A kind of preparation method of high-purity doripenem

Abstract

The invention discloses a method for preparing high purity doripenem. The method comprises the following steps: (1) conducting a contact reaction on carbapenem bicyclic nucleus and (2S,4S)-1-p-nitrocarbobenzoxy-4-sulfenyl-2-(N-sulfamoyl amino)methylpyrrolidine in a water and 1,4-dioxane mixed solvent in the presence of copper salt and triethylamine; adding water and ethyl acetate, stirring, standing for layering, concentrating the ethyl acetate layer; recrystallizing a dichloromethane and petroleum ether mixed solvent to obtain (1R,5S,6S)-2-[(3S,5S)-1-nitrophenyl formate-5-sulfamoyl amino methylpyrrolidine-3-sulfenyl]-6-[(1R)-1-ethoxyl]-1-methyl-1-carba-2-penem-3-p-nitrobenzyl carboxylate; and (2) adding the product obtained in the step (1), tetrabutyl ammonium chloride and 0.2M of phosphate buffered solution having a pH value of 8 into a reaction kettle which is filled with water, replacing three times with hydrogen, adding hydrogen to react, filtering, concentrating the filtrate, and recrystallizing in methanol to obtain doripenem.

Description

technical field

[0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of high-purity doripenem. Background technique

[0002] Doripenem is a broad-spectrum carbapenem antibiotic developed by Shionogi Co., Ltd., Japan. Its chemical name is (4R,5S,6S)-3-[((3S,5S)-5 -[[(sulfamoyl)amino]methyl]-3-pyrrolidinyl)mercapto-6-[(1R)-1-hydroxyethyl]4-methyl-7-oxyl-1-azadi Cyclo[3.2.0]hept-2-ene-2-carboxylic acid], the structural formula is as follows:

[0003]

[0004] It can be seen from the structural formula that doripenem is a 1β-methyl carbapenem antibiotic, and the 2-position side chain is a hydrogenated pyrrole ring substituted by aminosulfonamide. Its antibacterial mechanism is the same as that of other β-lactam antibiotics. Penicillin binding proteins (PBPs) bind to inhibit bacterial cell wall synthesis.

[0005] Those skilled in the art have conducted extensive research on the preparation method of ...

Examples

Embodiment 1

[0030] A preparation method of doripenem, the preparation method comprising the following steps:

[0031]1) In the presence of copper nitrate and triethylamine, the carbapenem bicyclic nucleus (60.8g, 0.1mol) was mixed with (2S,4S)-1-p-nitrobenzyloxycarbonyl-4-thio-2- (N-sulfamoylamino)methylpyrrolidine was contacted in a mixed solvent of 800mL water and 1,4-dioxane (the volume ratio of water and 1,4-dioxane was 1:15) , the conditions of the contact reaction include first reacting at 15°C until the reaction of the carbapenem bicyclic nucleus is completed, then cooling down to -10°C to continue the reaction for 2 hours, and then raising the temperature to 10°C for 2 hours. After the reaction, add water and ethyl acetate to stir, let stand to separate layers, concentrate the ethyl acetate layer, then recrystallize from the mixed solvent of dichloromethane and sherwood oil (the volume ratio of dichloromethane and sherwood oil is 1:8) Get (1R,5S,6S)-2-[(3S,5S)-1-benzyl p-nitrofor...

Embodiment 2

[0034] A preparation method of doripenem, the preparation method comprising the following steps:

[0035] 1) In the presence of copper nitrate and triethylamine, the carbapenem bicyclic nucleus (60.8g, 0.1mol) was mixed with (2S,4S)-1-p-nitrobenzyloxycarbonyl-4-thio-2- (N-sulfamoylamino) methylpyrrolidine is contacted in a mixed solvent of 800ml water and 1,4-dioxane (the volume ratio of water and 1,4-dioxane is 1:15) , the conditions of the contact reaction include first reacting at 13°C until the reaction of the carbapenem bicyclic nucleus is completed, then cooling down to -15°C to continue the reaction for 1 hour, and then raising the temperature to 15°C for 2 hours. After the reaction, add water and ethyl acetate to stir, let stand to separate layers, concentrate the ethyl acetate layer, then recrystallize from the mixed solvent of dichloromethane and sherwood oil (the volume ratio of dichloromethane and sherwood oil is 1:6) Get (1R,5S,6S)-2-[(3S,5S)-1-benzyl p-nitroform...

