Method for preparing cefprozil dimethyl formamide solvate

A technology of propylene dimethyl formamide and solvate, which is applied in the field of preparation of important intermediates of antibiotics, and can solve the problems of high price and unstable silylating reagents, etc.

Active Publication Date: 2012-05-09
CSPC MEGALITH BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] The object of the present invention is to provide a kind of preparation method of improved cefprozil DMF solvate, this method overcomes the instability of silylating reagent in the existing cef

Method used

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  • Method for preparing cefprozil dimethyl formamide solvate
  • Method for preparing cefprozil dimethyl formamide solvate
  • Method for preparing cefprozil dimethyl formamide solvate

Examples

Experimental program
Comparison scheme
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Example Embodiment

[0040] Example 1: Preparation of Cefprozil DMF Solvate (I)

[0041] (1) Synthesis of 7-APCA-tetramethylguanidine salt (Compound VII)

[0042] 7-APCA (31.155g, 0.1298mol) was suspended in dichloromethane (240mL), and the temperature was lowered to -15~-5°C. Tetramethylguanidine (14.928g, 0.1298mol) was added dropwise, the temperature was kept and stirred for 30 minutes, and the temperature was kept for later use.

[0043] (2) Synthesis of mixed anhydride (compound VIII)

[0044] D-p-hydroxyphenylglycine Deng potassium salt (45.36g, 0.1497mol) was added to a mixed solution of dichloromethane (60mL), DMF (120mL) and pyridine (0.39mL), and stirred at room temperature to obtain a suspension. When the temperature was lowered to -35°C, a mixed solution of pivaloyl chloride (18.63 mL) and dichloromethane (60 mL) was added dropwise. After the addition is complete, continue stirring at the same temperature for 3 hours.

[0045] (3) Condensation reaction

[0046] At -30°C, the 7-APCA-tetramethyl...

Example Embodiment

[0049] Example 2: Preparation of Cefprozil DMF Solvate (I)

[0050] (1) Synthesis of 7-APCA-tetramethylguanidine salt (Compound VII)

[0051] 7-APCA(III) (31.155g, 0.1298mol) was suspended in dichloromethane (240mL), and the temperature was lowered to -15~-5°C. Tetramethylguanidine (14.928g, 0.1298mol) was added dropwise, the temperature was kept and stirred for 30 minutes, and the temperature was kept for later use.

[0052] (2) Synthesis of mixed anhydride (compound VIII)

[0053] D-p-hydroxyphenylglycine Deng potassium salt (45.36 g, 0.1497 mol) was added to a mixed solution of dichloromethane (117 mL), DMF (74.55 mL) and pyridine (0.39 mL), and stirred at room temperature to obtain a suspension. When the temperature was lowered to -35°C, 18.63 mL of pivaloyl chloride was added dropwise. After the addition is complete, continue stirring at the same temperature for 2 hours, and finally add 62 mL of cold DMF to dilute.

[0054] (3) Condensation reaction

[0055] At -40°C to -30°C, th...

Example Embodiment

[0058] Example 3: Preparation of Cefprozil DMF Solvate (I)

[0059] (1) Synthesis of 7-APCA-tetramethylguanidine salt (Compound VII)

[0060] 7-APCA(III) (31.155g, 0.1298mol) was suspended in dichloromethane (240mL), and the temperature was lowered to -15~-5°C. Tetramethylguanidine (14.928g, 0.1298mol) was added dropwise, the temperature was kept and stirred for 30 minutes, and the temperature was kept for later use.

[0061] (2) Synthesis of mixed anhydride (compound VIII)

[0062] D-p-hydroxyphenylglycine Deng potassium salt (45.36 g, 0.1497 mol) was added to a mixed solution of dichloromethane (117 mL), DMF (74.55 mL) and pyridine (0.39 mL), and stirred at room temperature to obtain a suspension. When the temperature was lowered to -35°C, 18.63 mL of pivaloyl chloride was added dropwise. After the addition is complete, continue stirring at the same temperature for 2 hours, and finally add 62 mL of cold DMF to dilute.

[0063] (3) Condensation reaction

[0064] At -40°C to -30°C, th...

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Abstract

The invention relates to an improved method for preparing a cefprozil dimethyl formamide (DMF) solvate; the method comprises the following steps of: taking a 7-APCA-guanidine salt shown by the formula IV and a mixed anhydride shown by the formula VI as raw materials to carry out a condensation reaction under alkaline conditions, hydrolyzing reaction liquid in the presence of acids, separating the liquid, adding DMF to a water phase, and regulating a pH value with an alkaline to obtain the cefprozil DMF solvate shown by the formula I. The method of the invention avoids the usage of silanizing reagent with expensive cost and instability, improves yield greatly and reduces production cost to form a more economic and efficient preparation technology, wherein X+ and R6 are defined according to claim 1.

Description

technical field [0001] The present invention relates to a kind of preparation method of important intermediate of antibiotics, in particular to a kind of preparation method of cefprozil dimethylformamide solvate (hereinafter referred to as cefprozil DMF solvate) shown in formula I. [0002] Background technique [0003] The chemical name of cefprozil is (6R,7R)-7-[2-amino-2-(4-hydroxyphenyl)acetamido]-3-[(Z)-propenyl]-3-cephem-4- Carboxylic acid, which is a monohydrate for medicinal use (the structural formula is shown in formula II). This substance is a cephalosporin broad-spectrum antibacterial drug developed by Bristol-Myers Squibb Company of the United States. + , G - Bacteria and anaerobic bacteria have strong antibacterial activity, against G + Bacteria are particularly prominent. [0004] [0005] Cefprozil DMF solvate is an important intermediate in the synthesis of cefprozil. [0006] In U.S. Patents US20040087786, US20090048460, Chinese patents CN1694888...

Claims

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Application Information

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IPC IPC(8): C07D501/22C07D501/04
Inventor 宋灵杰刘长鹰郑旭光付德才康钰
Owner CSPC MEGALITH BIOPHARMACEUTICAL CO LTD
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