Preparation method of cephalosporin nucleus intermediate

An intermediate and mother nucleus technology, applied in the field of preparation of cephalosporin nucleus intermediates, can solve the problems of great influence on the purity of downstream cephalosporin nucleus, destruction of cephalosporin nucleus, difficulty in product purification, etc., and achieves high GCLE content and reduced The effect of decomposing and reducing the generation of chlorinated by-products

Active Publication Date: 2012-08-22
APELOA PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the closed-loop molar yield of this process can reach 81.2% to 85.1%, since the alcohol base is a strong alkaline organic matter, the reaction process is easy to cause damage to the cephalosporin nuclei, and

Method used

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  • Preparation method of cephalosporin nucleus intermediate
  • Preparation method of cephalosporin nucleus intermediate
  • Preparation method of cephalosporin nucleus intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Preparation of Compound 2:

[0050] Put 32g of compound 3 (0.0539moL) into a 2000mL three-necked flask, stir and dissolve with 1000mL of dioxane, add catalyst 1,2-propylene oxide 10.6mL (0.15moL) and absolute ethanol 9.8mL (0.15moL), both The mixing ratio is 1:1, the temperature is lowered to -5°C, chlorine gas is slowly introduced, and when the residual raw material compound 3 is determined to be ≤0.5wt% (HPLC detection), the chlorination reaction is completed, and the solvent is recovered under reduced pressure to obtain a light yellow liquid (compound 2) 36.8g (with a small amount of solvent residue). (HPLC purity analysis: wherein monochloride 88.5wt%, dichloride 1.45wt%, polychloride 0.9wt%).

[0051] Preparation of Compound 1:

[0052] Put the prepared compound 2 into a 500mL three-necked flask, add 120mL of N,N-dimethylformamide (DMF) and stir to dissolve, add CaCl 2 (H 2 O) 2 5.33g (0.036moL), ammonium chloride 1.78g (0.033moL). The temperature was lowere...

Embodiment 2

[0054] Preparation of Compound 2:

[0055] Put 0.15moL of compound 3 into a 3000mL three-necked flask, stir and dissolve with 2000mL ethyl acetate, add 20.6mL (0.30moL) of epichlorohydrin catalyst and 0.15moL of anhydrous isopropanol, the mixing ratio of the two is 2:1, and cool down to 0 ℃, slowly feed chlorine gas, and measure the residual raw material compound 3≤0.5wt% (HPLC detection), the chlorination reaction ends, and the solvent is recovered under reduced pressure to obtain 105.2 g of light yellow liquid (compound 2) (containing a small amount of solvent residue). (HPLC purity analysis: wherein monochloride 89.1wt%, dichloride 1.42wt%, polychloride 0.86wt%).

[0056] Preparation of Compound 1:

[0057] Put the prepared compound 2 into a 3000mL three-necked flask, add 2500mL tetrahydrofuran (DMF) and stir to dissolve, add 2.6g (0.4moL) of CaO and 1.78g (0.8moL) of ammonium carbonate. The temperature was lowered to -15°C, and 0.18 mol of ethylamine was added dropwise. ...

Embodiment 3

[0059] Preparation of Compound 2:

[0060] Put 96g (0.16moL) of compound 3 into a 5000mL three-necked flask, stir and dissolve it with 3000mL of diethylene glycol monoethyl ether, add 10.6mL (0.9moL) of catalyst ethylene oxide and 6.0moL of acetic acid, cool down to 15°C, and slowly introduce chlorine gas, When it is determined that the residual raw material compound 3≤0.5wt% (HPLC detection), the chlorination reaction is completed, and the solvent is recovered under reduced pressure to obtain 120 g of a light yellow liquid (compound 2) (containing a small amount of solvent residue). (HPLC purity analysis: wherein monochloride 91wt%, dichloride 1.40wt%, polychloride 0.86wt%).

[0061] Preparation of Compound 1:

[0062] Put the prepared compound 2 into a 3000mL three-neck flask, add 2500mL of 1,3-dimethyl-2-imidazolonetetrafluoroboron and stir to dissolve, add 1.6moL of calcium hydroxide and 0.2moL of ammonium acetate. The temperature was lowered to -5°C, and 2.5 moL of ammo...

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PUM

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Abstract

The invention discloses a preparation method of a cephalosporin nucleus intermediate, which comprises chlorination reaction (a) and ring-closure reaction (b), wherein in step (a), mixed catalysts of alkylene oxide and protic solvent are adopted in chlorination reaction; and in step (b), mixed catalysts of calcium salt compound and ammonium salt compound are adopted, and the calcium salt compound and the ammonium salt compound are both inorganic salt compounds. According to the preparation method disclosed by the invention, double catalysts are adopted in both of the chlorination reaction and the ring-closure reaction for catalysis, the generation of chlorination by-products is reduced, the reaction speed and the reaction temperature of the chlorination reaction and the ring-closure reaction are increased, the decomposition of a product is reduced, the content of GCLE (7-Phenglacetamido-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester) in the obtained product is high, the yield of the product is high, the process control condition is lowered, production energy consumption is reduced, and the preparation method is more suitable for industrial large-scale production.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a preparation method of a cephalosporin nucleus intermediate. Background technique [0002] 7-phenylacetamido-3-chloromethyl cephalosporanic acid p-methoxybenzyl ester (GCLE) is an important antibiotic raw material, mainly used to synthesize cephalosporin drugs. With the development of the national economy, the market demand for GCLE continues to expand. At the end of the last century, my country mainly imported from Japan, and now it has become a major exporter. However, in the existing synthesis process, the yield of chlorination and ring closure in the final process of synthesis has not been very high, and the process conditions are harsh, and most of them need to be reacted at a low temperature of -60 to -40°C. [0003] CN200380102393.7; CN1849324A; US2004039813; Tetrahedron Letters, 23.2187 (1982) and other documents: [0004] (1), chlorination reaction [0005]...

Claims

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Application Information

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IPC IPC(8): C07D501/24C07D501/08
Inventor 厉昆
Owner APELOA PHARM CO LTD
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