The preparation method of latamoxef sodium

A technology of laoxef sodium and p-methoxybenzyl, applied in the field of laoxef sodium, can solve the problems of increasing equipment investment, increasing post-processing steps, affecting production efficiency, etc., and achieves reducing equipment investment, reducing energy consumption, The effect of improving production efficiency

Inactive Publication Date: 2011-11-30
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] 1), when preparing compound (R, S)-I, since it is an amorphous powder, silica gel column chromatography purification is required, which not only increases post-processing steps, affects production efficiency, but also increases equipment investment;
[0014] 2), in order to obtain the high-purity latamoxycetidine, need to carry out adsorption resin desalination purification treatment, in order to remove elution solvent methanol (or acetone) and water, not only need low-temperature decompression distillation to reclaim methyl alcohol (or acetone), and in order to reduce The destruction of Latamoxefac requires membrane concentration to remove water, which not only increases the processing steps, but also increases the equipment investment;
[0015] 3), when latamoxef acid is neutralized with sodium hydroxide in the aqueous phase, latamoxef sodium is obtained, and alkali will destroy latamoxef, reducing the purity of latamoxef sodium
[0021] We find that although the S-I compound of a single configuration has the above advantages, there is no report how to synthesize Latamoxef sodium by the S-I compound of a single configuration so far

Method used

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  • The preparation method of latamoxef sodium
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  • The preparation method of latamoxef sodium

Examples

Experimental program
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Effect test

Embodiment 1

[0052] Compound (S)-I (R1=p-methoxybenzyl, R2=p-methoxybenzyl, R3=benzhydryl) (3.5Kg) was dissolved in dichloromethane (2L), cooled to 0°C , add anisole (15L), dropwise add trifluoroacetic acid (3.5Kg), keep warm at 0°C for 1.0h, add dropwise methyl tert-butyl ether (20L), stir, filter, and dissolve the solid with acetone (20L), Cool to 0°C, add sodium isooctanoate (1.9Kg) / acetone (30L) dropwise, after the addition is complete, react for 30min, filter, dissolve the solid in deionized water (8L), wash with isopropyl acetate (5L), and Decolorized with activated carbon, filtered, and freeze-dried to obtain Latamoxef Sodium. Yield: 87.5%.

Embodiment 2

[0054] Compound (S)-I (R1=H, R2=p-methoxybenzyl, R3=benzhydryl) (3Kg) was dissolved in dichloromethane (5L), cooled to -20°C, and anisole was added (8L), add trifluoroacetic acid (13Kg) dropwise, keep warm at -20°C to -15°C for 1.0h, heat up to 0°C to 15°C for 1.0h, recover dichloromethane and trifluoroacetic acid under reduced pressure, add diethyl ether ( 20L), stirred, filtered, dissolved the solid with methanol (6L), cooled to -5~10°C, added dropwise sodium isooctanoate (1.4Kg) / tetrahydrofuran (60L), after the dropwise addition was completed, reacted for 30min, filtered, and the solid was dissolved in In deionized water (10 L), washed with ethyl acetate (5 L), decolorized with activated carbon in the aqueous phase, filtered, and lyophilized to obtain Latamoxef sodium. Yield: 90%.

Embodiment 3

[0056] Compound (S)-I (R1=H, R2=p-methoxybenzyl, R3=benzhydryl) (3Kg) was dissolved in dichloromethane (10L), cooled to -30°C, and anisole was added (3L), add trifluoroacetic acid (18Kg) dropwise, and slowly heat up to -10°C~0°C for 1.5h after dropping, add isopropyl ether (50L) dropwise, stir, filter, and dissolve the solid with ethyl acetate (25L) , cooled to 0 ~ 10 ° C, dropwise added sodium isooctanoate (1.4Kg) / ethyl acetate (20L), after the dropwise addition was completed, reacted for 30min, filtered, the solid was dissolved in deionized water (10L), butanone (5L) Wash, decolorize with activated carbon in the aqueous phase, filter, and freeze-dry to obtain Latamoxef Sodium. Yield: 92%.

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Abstract

The invention relates to a production method of latamoxef sodium which can be used as an antibacterial drug. The preparation method of latamoxef sodium of the present invention, by S-I compound in organic solvent, removes protecting group under the action of trifluoroacetic acid and carbocation absorbent; Then in alcohol, ketone or ester, add R4CO2Na solution, will The solid is filtered and washed to obtain the crude product of latamoxef sodium; finally, the crude product of latamoxef sodium is dissolved in water, extracted with an organic solvent, decolorized by activated carbon, and freeze-dried in the water phase to obtain latamoxef sodium. The invention provides a brand-new method for synthesizing Latamoxef Sodium from a single-configuration intermediate, directly reacting with sodium carboxylate to obtain the crude Latamoxef Sodium, and the final obtained refined product meets the standards of the Chinese Pharmacopoeia without the need for purification. Adsorption resin purification reduces the amount of purified water, improves production efficiency, reduces energy consumption, reduces equipment investment, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a production method of latamoxef sodium which can be used as an antibacterial drug. Background technique [0002] Latamoxycephalic acid and Latamoxycephalic acid sodium are oxycephem antibiotics developed by Shionogi Pharmaceutical Co., Ltd. in Japan. In 1981, they were first listed in Germany under the trade name "Festmoxin". After 1982, they were mainly sold in Japan and South Korea for Clinically, the trade name is "shiomarin". At present, Hainan Hailing Chemical Pharmaceutical Co., Ltd. mainly imports raw materials from Japan and then repacks the preparations in China. At present, there is no production of its products in China. Latamoxef has a broad antibacterial spectrum, and its antibacterial activity is similar to that of the third-generation cephalosporins. Its effect on Gram-negative bacilli is 4 to 16 times stronger than that of general cephalosporins, and its effect on anaerobic bacteria, especially Bacteroides fra...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D505/20C07D505/06
Inventor 刘相奎胡志袁哲东杨玉雷俞雄
Owner SHANGHAI INST OF PHARMA IND CO LTD
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