A kind of synthetic method of n-boc piperazine

Abstract

The invention discloses a synthetic method of N-Boc piperazine. According to the method, diethylamine alcohol is taken as a starting material, and three steps of chlorination, Boc protection and aminolysis cyclization are carried out to synthesize N-Boc piperazine. The method is readily available in raw materials, mild in reaction conditions, low in product cost, high in yield, high in purity andsuitable for industrial production.

Description

technical field

[0001] The invention relates to a synthesis method of N-Boc piperazine, which belongs to the technical field of organic synthesis. Background technique

[0002] N-Boc piperazine, Chinese aliases: N-tert-butoxycarbonyl piperazine, piperazine-1-tert-butyl carboxylate; Molecular formula C 9 h 18 N 2 o 2 , molecular weight: 186.25. The chemical structural formula is as follows:

[0003]

[0004] N-Boc piperazine belongs to piperazine monosubstituted compounds. Due to its special structure, piperazine monosubstituted compounds have become key intermediates in the synthesis of many drugs, such as glucocorticoids such as palbociclib, ranolazine, and dexamethasone. Therefore, the synthesis of piperazine monosubstituted compounds has very important pharmaceutical and economic value.

[0005] The method for synthesizing N-Boc piperazine mainly contains following two kinds at present:

[0006] Method 1: Use anhydrous piperazine to drop di-tert-butyl dicarbona...

Examples

Embodiment 1

[0030] 1) Add 357g (3mol) of thionyl chloride to a 2000ml reaction flask, dropwise add 105g (1mol) of diethanolamine, heat up and reflux for 4 hours; cool down to below 10°C, add 1000ml of purified water and stir until no heat release;

[0031] 2) Add 636g (6mol) of sodium carbonate to dissolve, pH>10; within a temperature control of 10-20°C, add 218g (1mol) of Boc anhydride dropwise, and react at 25°C for 12 hours to keep the reaction system alkaline;

[0032] 3) Raise the temperature to 60°C, slowly add 182g (3mol) of ammonia water dropwise, and finish dripping in about 3 hours; control the temperature at 60°C for 3 hours, then lower the temperature to below 25°C, and extract the reaction solution three times with 900ml of ethyl acetate (300ml each time ), dry the ethyl acetate layer with sodium sulfate, filter, concentrate under reduced pressure below 60°C, evaporate the ethyl acetate to dryness, and cool to obtain 174.8g of N-Boc piperazine, with a yield of 94.0% and a puri...

Embodiment 2

[0034] 1) Add 327g (2.75mol) of thionyl chloride to a 2000ml reaction flask, dropwise add 105g (1mol) of diethanolamine, heat up and reflux for 4.5h; cool down to below 10°C, add 1000ml of purified water and stir until no heat release;

[0035] 2) Add 583g (5.5mol) of sodium carbonate to dissolve, pH>10; within a temperature control of 10-20°C, add 214g (0.98mol) of Boc anhydride dropwise, and react at 25°C for 14 hours to keep the reaction system alkaline;

[0036] 3) Raise the temperature to 60°C, slowly add 170g (2.8mol) of ammonia water dropwise, and finish dripping in about 3 hours; control the temperature at 60°C for 3.5 hours, lower the temperature below 25°C, and extract the reaction liquid three times with 900ml ethyl acetate, Yuan Mingfen Dry the ethyl acetate layer, filter, concentrate under reduced pressure below 60°C, evaporate the ethyl acetate to dryness, and cool to obtain 174.5 g of N-Boc piperazine with a yield of 93.8% and a purity of 99.72%.

Embodiment 3

[0038] 1) Add 387g (3.25mol) of thionyl chloride to a 2000ml reaction flask, dropwise add 105g (1mol) of diethanolamine, heat up and reflux for 3.5h; cool down to below 10°C, add 1000ml of purified water and stir until no heat release;

[0039] 2) Add 689g (6.5mol) of sodium carbonate to dissolve, pH>10. Control the temperature at 10-20°C, add 222g (1.02mol) of Boc anhydride dropwise, and react at 25°C for 12 hours to keep the reaction system alkaline;

[0040] 3) Raise the temperature to 60°C, slowly add 194g (3.2 mol) of ammonia water dropwise, and drop it in about 3 hours. Control the temperature at 60°C for 2.5 hours, lower the temperature below 25°C, extract the reaction liquid three times with 900ml of ethyl acetate, dry the ethyl acetate layer with sodium sulfate, filter, concentrate under reduced pressure below 60°C, evaporate the ethyl acetate to dryness, and cool to obtain N -Boc piperazine 175.3g, yield 94.3%, purity 99.42%.

