Preparation method of morpholine derivative

A morpholine derivative and morpholine technology, applied in organic chemistry methods, organic chemistry, etc., can solve the problems of increasing the difficulty of reaction treatment, not suitable for industrial production, long process, etc., to achieve mild conditions, reduce difficulty, and simple operation Effect

Active Publication Date: 2017-04-26
江苏富泽药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The whole process is long, which objectively increases the difficulty of reaction treatment, and is not suitable for industrial production

Method used

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  • Preparation method of morpholine derivative
  • Preparation method of morpholine derivative
  • Preparation method of morpholine derivative

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Experimental program
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Effect test

Embodiment 1

[0040] (R)-4-benzyl-2-hydroxy-morpholin-3-one (3.11g, 15mmol), (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl -1-ol (4.65 g, 18 mmol) and triphenylphosphine (4.72 g, 18 mmol) were dissolved in 150 mL of tetrahydrofuran. Below 10°C, a solution of diethyl azodicarboxylate in tetrahydrofuran (3.13 g, 18 mmol of diethyl azodicarboxylate dissolved in 20 mL of tetrahydrofuran) was slowly added dropwise. After the dropwise addition, the reaction solution was raised to room temperature and continued to stir for 12 h. Concentrate the reaction solution to dryness under reduced pressure, add 100 mL of n-hexane and 100 mL of water, heat to 50°C, and stir well. Stand still, separate the liquids, dry the upper organic phase with anhydrous sodium sulfate, distill off a large amount of n-hexane under reduced pressure, cool the remaining solution to 0°C for crystallization, filter with suction, wash the obtained solid with ice n-hexane (25mL×2), After air drying at 40°C, 5.84 g of a white solid...

Embodiment 2

[0045] (R)-4-benzyl-2-hydroxy-morpholin-3-one (3.11g, 15mmol), (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl -1-ol (15.49 g, 60 mmol) and triphenylphosphine (15.74 g, 60 mmol) were dissolved in 150 mL of tetrahydrofuran. Below 10°C, a solution of diethyl azodicarboxylate in tetrahydrofuran (10.45 g, 60 mmol of diethyl azodicarboxylate dissolved in 20 mL of tetrahydrofuran) was slowly added dropwise. After the dropwise addition, the reaction solution was raised to room temperature and continued to stir for 12 h. Concentrate the reaction solution to dryness under reduced pressure, add 100 mL of n-hexane and 100 mL of water, heat to 50°C, and stir well. Stand still, separate the liquids, dry the upper organic phase with anhydrous sodium sulfate, distill off a large amount of n-hexane under reduced pressure, cool the remaining solution to 0°C for crystallization, filter with suction, wash the obtained solid with ice n-hexane (25mL×2), Air-dried at 40°C to finally obtain 5.95 g of ...

Embodiment 3

[0050] (R)-4-benzyl-2-hydroxy-morpholin-3-one (3.11g, 15mmol), (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl -1-ol (7.75 g, 30 mmol) and triphenylphosphine (7.87 g, 30 mmol) were dissolved in 150 mL of dichloromethane. Below 10°C, a solution of di-p-chlorobenzyl azodicarboxylate in dichloromethane (11.02 g, 30 mmol of di-p-chlorobenzyl azodicarboxylate dissolved in 20 mL of dichloromethane) was slowly added dropwise. After the dropwise addition, the reaction solution was raised to room temperature and continued to stir for 12 h. Concentrate the reaction solution to dryness under reduced pressure, add 100 mL of n-hexane and 100 mL of water, heat to 50°C, and stir well. Stand still, separate the liquids, dry the upper organic phase with anhydrous sodium sulfate, distill off a large amount of n-hexane under reduced pressure, cool the remaining solution to 0°C for crystallization, filter with suction, wash the obtained solid with ice n-hexane (25mL×2), Air-dried at 40°C to finally...

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Abstract

The invention provides a preparation method of a morpholine derivative represented as the formula (I), wherein the preparation method includes the steps of: (1) dissolving trialkyl (aryl) phosphine, azodicarboxylic acid diester, (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl-1-ol, and (R)-4-benzyl-2-hydroxyl-morpholine-3-one in a reaction solvent; (2) adding the azodicarboxylic acid diester so that the trialkyl (aryl) phosphine and the azodicarboxylic acid diester are subjected to an addition reaction quickly in the reaction solvent to generate zwitter-ions, which are then converted into quaternary phosphonium salt by means of a hydrogen proton supplied by the hydroxyl group in the (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl-1-ol; (3) enabling the hydroxyl group on the 2-position of the (R)-4-benzyl-2-hydroxyl-morpholine-3-one to be reacted with the quaternary phosphonium salt to generate morpholine oxy-phosphonium salt; and (4) with the (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl-1-ol, which loses the hydrogen proton, as a nucleophilic reagent, performing an SN2 reaction with the morpholine oxy-phosphonium salt to obtain a product which has turned configuration. The method has high stereo-selectivity, avoids generation of an isomer byproduct during the reaction process, and reduces the load of separation and purification of the product in the later period.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical production, and relates to a morpholine derivative (2R, 2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy] - A stereoselective synthesis method of morpholin-3-one, the compound is an important pharmaceutical intermediate used for the preparation of antiemetics aprepitant and fosaprepitant. Background technique [0002] Aprepitant CAS registration number: 170729-80-3, fosaprepitant CAS registration number: 265121-04-8, the compound structure formula is shown in the following formula. Both are used to treat acute and delayed nausea and vomiting caused by chemotherapy. Among them, fosaprepitant can be regarded as the prodrug of aprepitant, which will be rapidly converted into aprepitant in the body after injection. [0003] [0004] A key intermediate for the preparation of aprepitant and fosaprepitant, namely (2R,2αR)-4-benzyl-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy ]-morpho...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D265/32
CPCC07B2200/07C07D265/32
Inventor 吴鹏程李浩源谢卫峰何智健
Owner 江苏富泽药业有限公司
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