Method for preparing cefonicid or its medicinal salt and intermediate

Abstract

The invention provides a method for preparing cephalosporin nixi or its salt and its intermediate. The invention employs alkyl sulfonic acid to replace BF3 used in curretn technique as catalyst for reaction of 1- methanesulfonic acid- 5- mercapto- 1, 2, 3, 4- tetrazole acid or its salt and 7-aminocephalosporanic acid or its salt. It is characterized by reduced cost, decreased energy consumption, less toxic waste gas discharge and apparent economic benefit.

Description

technical field

[0001] The present invention relates to a preparation method of a compound, especially a method for preparing cefnixime or its pharmaceutically acceptable salt and its intermediate. Background technique

[0002] Cefonicid, the English name is Cefonicid, and the main medicinal salt is cefonicid sodium. Cefnixime Sodium, Molecular Formula C 18 h 16 N 6 Na 2 o 8 S 3 , molecular weight 585.9987. Cefnicest sodium is a second-generation cephalosporin developed by GlaxoSmithKline in the UK. It was launched in the U.S. under the trade name of "monocid" in 1984, and was successively launched in Belgium and Spain. It is used for sepsis, joints, skin, lower respiratory tract and urinary tract. Infection treatment.

[0003] The early bibliographical reports of the synthesis of cefnixime sodium are represented by US Pat. -1-methanesulfonic acid); then condensed with 7-D-mandelic acid amido-cephalosporanic acid methyl ester, decarboxylated and salified to obtain t...

Examples

Embodiment 1

[0033] The preparation of embodiment 1 BP1 acid

[0034] Add 300mL of methanesulfonic acid and 115ml of dichloromethane into the dry reaction kettle, add 52g of TSA acid under stirring, and stir for 30 minutes until completely dissolved. Cool down to 20°C, add 76.5g of 7-ACA, and react at 25°C for 60 minutes. After the reaction was completed, 382.5 ml of water and 612 ml of methanol were added at room temperature. Adjust the pH to 2.5-3.0 with sodium bicarbonate, and stir at room temperature for 30 minutes. After filtering, the filter cake was washed twice with a mixed solution of methanol and water. The material was filtered and dried in vacuum at 35° C. to constant weight to obtain about 108 g of product BP1 acid. (yield 96%, HPLC purity 99%)

Embodiment 2

[0035] The preparation of embodiment 2 cefnixin sodium

[0036] 1) Acetylation: Add BP1 acid (100 g) to a mixture of pure water (800 ml) and tetrahydrofuran (600 ml), stir well, and cool down to 2°C. Then add 35ml of dilute ammonia (1:1) to dissolve it completely. Control the temperature at 0°C, add D-(-)-formylmandelic acid chloride solution (53g of D-(-)-formylmandelic acid chloride solution is dissolved in 200ml of tetrahydrofuran), and add dilute ammonia water (1:1) dropwise during the process Maintain the pH between 6.5 and 7.0. After the addition, the temperature was controlled at 0°C for 30 minutes. Then the reaction solution was washed twice with dichloromethane, adding 150 ml of dichloromethane each time.

[0037] 2) Deformylation: Add HCl (35-40ml) dropwise to the above aqueous solution, adjust the pH to 1.0, keep warm at 30°C for 20 hours, then cool down to 20°C, and decolorize with 10g of activated carbon for 30 minutes.

[0038] 3) Extraction: filter, and wash...

technical field

[0001] The present invention relates to a preparation method of a compound, especially a method for preparing cefnixime or its pharmaceutically acceptable salt and its intermediate. Background technique

[0002] Cefonicid, the English name is Cefonicid, and the main medicinal salt is cefonicid sodium. Cefnixime Sodium, Molecular Formula C 18 h 16 N 6 Na 2 o 8 S 3 , molecular weight 585.9987. Cefnicest sodium is a second-generation cephalosporin developed by GlaxoSmithKline in the UK. It was launched in the U.S. under the trade name of "monocid" in 1984, and was successively launched in Belgium and Spain. It is used for sepsis, joints, skin, lower respiratory tract and urinary tract. Infection treatment.

[0003] The early bibliographical reports of the synthesis of cefnixime sodium are represented by US Pat. -1-methanesulfonic acid); then condensed with 7-D-mandelic acid amido-cephalosporanic acid methyl ester, decarboxylated and salified to obtain t...

Examples

Embodiment 1

[0033] The preparation of embodiment 1 BP1 acid

[0034] Add 300mL of methanesulfonic acid and 115ml of dichloromethane into the dry reaction kettle, add 52g of TSA acid under stirring, and stir for 30 minutes until completely dissolved. Cool down to 20°C, add 76.5g of 7-ACA, and react at 25°C for 60 minutes. After the reaction was completed, 382.5 ml of water and 612 ml of methanol were added at room temperature. Adjust the pH to 2.5-3.0 with sodium bicarbonate, and stir at room temperature for 30 minutes. After filtering, the filter cake was washed twice with a mixed solution of methanol and water. The material was filtered and dried in vacuum at 35° C. to constant weight to obtain about 108 g of product BP1 acid. (yield 96%, HPLC purity 99%)

Embodiment 2

[0035] The preparation of embodiment 2 cefnixin sodium

[0036] 1) Acetylation: Add BP1 acid (100 g) to a mixture of pure water (800 ml) and tetrahydrofuran (600 ml), stir well, and cool down to 2°C. Then add 35ml of dilute ammonia (1:1) to dissolve it completely. Control the temperature at 0°C, add D-(-)-formylmandelic acid chloride solution (53g of D-(-)-formylmandelic acid chloride solution is dissolved in 200ml of tetrahydrofuran), and add dilute ammonia water (1:1) dropwise during the process Maintain the pH between 6.5 and 7.0. After the addition, the temperature was controlled at 0°C for 30 minutes. Then the reaction solution was washed twice with dichloromethane, adding 150 ml of dichloromethane each time.

[0037] 2) Deformylation: Add HCl (35-40ml) dropwise to the above aqueous solution, adjust the pH to 1.0, keep warm at 30°C for 20 hours, then cool down to 20°C, and decolorize with 10g of activated carbon for 30 minutes.

[0038] 3) Extraction: filter, and wash...

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