Method for preparing enamine derivates

A technology for derivatives and enamines, applied in the field of preparation of enamine derivatives, can solve the problems of large consumption of triethyl orthoformate and acetic anhydride, unsuitable for large-scale production, trivial preparation of DMFA, etc., and achieves low cost and high reaction efficiency. Mild conditions and high yields

Active Publication Date: 2012-01-25
ZHEJIANG GUOBANG PHARMA
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Problems solved by technology

[0021] In the above-mentioned synthetic method, because the synthesis of 2,4-dichloro-5-fluorobenzoyl chloride as a raw material is complex and costly, it is not suitable for large-scale production
At present, most of the domestic use of p-keto esters is the synthetic method of starting raw material, wherein the second, the synthetic route of 1, the process is mature, but the consumption of triethyl orthoformate and acetic anhydride is large, and the pollution is serious; the second, the second of 2 Synthetic route is a very promising process route, but the preparation of intermediate enamine derivatives (" needs to use DMFA, and the preparation of DMFA is more loaded down with trivial details

Method used

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  • Method for preparing enamine derivates
  • Method for preparing enamine derivates
  • Method for preparing enamine derivates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1, the preparation of imide salt (Methoxymethylen) dimethylammonium-methylsulfat (molecular formula such as V):

[0049]

[0050] Add DMF (37.0g, 0.51mol) into a 250ml three-necked flask, stir and raise the temperature to 55°C, slowly add dimethyl sulfate (63.1g, 0.50mol) dropwise, maintain the temperature in the flask at 50-60°C, and drop for about 60min complete. After dropping, raise the temperature to 75°C and keep it warm for 3 hours. After cooling, the imide salt can be obtained.

Embodiment 2

[0051]The preparation of embodiment 2, 3-(S-hydroxypropyl-2-amine)-2-(2,3,4,5-benzoyl) ethyl acrylate, the following steps are carried out successively:

[0052] 1. Throw 9.7g of sodium hydride and 200ml of toluene into a 500ml four-neck flask, and add dropwise 2,3,4,5-tetrafluorobenzoyl ethyl acetate solution (40g / 69ml of toluene, that is, 69ml Add 40g of ethyl 2,3,4,5-tetrafluorobenzoylacetate to toluene), drop it in about 2 to 3 hours, and react at 0°C for 8 hours to obtain 2,3,4,5- Toluene solution of ethyl tetrafluorobenzoyl acetate sodium salt.

[0053] 2. At about -5°C, add 61.5 g of the imide salt obtained in Example 1 dropwise to the toluene solution of the above-mentioned 2,3,4,5-tetrafluorobenzoyl ethyl acetate sodium salt (the molar ratio is 1: 2.04 ), the drop was completed in about 1.5 hours, and after the drop was completed, the reaction was incubated at -5°C for 15 hours, and the end point of the reaction was detected by spotting the plate. After the reaction...

Embodiment 3

[0055] Example 3, the preparation of 3-cyclopropylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylic acid acetonitrile, the following steps were carried out in sequence:

[0056] 1. Throw 6.5g of sodium hydride and 200ml of toluene into a 500ml four-neck flask. Control the temperature at about 0°C and add 2,4-dichloro-5-fluorobenzoyl acetonitrile solution (37g / 70ml toluene) dropwise, drop it in about 2 to 3 hours, and keep the reaction at the above temperature for 8 hours to obtain 2 , 4-Dichloro-5-fluorobenzoylacetonitrile sodium salt in toluene.

[0057] 2. Add dropwise 40 g of the imide salt (2,4-dichloro-5-fluoro The molar ratio of benzoyl acetonitrile to imide salt is 1:1.26), and the dripping is finished in about 2 hours; after the dripping, the temperature is kept at this temperature for 5 hours, and the temperature is raised to 40°C for 10 minutes after the warming, suction filtration, and the filtrate is recovered under reduced pressure To dryness, 3-dimethylamino-2-(2,4...

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Abstract

The invention discloses a method for preparing enamine derivatives, which comprises the steps that: 1) the iminium salts with a molecular structural formula as III and the metal salt comprising active methylene with a molecular structural formula as II are selected as raw materials, and the molar ratio of iminium salts to metal salts comprising active methylene ranges from 1 : 1 to 3 : 1 ; 2) under a temperature of -50 DEG C to 100 DEG C, the iminium salts are gradually added into the organic solvent containing the metal salts comprising active methylene, to carry out a react for 0 to 40 hours with heat preservation under minus 50DEG C to 100DEG C; the solution of enamine derivatives with a molecular structural formula as I is obtained. The method for preparing enamine derivatives has simple process with high yield and mild reactive condition.

Description

technical field [0001] The invention relates to a preparation method of an enamine derivative (molecular structural formula I), which can be used to synthesize fluoroquinolone drug intermediates (molecular structural formula IV) and other compounds. Background technique [0002] Fluoroquinolones are widely used as antibiotics, and the synthetic methods of their key intermediates (IV) have multiple reports. Taking the synthesis of the main ring compound of ciprofloxacin-cyclopropanecarboxylic acid (molecular structural formula is A) as an example, the synthetic method of the key intermediate (IV) is introduced. [0003] [0004] Molecular structure IV: R 1 is a substituent with electron-withdrawing effect; R 4 Any one of C1~C6 alkyl; X 1 、X 2 、X 3 and x 4 Both are halogen, hydrogen, amino or nitro; X 5 for halogen. [0005] The synthetic routes suitable for industrialized production are mainly divided into two categories according to different starting materials: o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C229/34C07C227/10C07D215/56
Inventor 刘聪缪士学姚礼高
Owner ZHEJIANG GUOBANG PHARMA
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