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Preparation method of cefprozil

A technology of cefprozil and organic solvent, which is applied in the field of preparation of cefprozil, and can solve the problems of difficult acquisition of starting materials, complicated operation and long synthesis steps, etc.

Inactive Publication Date: 2012-08-15
吴彬 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] China Journal of Pharmaceutical Industry, 2004, 35 (7), 388~390 reported a method for the synthesis of cefprozil using GCLH as the starting material. Same as the GCLE route, the process also has the difficulty of getting the starting material, long synthesis steps, and difficult operation. Complicated and many wastes are discharged, and the total yield is only 16.4%. The route is as follows:

Method used

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  • Preparation method of cefprozil
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  • Preparation method of cefprozil

Examples

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Embodiment 1

[0018] Under nitrogen protection, add 35 grams of 7-amino-3-propenylcephalosporanic acid and 200 milliliters of dichloromethane into a three-necked flask, cool down to -45~-55 ° C, add 18 grams of tetramethylguanidine, stir to dissolve, and control Warm to -20~-25°C, keep warm for later use. In another flask, add 100ml of dichloromethane, 100ml of N,N-dimethylformamide, 300ml of picolin, cool down to -50°C, add 55g of p-hydroxydane, and control the temperature at about -50°C Add 22 grams of pivaloyl chloride, after the addition is complete, keep the temperature at -20~-25°C for 1 hour, cool down to -70°C, add a dichloromethane solution of 7-amino-3-propenylcephalosporanic acid, and complete the addition. Raise the temperature to -20~-25°C, control the temperature and react for 2 hours, monitor 7-amino-3-propenyl cephalosporanic acid <<3% by HPLC, stop the reaction, add 90 ml of water and 37 g of hydrochloric acid, heat up to 5°C , adjust pH=1.5, stir for 30 minutes, stand to ...

Embodiment 2

[0020] Under the protection of nitrogen, add 32 grams of 7-amino-3-propenyl cephalosporanic acid and 200 milliliters of dichloroethane into the three-necked flask, cool down to -65~-75 ° C, add 18 grams of tetramethylguanidine, stir to dissolve, Control the temperature to -30~-35°C and keep warm for later use. In another flask, add 100ml of dichloroethane, 100ml of N,N-dimethylformamide, 300ml of picolin, cool down to -70°C, add 58g of p-Hydroxydan salt, and control the temperature at -70°C Add about 25 grams of pivaloyl chloride, after the addition, keep the temperature at -15~-20°C for 1 hour, cool down to -70°C, add the dichloroethane solution of 7-amino-3-propenylcephalosporanic acid, add Complete, heat up to -15~-20 ℃, temperature control reaction 2 hours, HPLC monitors to 7-amino-3-propenyl cephalosporanic acid <<3%, stop reaction, add 90 milliliters of water and 37 grams of hydrochloric acid, heat up to 0°C, adjust pH=2.8, stir for 30 minutes, stand to separate layers,...

Embodiment 3

[0022] Under nitrogen protection, add 33 grams of 7-amino-3-propenyl cephalosporanic acid and 200 milliliters of dichloroethane into the three-necked flask, cool down to -30~-35 °C, add 19 grams of tetramethylguanidine, stir to dissolve, Control the temperature to -5 ~ 0 ℃, keep warm for later use. In another flask, add 100 ml of dichloroethane, 100 ml of N,N-dimethylformamide, 280 ml of picolin, cool down to -30°C, add 59 g of p-hydroxydane, and control the temperature at -30°C Add about 24 grams of pivaloyl chloride, after the addition, keep the temperature at -5-0°C for 1 hour, cool down to -50°C, add the dichloroethane solution of 7-amino-3-propenylcephalosporanic acid, and finish the addition , heated up to 0-5°C, and reacted with temperature control for 2 hours. HPLC monitored that 7-amino-3-propenyl cephalosporanic acid <<3%, stopped the reaction, added 110 ml of water and 40 g of hydrochloric acid, and heated to 10°C. Adjust pH=2, stir for 30 minutes, stand to separat...

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Abstract

The invention discloses an economical and effective method for preparing cefprozil, which comprises the following steps: carrying out acylation reaction on 7-amino-3-propenylcephalosporanic acid, which is used as an initial raw material, and mixed anhydrides of p-hydroxyl phenyl glycine potassium salt and pivaloyl chloride in a solvent, hydrolyzing, and refining to obtain the cefprozil.

Description

technical field [0001] The invention relates to a preparation method of cefprozil and belongs to the field of drug antibiotics. Background technique [0002] Cefprozil (Cefprozil), the chemical name is (6R, 7R)-7-[(2R)-amino(4-hydroxyphenyl)acetamido]-8-oxo-3-(1-propenyl)-5- Thio-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, which is a monohydrate for medicinal use, is a cephalosporin spectrum antibacterial drug developed by Bristol-Myers Squibb Company in the United States. The antibacterial activities of G+, G- bacteria and anaerobic bacteria are all very strong, and the activity against G+ bacteria is particularly prominent. It is clinically used for mild and moderate infections caused by sensitive bacteria, including upper and lower respiratory tract infections, as well as skin and skin soft tissue infections. [0003] Regarding the synthesis of cefprozil, it is mainly divided into two routes, GCLE and 7-ACA, according to the starting materials. Wherein US4694079, US...

Claims

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Application Information

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IPC IPC(8): C07D501/22C07D501/04
Inventor 吴彬胡国刚
Owner 吴彬
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