morpholinone (I).

Description

technical field [0001] The present invention relates to a new method for preparing (5R,6S)-5,6-diphenylmorpholin-2-one (I). Background technique [0002] (5R,6S)-5,6-diphenylmorpholin-2-one (I), is an important intermediate of many active molecules, such as the molecule nakadomarin A with bactericidal activity, the molecule spirotryprostatin B with anti-tumor activity, etc. . [0003] [0004] At present, there are not many methods for the synthesis of (5R, 6S)-5,6-diphenylmorpholin-2-one (I), and the documents JOC, 2005, 6653 and JACS, 1988, 1547 all describe the same method : [0005] [0006] The method uses (1S,2R)-2-amino-1,2-diphenylethanol as a raw material, first reacts with ethyl bromoacetate, and substitutes on the amino group. Then, in order to make the ring-closing reaction proceed smoothly, it is necessary to carry out tert-butoxycarbonyl protection to the amine group. Subsequent acid-catalyzed ring closure forms a six-membered ring. Finally, it needs...

Claims

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Application Information

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IPC IPC(8): C07D265/32C07C227/18C07C229/14
CPCC07D265/32C07C227/18
Inventor 陈宇陈欢生邹青梁俊高梓丰
Owner SHANGHAI AOBO PHARMTECH INC LTD
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