technical field

[0001] The invention relates to a synthesis method of N-Boc piperazine, which belongs to the technical field of organic synthesis. Background technique

[0002] N-Boc piperazine, Chinese aliases: N-tert-butoxycarbonyl piperazine, piperazine-1-tert-butyl carboxylate; Molecular formula C 9 h 18 N 2 o 2 , molecular weight: 186.25. The chemical structural formula is as follows:

[0003]

[0004] N-Boc piperazine belongs to piperazine monosubstituted compounds. Due to its special structure, piperazine monosubstituted compounds have become key intermediates in the synthesis of many drugs, such as glucocorticoids such as palbociclib, ranolazine, and dexamethasone. Therefore, the synthesis of piperazine monosubstituted compounds has very important pharmaceutical and economic value.

[0005] The method for synthesizing N-Boc piperazine mainly contains following two kinds at present:

[0006] Method 1: Use anhydrous piperazine to drop di-tert-butyl dicarbona...

Examples

Embodiment 1

[0030] 1) Add 357g (3mol) of thionyl chloride to a 2000ml reaction flask, dropwise add 105g (1mol) of diethanolamine, heat up and reflux for 4 hours; cool down to below 10°C, add 1000ml of purified water and stir until no heat release;

[0031] 2) Add 636g (6mol) of sodium carbonate to dissolve, pH>10; within a temperature control of 10-20°C, add 218g (1mol) of Boc anhydride dropwise, and react at 25°C for 12 hours to keep the reaction system alkaline;

[0032] 3) Raise the temperature to 60°C, slowly add 182g (3mol) of ammonia water dropwise, and finish dripping in about 3 hours; control the temperature at 60°C for 3 hours, then lower the temperature to below 25°C, and extract the reaction solution three times with 900ml of ethyl acetate (300ml each time ), dry the ethyl acetate layer with sodium sulfate, filter, concentrate under reduced pressure below 60°C, evaporate the ethyl acetate to dryness, and cool to obtain 174.8g of N-Boc piperazine, with a yield of 94.0% and a puri...

Embodiment 2

[0034] 1) Add 327g (2.75mol) of thionyl chloride to a 2000ml reaction flask, dropwise add 105g (1mol) of diethanolamine, heat up and reflux for 4.5h; cool down to below 10°C, add 1000ml of purified water and stir until no heat release;

[0035] 2) Add 583g (5.5mol) of sodium carbonate to dissolve, pH>10; within a temperature control of 10-20°C, add 214g (0.98mol) of Boc anhydride dropwise, and react at 25°C for 14 hours to keep the reaction system alkaline;

[0036] 3) Raise the temperature to 60°C, slowly add 170g (2.8mol) of ammonia water dropwise, and finish dripping in about 3 hours; control the temperature at 60°C for 3.5 hours, lower the temperature below 25°C, and extract the reaction liquid three times with 900ml ethyl acetate, Yuan Mingfen Dry the ethyl acetate layer, filter, concentrate under reduced pressure below 60°C, evaporate the ethyl acetate to dryness, and cool to obtain 174.5 g of N-Boc piperazine with a yield of 93.8% and a purity of 99.72%.

Embodiment 3

[0038] 1) Add 387g (3.25mol) of thionyl chloride to a 2000ml reaction flask, dropwise add 105g (1mol) of diethanolamine, heat up and reflux for 3.5h; cool down to below 10°C, add 1000ml of purified water and stir until no heat release;

[0039] 2) Add 689g (6.5mol) of sodium carbonate to dissolve, pH>10. Control the temperature at 10-20°C, add 222g (1.02mol) of Boc anhydride dropwise, and react at 25°C for 12 hours to keep the reaction system alkaline;

[0040] 3) Raise the temperature to 60°C, slowly add 194g (3.2 mol) of ammonia water dropwise, and drop it in about 3 hours. Control the temperature at 60°C for 2.5 hours, lower the temperature below 25°C, extract the reaction liquid three times with 900ml of ethyl acetate, dry the ethyl acetate layer with sodium sulfate, filter, concentrate under reduced pressure below 60°C, evaporate the ethyl acetate to dryness, and cool to obtain N -Boc piperazine 175.3g, yield 94.3%, purity 99.42%.

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