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Preparation and application of novel Swern reagent

A technology of reaction and organic solvent, applied in the field of novel methyl sulfoxide reagent, can solve the problems of unsolved reaction temperature, complicated operation, long time required for separation process, etc.

Active Publication Date: 2016-05-18
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In 2001, Crich et al. developed another odorless Swern oxidation, which replaced a methyl group in dimethyl sulfoxide with a long aliphatic chain substituted by fluorine atoms (structural formula as shown in the figure below), and also avoided The formation of dimethyl sulfide, and the reaction temperature was raised to -30 ° C, made great progress, but the separation process of the product takes a long time, uses a variety of organic solvents, and the operation is cumbersome
[0011] In 2011, methyl sulfoxide (structural formula as shown in the figure below) supported by Togo plasma replaced dimethyl sulfoxide. The reaction yield was high, and the separation and purification of the product was simple. Unfortunately, this method did not solve the problems of low reaction temperature and carbon monoxide release.
(Luca, L.D.; Giacomelli, G.; Porcheddu, A.J. Org. Chem., 2001, 66(23):7907-7909. Wang, Y.; Wang, C.; Sun, J. Synth. Commun., 2014, 44:2961-2965.Nguyen, T.V.; Hall, M.TetrahedronLet., 2014,55(50):6895-6898.) The common feature of these methods is that the reaction temperature is all improved, but the by-product di Production of methyl sulfide

Method used

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  • Preparation and application of novel Swern reagent
  • Preparation and application of novel Swern reagent
  • Preparation and application of novel Swern reagent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1: Preparation of 4-(2-(2-(methylsulfoxide) ethyl)-4-nitrophenyl)morpholine (I)

[0056] (1) Add 5.0g (24.79mmol) of 2-(2-chloro-5nitro)phenylethanol (II) into a 100mL three-neck round bottom flask, add 10.8g (5eq, 123.95mmol) of morpholine, and stir in an oil bath Heated to 120°C for reaction, followed by TLC until the reaction was complete, recovered excess morpholine under reduced pressure, added 25 mL of water, stirred for 1.0 h, then filtered with suction, washed the filter cake with water until the filtrate was colorless, and the yellow compound 2-(2-morpholine-5 -Nitrophenyl)ethanol (III), drying, yield 99.9%.

[0057] (2) Weigh 5.0g (19.82mmol) of the morpholine substitute (III) prepared above and add to a 100mL three-necked round-bottomed flask, 25mL of toluene is used as a solvent, and 2.16g of bis(trichloromethyl)carbonate is added dropwise at 100°C ( 0.36eq, 7.27mmol) of 5mL toluene solution, TLC followed the reaction until complete, after the tolue...

Embodiment 2

[0058] Example 2: Preparation of 4-(2-(2-(methylsulfoxide) ethyl)-4-nitrophenyl)morpholine (I)

[0059] (1) Add 5.0g (24.79mmol) of 2-(2-chloro-5nitro)phenylethanol (II) into a 100mL three-neck round bottom flask, add 6.48g (3eq, 74.37mmol) of morpholine, and stir in an oil bath under magnetic force Heated to 120°C to react, followed by TLC to complete the reaction, recovered excess morpholine under reduced pressure, added 30mL of water, stirred for 1.0h, then filtered with suction, washed the filter cake with water until the filtrate was colorless, and the yellow compound 2-(2-morpholine-5 -Nitrophenyl)ethanol (III), drying, yield 99.9%.

[0060] (2) Weigh 5.0g (19.82mmol) of the above-prepared morpholine substitute (III) into a 100mL three-neck round-bottomed flask, use 20mL of chlorobenzene as a solvent, and add 1.94g of bis(trichloromethyl)carbonate dropwise at 100°C (0.33eq, 6.54mmol) in 5mL of chlorobenzene solution, TLC followed the reaction until complete, and recover...

Embodiment 3-22

[0061] Embodiment 3-22 is the application of novel Swern reagent in the oxidation reaction of general alcohol and the intermediate 1-adamantanemethanol of saxagliptin drug for treating diabetes

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Abstract

The invention discloses 4-(2-(2-methyl sulfoxide)ethyl)-4-nitrobenzene)morpholine shown in the formula (I) and preparation and application thereof. A preparation method includes the steps that 2-(2-chlorine-5 nitro)phenethyl alcohol shown in the formula (II) and morpholine are mixed to prepare 2-(2-morpholine-5-nitrobenzene)ethanol shown in the formula (III); bis(trichloromethyl)carbonate ester, a sodium methyl mercaptide aqueous solution and an aqueous hydrogen peroxide solution are sequentially added dropwise to 2-(2-morpholine-5-nitrobenzene)ethanol shown in the formula (III), and finally 4-(2-methyl sulfoxide)ethyl)-4-nitrobenzene)morpholine is prepared. According to the application of 4-(2-methyl sulfoxide)ethyl)-4-nitrobenzene)morpholine, the obtained Swern reagent reacts with an alcohol compound shown in the formula (IV), and aldehyde or ketone is prepared after after-treatment. The defects of an existing Swern oxidation method are overcome, generation of a stink byproduct dimethyl sulfide and toxic carbon monoxide is avoided from the source, the reaction temperature is increased to be -30 DEG C to 0 DEG C, and an odorless byproduct novel sulfur ether can be recycled and reused. The formulas are shown in the description.

Description

(1) Technical field [0001] The invention relates to a novel methyl sulfoxide reagent based on the Swern oxidation reaction. The novel Swern reagent prepared by reacting the reagent with bis(trichloromethyl)carbonate can oxidize alcohols into corresponding aldehydes or ketones. (2) Technical background [0002] The oxidation of alcohols to carbonyl compounds is a very critical class of reactions in organic synthesis, and also plays an extremely important role in the synthesis of drugs. Swern oxidation is a method for efficiently oxidizing alcohols to carbonyl compounds, which plays an irreplaceable role in the preparation of pharmaceutical intermediates. [0003] The Swern oxidation method is a method for the efficient oxidation of alcohols to carbonyl compounds developed by Swern et al. in 1978. The reaction is carried out in anhydrous system at -60°C, and the reagents used are cheap and easy to obtain. The method has good effects on aromatic alcohols and long-chain aliphat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/096C07C47/54C07C45/29C07C49/76C07C47/575C07C47/55C07C205/44C07C201/12C07C49/786C07C49/807C07C47/445C07B41/06
CPCY02P20/582C07C45/29C07B41/06C07C201/12C07C47/575C07C49/76C07C47/54C07C47/55C07C205/44C07C49/786C07C49/807C07C47/445
Inventor 钟为慧叶小静苏为科
Owner ZHEJIANG UNIV OF TECH
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