Synthetic method of nafcillin sodium

A technology of nafcillin sodium and its synthesis method, which is applied in the field of synthesis of semi-synthetic antibiotic nafcillin sodium, can solve the problems of incomplete reaction, low condensation reaction temperature, and many side reactions in the reaction system, and improve the purity and yield , improve yield and quality, and reduce pollution

Active Publication Date: 2009-06-17
朗致集团江西医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The main reason for the low yield of this synthetic method is that the consumption of thionyl chloride is large, and there are many side reactions in the reaction system; the second is that the condensation reaction temperature is low and the time is short, resulting in incomplete reaction

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Add 100kg of dichloromethane, 40kg of 2-ethoxy-1-naphthoic acid and 1.9kg of triethylamine into a dry reaction tank, add 22kg of thionyl chloride at room temperature, raise the temperature to 65°C for reflux reaction for 3h, then cool down to room temperature , and the resulting acid chloride reaction hydraulic pressure into the high level tank for standby.

[0028] Add 400kg of dichloromethane and 37kg of 6-APA into another dry reaction tank, add 42kg of triethylamine dropwise, and stir to dissolve and clarify the 6-APA.

[0029] Add the above-mentioned acid chloride reaction solution that was pressed into the high-level tank dropwise into the 6-APA solution, and keep the reaction at 15°C for 60 minutes. After the reaction, acidify to pH=1.5-2.0 with 5% sulfuric acid, separate the phases of the solution, discard the aqueous phase, add 960L of 4% aqueous sodium carbonate solution to the organic phase, separate the phases of the solution, reclaim the organic phase, and k...

Embodiment 2

[0031] Add 100kg of dichloroethane, 40kg of 2-ethoxyl-1-naphthoic acid and 0.65kg of pyridine into a dry reaction tank, and add 24.2kg of thionyl chloride at room temperature. Raise the temperature to 68°C for reflux reaction for 2 hours, then cool down to room temperature, and put the obtained acid chloride reaction fluid into the high level tank for later use.

[0032] Add 400kg of dichloroethane and 37kg of 6-APA into another dry reaction tank, add 42kg of triethylamine dropwise, and stir to dissolve and clarify the 6-APA.

[0033] Add the above acid chloride reaction liquid that was pressed into the high level tank dropwise into the 6-APA solution, and keep the reaction at 17°C for 45 minutes. After the reaction, acidify to pH=1.5-2.0 with 5% sulfuric acid, separate the phases of the solution, discard the aqueous phase, add 750 L of 4% aqueous sodium bicarbonate solution to the organic phase, separate the phases of the solution, and reclaim the organic phase. Retain the a...

Embodiment 3

[0035] Add 100kg of chloroform, 40kg of 2-ethoxyl-1-naphthoic acid and 1kg of diisopropylamine in a dry reaction tank, and add 25.3kg of thionyl chloride at room temperature. Raise the temperature to 73°C, reflux the reaction for 1.5h, cool down to room temperature, and put the obtained acid chloride reaction liquid into the high level tank for later use.

[0036] Add 400kg of chloroform and 37kg of 6-APA into another dry reaction tank, add dropwise 42kg of triethylamine, and stir to dissolve and clarify the 6-APA.

[0037] Add the acid chloride reaction liquid that was pressed into the high-level tank above dropwise into the 6-APA solution, and keep warm at 20°C for 0.5h. After the reaction, acidify to pH=1.5-2.0 with 5% sulfuric acid, separate the phases of the solution, discard the aqueous phase, add 750 L of 2% aqueous sodium hydroxide solution to the organic phase, separate the phases of the solution, reclaim the organic phase, and keep The crude product of nafcillin sod...

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PUM

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Abstract

The invention relates to a method for synthesizing nafcillin sodium, which comprises the following steps: in the presence of an organic base catalyst, dripping thionyl chloride into an organic solution of 2-ethoxy-1-naphthoic acid to prepare an acyl chloride solution through reflux reaction; dissolving 6-APA in an organic solvent of trimethylamine, dripping the acyl chloride solution into the organic solvent to carry out a condensation reaction, acidifying the solution after the reaction is finished to split phase for the solution, removing a water phase, reserving an organic phase, alkalifying the solution to split the phase, and reserving the water phase to obtain a crude product of the nafcillin sodium. The method for synthesizing the crude product of the nafcillin sodium eliminates damage to acyl chloride during reducing pressure and evaporating excessive thionyl chloride after acyl chlorination reaction, improves yield and quality of the acyl chlorination reaction, reduces environmental pollution to the utmost extent simultaneously, provides optimal temperature and time of condensation reaction, improves purity and yield of the product, and lowers cost greatly.

Description

technical field [0001] The invention relates to a method for synthesizing a semi-synthetic antibiotic nafcillin sodium, in particular to a method for synthesizing a crude product of nafcillin sodium. The crude product of nafcillin sodium of the present invention exists in the form of an aqueous solution. Background technique [0002] Nafcillin sodium is also known as ethoxynaphthylin, new penicillin III, chemical name (2S, 5R)-3,3-dimethyl-6-(2-ethoxy-1-naphthyl)-7-oxidation- 4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid sodium salt monohydrate, molecular formula C 21 h 21 o 5 N 2 SNa·H 2 O, molecular weight 454.49, trade name Unipen, first developed by Wyeth Company of the United States, suitable for penicillin-resistant staphylococcal infections and other penicillin-sensitive bacterial infections, such as: sepsis, endocarditis, empyema, liver abscess, pneumonia, Osteomyelitis etc. Nafcillin sodium is acid-resistant and penicillinase-resistant, which can be take...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D499/74
Inventor 李忠华陆晨阳刘秀兰郭剑虹杨秉一郭锦玉任青花杜容
Owner 朗致集团江西医药有限公司
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