Embodiment 3

[0038] A preparation method of doripenem, the preparation method comprising the following steps:

[0039] 1) In the presence of copper chloride and triethylamine, the carbapenem bicyclic nucleus (60.8g, 0.1mol) was mixed with (2S,4S)-1-p-nitrobenzyloxycarbonyl-4-thio-2 -(N-sulfamoylamino)methylpyrrolidine is contacted in a mixed solvent of 800ml water and 1,4-dioxane (the volume ratio of water and 1,4-dioxane is 1:10) Reaction, the conditions of the contact reaction include first reacting at 10°C until the reaction of the carbapenem bicyclic nucleus is completed, then cooling down to -10°C to continue the reaction for 2 hours, and then raising the temperature to 15°C for 3 hours. After the reaction, add water and ethyl acetate to stir, let stand to separate layers, concentrate the ethyl acetate layer, then recrystallize from the mixed solvent of dichloromethane and sherwood oil (the volume ratio of dichloromethane and sherwood oil is 1:5) Get (1R,5S,6S)-2-[(3S,5S)-1-benzyl p-...

technical field

[0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of high-purity doripenem. Background technique

[0002] Doripenem is a broad-spectrum carbapenem antibiotic developed by Shionogi Co., Ltd., Japan. Its chemical name is (4R,5S,6S)-3-[((3S,5S)-5 -[[(sulfamoyl)amino]methyl]-3-pyrrolidinyl)mercapto-6-[(1R)-1-hydroxyethyl]4-methyl-7-oxyl-1-azadi Cyclo[3.2.0]hept-2-ene-2-carboxylic acid], the structural formula is as follows:

[0003]

[0004] It can be seen from the structural formula that doripenem is a 1β-methyl carbapenem antibiotic, and the 2-position side chain is a hydrogenated pyrrole ring substituted by aminosulfonamide. Its antibacterial mechanism is the same as that of other β-lactam antibiotics. Penicillin binding proteins (PBPs) bind to inhibit bacterial cell wall synthesis.

[0005] Those skilled in the art have conducted extensive research on the preparation method of ...

Examples

Embodiment 1

[0030] A preparation method of doripenem, the preparation method comprising the following steps:

[0031]1) In the presence of copper nitrate and triethylamine, the carbapenem bicyclic nucleus (60.8g, 0.1mol) was mixed with (2S,4S)-1-p-nitrobenzyloxycarbonyl-4-thio-2- (N-sulfamoylamino)methylpyrrolidine was contacted in a mixed solvent of 800mL water and 1,4-dioxane (the volume ratio of water and 1,4-dioxane was 1:15) , the conditions of the contact reaction include first reacting at 15°C until the reaction of the carbapenem bicyclic nucleus is completed, then cooling down to -10°C to continue the reaction for 2 hours, and then raising the temperature to 10°C for 2 hours. After the reaction, add water and ethyl acetate to stir, let stand to separate layers, concentrate the ethyl acetate layer, then recrystallize from the mixed solvent of dichloromethane and sherwood oil (the volume ratio of dichloromethane and sherwood oil is 1:8) Get (1R,5S,6S)-2-[(3S,5S)-1-benzyl p-nitrofor...

Embodiment 2

[0034] A preparation method of doripenem, the preparation method comprising the following steps:

[0035] 1) In the presence of copper nitrate and triethylamine, the carbapenem bicyclic nucleus (60.8g, 0.1mol) was mixed with (2S,4S)-1-p-nitrobenzyloxycarbonyl-4-thio-2- (N-sulfamoylamino) methylpyrrolidine is contacted in a mixed solvent of 800ml water and 1,4-dioxane (the volume ratio of water and 1,4-dioxane is 1:15) , the conditions of the contact reaction include first reacting at 13°C until the reaction of the carbapenem bicyclic nucleus is completed, then cooling down to -15°C to continue the reaction for 1 hour, and then raising the temperature to 15°C for 2 hours. After the reaction, add water and ethyl acetate to stir, let stand to separate layers, concentrate the ethyl acetate layer, then recrystallize from the mixed solvent of dichloromethane and sherwood oil (the volume ratio of dichloromethane and sherwood oil is 1:6) Get (1R,5S,6S)-2-[(3S,5S)-1-benzyl p-nitroform...

Embodiment 3

[0038] A preparation method of doripenem, the preparation method comprising the following steps:

[0039] 1) In the presence of copper chloride and triethylamine, the carbapenem bicyclic nucleus (60.8g, 0.1mol) was mixed with (2S,4S)-1-p-nitrobenzyloxycarbonyl-4-thio-2 -(N-sulfamoylamino)methylpyrrolidine is contacted in a mixed solvent of 800ml water and 1,4-dioxane (the volume ratio of water and 1,4-dioxane is 1:10) Reaction, the conditions of the contact reaction include first reacting at 10°C until the reaction of the carbapenem bicyclic nucleus is completed, then cooling down to -10°C to continue the reaction for 2 hours, and then raising the temperature to 15°C for 3 hours. After the reaction, add water and ethyl acetate to stir, let stand to separate layers, concentrate the ethyl acetate layer, then recrystallize from the mixed solvent of dichloromethane and sherwood oil (the volume ratio of dichloromethane and sherwood oil is 1:5) Get (1R,5S,6S)-2-[(3S,5S)-1-benzyl p-...

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