Method for preparing enamine derivates

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...

Examples

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...

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...

Examples

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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