Preparation method of cefoxitin sodium

A technology of cefoxitin sodium and cephalosporanic acid, applied in the direction of organic chemistry, can solve the problems of cumbersome process, difficult to obtain, long reaction steps, etc., and achieve the effect of simple operation process, high yield and purity, and high selectivity

Active Publication Date: 2013-12-18
HAINAN HULUWA PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are three main synthetic routes: (1) Using cephamycin as a raw material, first modify the amino group on its carboxylic acid side chain, and then modify its four-membered ring. This route has cumbersome processes and requires precious metal catalysts and other shortcomings, so it has not met the needs of large-scale industrial production; (2) Using cephalosporin acid or sodium salt as raw material, first modify the C of 7-aminocephalosporanic acid (7-ACA) 3 The side chain on the position, and then modify the C 7 Amino side chain or ceftinic acid or sodium salt as raw material, first modify the C of 7-ACA 7 Amino side chain, then modify C 3 Although the raw material of this route is cheap and easy to get, molecular sieves need to be used in the reaction process and the reaction steps are generally long, so it has not been able to industrialized production; (3) with methoxycephalosporin (7- MAC) as the raw material, first modify the C of 7-MAC 7 amino side chain, and then modify the side chain on the C3 position. Although the synthesis steps of this route are relatively simple, 7-MAC is expensive and not easy to obtain, so it has not been applied to industrial production.

Method used

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  • Preparation method of cefoxitin sodium
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  • Preparation method of cefoxitin sodium

Examples

Experimental program
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Effect test

Embodiment 1

[0035] Synthesis of 7-α-methoxy-7-[(2-thienyl)acetamido]-4-cephalosporanic acid cyclohexylamine salt (IV)

[0036] (1) Add 324ml of dichloromethane, 36ml of methanol, and 360g of cephalothin into a three-neck reaction flask, and cool down to -20°C. Stir well. Add 10.12g of methanesulfonic acid, cool, add NBS (N-bromosuccinimide) (256g) in batches, add sodium methoxide (1163g), fully stir the reaction for 2h, after the reaction is complete, add 8.24g of sodium sulfite, acetic acid 60ml, saturated sodium chloride solution. After reacting for 3 hours, heat up to 0°C, adjust the pH value to 2 with 2mol / L hydrochloric acid, separate the liquid, wash the organic layer with water, add cyclohexylamine solution to pH 6.5, add isopropyl ether, and stir at 0°C for 2h , precipitated white crystals, stood overnight, filtered, washed the filter cake with acetone, and dried to obtain 43.5g of compound IV (97.9% yield, 97.6% purity);

[0037] The above compound was subjected to elemental a...

Embodiment 2

[0040] Synthesis of 3-Hydroxymethyl-7-α-[(2-thienyl)acetamido]-4-cephalosporanic acid benzathine acetate salt (IV)

[0041] (2) Add 130.4ml of water and 146.4ml of methanol into a three-neck reaction flask, cool down, add 410g of compound IV, and cool down. Slowly add pre-cooled 4mol / L sodium hydroxide solution to adjust the pH value to 10, stir well until complete reaction. Adjust the pH with acetic acid, raise the temperature to adjust the pH, raise the temperature to 25°C, add ethyl acetate and 16g of benzathine acetate, and keep stirring at 25°C for 2h. Filter and filter cake with water in turn. Rinse with ethyl acetate and dry to obtain compound V287.11g (96% yield, 97.63% purity).

Embodiment 3

[0043] Synthesis of Cefoxitin Sodium (I)

[0044] (3) Add 287.11 g of compound IV and THF into a three-neck reaction flask, cool, add 158.97 g of pre-cooled chlorosulfonyl isocyanate in batches, and fully stir until the reaction is complete. Pour the reaction solution into pre-cooled distilled water, stir for 2 hours, add ethyl acetate, filter the contents, and add 10% sodium chloride solution to the filtrate. Stir for 10 min. Separate the liquid, wash the organic layer with 10% sodium chloride solution, adjust the pH value to 2.0 with 2 mol / L hydrochloric acid, precipitate white crystals, let stand overnight, filter, wash the filter cake with ethyl acetate, and dry in vacuo. Get cefoxitin. Add acetone solution, add 2.0 g of sodium lactate at 30°C, stir for 10 min, then add acetone, filter and dry the obtained solid in vacuum to obtain 319.59 g of cefoxitin sodium (95% yield, 99.5% purity).

[0045] The above compound was subjected to elemental analysis, and the results wer...

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Abstract

The invention discloses a preparation method of cefoxitin sodium. The preparation method comprises the following steps: (1) bromizing, for example, the site 7 of a main nucleus of cefalotin by using an NBS (N-bromosuccinimide) reagent to form a bromination compound; performing nucleophilic substitution at the site 5 by using a methoxyl group to generate an intermediate IV; (2) performing acyl group hydrolysis on the site 3 of the intermediate IV to obtain an intermediate V; (3) substituting hydrogen atoms on the hydroxyl group by using chloriosulfonyl isocyanate, and then hydrolyzing to obtain the cefoxitin sodium. The method has the advantages of simple process, high product yield, high purity and high reaction selectivity; no special equipment is used in the production; the preparation method is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of raw material medicine preparation, in particular to a preparation method of cefoxitin sodium. Background technique [0002] Cefoxitin sodium, chemical name: (6R,7S)-3-carbamoyloxymethyl-7-methoxy-8-oxo-7-[2(2-thiophene, acetamido)]- 5-Thia-1-azabicyclo-[4,2,0]-oct-2-ene-carboxylic acid sodium salt, molecular formula: C 16 h 16 N 3 NaO 7 S 2 , molecular weight: 449.43, the chemical structure is as follows: [0003] [0004] Cefoxitin Sodium, developed by Merk Company of the United States and listed in 1994, is a new type of antibiotic produced by semi-synthesis of methoxycephalosporin C produced by Streptomyces. Cefoxitin sodium can kill bacteria due to its ability to inhibit the synthesis of bacterial cell walls, and due to its structural specificity, it is stable to the β-lactamase produced by bacteria, so it has huge market potential. [0005] At present, the synthetic method of cefoxitin sodium has man...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/57C07D501/04
Inventor 刘全国陈克领
Owner HAINAN HULUWA PHARMA GRP CO LTD
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