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A kind of efficient preparation method of new cefotaxime sulfate intermediate

A technology for cefotaxime sulfate and intermediates, which is applied in the field of preparation of cefotaxime sulfate intermediates, can solve the problems of reduced reaction yield and prolonged reaction time, and achieve the effects of high yield and short reaction time

Active Publication Date: 2020-07-17
连云港恒运药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] CN101993450A discloses a method for preparing cefotaxime sulfate, which involves the preparation of formula (II), but according to the patented method, in the preparation process of formula (II), after adding Boc2 for 8 hours of reaction, there are still a large amount of raw materials remaining, It is usually necessary to continue the reaction for 12 hours before the raw materials can be basically reacted completely, but at the same time, the prolongation of the reaction time leads to a reduction in the reaction yield

Method used

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  • A kind of efficient preparation method of new cefotaxime sulfate intermediate
  • A kind of efficient preparation method of new cefotaxime sulfate intermediate
  • A kind of efficient preparation method of new cefotaxime sulfate intermediate

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preparation example Construction

[0010] The preparation of reference example formula (I) compound

[0011]

[0012] CH 2 Cl 2 (3L), PCl 5 (374.4g) was sequentially added to a 10L reaction flask, stirred at room temperature to reduce the internal temperature to about 0°C, slowly added pyridine (200mL) dropwise, and the rate of addition was controlled so that the internal temperature did not exceed 5°C. After continuing the reaction for 1 hour, the temperature was lowered to -5°C, and GCLE (7-phenylacetamide-3-chloromethylcephemenoic acid p-methoxybenzyl ester, 584.4g) was added in batches, and the internal temperature was controlled at -5°C to 0°C. Between ℃, continue to react for 3h. The temperature was rapidly lowered to -30°C, methanol (1500 mL) was slowly added dropwise, and the reaction was continued at -30°C for 1 h. The temperature was raised to -10°C, 1500mL of water was added dropwise, and the temperature was controlled from -10 to 0°C to react for 1h. Finally, add 1500mL of water at one time,...

Embodiment 1

[0013] Preparation of embodiment one formula (II) compound

[0014]

[0015] Weigh the reference example product (450g) and place it in a 5L reaction flask, add 1,4-dioxane (1L), add 500mL of aqueous sodium hydroxide solution (1mol / L) gradually to adjust the pH value to 8-9, then add Benzyltriethylammonium chloride (10g), methanol 50ml, after stirring, add di-tert-butyl dicarbonate (450g), and react at 35°C for 5h. After TLC monitors that the reaction is complete, add ethyl acetate (1000mL) for extraction, separate the layers, add 150mL of ethyl acetate to the aqueous layer for extraction, separate the layers, combine the organic phases, wash with saturated brine (250mL×2), anhydrous sodium sulfate (200g ) was dried, filtered, and concentrated to obtain an oily substance, which was fully dissolved by adding 600mL of ethyl acetate and then dripping sherwood oil (1000ml) to crystallize, after stirring for 1h, suction filtered, and the filter cake was vacuum-dried at room temp...

Embodiment 2

[0017] Preparation of embodiment two formula (II) compound (referring to CN101993450A)

[0018]

[0019] Weigh the reference example product (81.0g) into a 2L reaction flask, add tetrahydrofuran (400mL), triethylamine (24.3g), cool down to 0-5°C, add di-tert-butyl dicarbonate (48.0g) dropwise, After completion of the dropwise addition, return to room temperature and stir for 8 hours to react. TLC detects that there is still a large amount of raw material formula (I) remaining. Continue to stir and react for about 12 hours. The basic reaction of the raw materials is complete. The reaction solution is concentrated to 150 mL, and 500 mL of ethyl acetate is added. Wash with 20mL of 1N hydrochloric acid and 200mL of saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate to dryness, add petroleum ether (60-90°C) to freeze and crystallize, filter, and dry to obtain 55.0g of white solid. The rate is 58.6%.

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Abstract

The invention discloses a novel efficient preparation method of ceftiofur sulfate intermediate. Specifically, the invention relates to a novel efficient preparation method of ceftiofur sulfate intermediate, which relates to a ceftiofur sulfate intermediate shown in formula (II) and the preparation method thereof, the preparation method is short in reaction time and high in yield.

Description

technical field [0001] The present invention relates to a kind of preparation method of new cefotaxime sulfate intermediate, especially cefotaxime sulfate intermediate shown in formula (II) and preparation method thereof. Background technique [0002] Cefoselis sulfate (Cefoselis sulfate) belongs to the fourth generation cephalosporin antibiotics. The drug was jointly developed by Fujisawa Pharmaceutical Company of Japan and Johnson Company of the United States, and was first listed in Japan in 1998. Its trade name is FK- 037, is a typical representative of the fourth-generation cephalosporin antibiotics. At present, the excellent antibacterial effect of the drug in vitro and in animal infection models has been confirmed by a large number of clinical experiment reports worldwide. It has been successfully used in surgical infection, respiratory tract infection, obstetric and gynecological infection and ophthalmic infection at home and abroad. [0003] So far, the synthesis ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D501/24C07D501/04
CPCC07D501/04C07D501/24
Inventor 陈之峰张庆捷陈刚胜胡春勇张晓瑜
Owner 连云港恒运药业有限公司
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