Preparation method of biapenem aseptic powder

A technology of biapenem and sterile powder, applied in the field of preparation of biapenem and its sterile powder, can solve the problems of poor solubility, increase in substance, prolong operation time and the like, achieve easy quality control and increase stability , the effect of increasing solubility

Active Publication Date: 2012-08-01
CHIA TAI TIANQING PHARMA GRP CO LTD
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Problems solved by technology

[0004] 1. The patent CN101121716 and the document Toshio Kumagai, J.O.C., 1998, 63:8145-8149 reported that zinc powder was used as a catalyst to remove the protective group in a phosphate buffer solution with a pH of 5.6, and the post-treatment was purified by an adsorption resin to obtain Products, in which a large amount of eluent needs to be concentrated and freeze-dried, and carbapenems are easy to degrade in solution, so it is difficult to produce in large quantities
[0005] 2. Literature Kenneth J. Wildonger, Journal of antibiotics, 1993, 46(12): 1866-1882 reported that Pd(OH) 2 As a catalyst, the protective group is removed in phosphate buffer, purified by ion exchange resin Dowex 50-X4, concentrated, and freeze-dried to obtain the product with a yield of less than 30%.
Due to the poor solubility of biapenem, it is slightly soluble in water, and a small amount of biapenem requires a large amount of water to dissolve completely; at the same time, the stability of the aqueous solution of biapenem is not good, and after several hours of standing The content of related substances will increase significantly, suggesting that biapenem will be degraded after being left in water for a long time; increasing the temperature will slightly increase the solubility of biapenem in water, but also accelerate the degradation rate of biapenem; In the process of preparing apenem aseptic powder, it is necessary to use water to dissolve the crude product of biapenem, then filter it with a microporous membrane, and then recrystallize it with an organic solvent. The poor solubility leads to the need for a very large amount of biapenem in large-scale industrial production. Water, which prolongs the operation time and increases the degradation rate of biapenem in water, resulting in the increase of related substances, and the quality of the product is difficult to control, which is very unfavorable for the production of biapenem aseptic powder

Method used

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  • Preparation method of biapenem aseptic powder
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  • Preparation method of biapenem aseptic powder

Examples

Experimental program
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Embodiment 1

[0044] Example 1 Preparation of Biapenem Aseptic Powder

[0045] 1.16-[(4R,5S,6S)-6-[(1R)-1-Hydroxyethyl]-4-methyl-2-p-nitrobenzyloxycarbonyl-7-oxo-1-azabicyclo [3.2.0] Hept-2-en-3-yl]thio-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]-triazole-4- Synthesis of Onium Chloride(II)

[0046] In the reaction kettle, add 104Kg of acetonitrile, 16.5Kg of compound of formula III (MAP) and 5.9Kg of compound of formula IV, stir, the mixture is cooled to 0-5°C, and 5.3Kg of diisopropylethylamine is added dropwise thereto. Keeping the temperature at 0-5° C. to continue the reaction for about 3.5 hours, the precipitated solid in the reaction solution was filtered off and dried to obtain 14 Kg of the compound of formula II in the form of light yellow solid, yield: 94%.

[0047] m.p. = 162.0-163.6°C (decomposition).

[0048] 1.2 Synthesis of crude biapenem

[0049] Heat 75Kg of water for injection to 30-35°C, add 5Kg of the compound of formula II, add 25L of tetrahydrofuran under stirring, and st...

Embodiment 2

[0056] Example 2 Preparation of Biapenem Aseptic Powder

[0057] In the aseptic workshop, first heat 125Kg of water for injection adjusted to pH = 4.5 with acetic acid to 60°C, then add 6.25Kg of crude biapenem, stir to dissolve, if it is not clear, add water for injection until clear, add activated carbon to keep warm After 15 minutes, filter out the active carbon, filter the filtrate with a 0.22 μm microporous membrane, check the clarity of the filtrate, and add ethanol that is 2 times the volume of water for injection after passing through a 0.22 μm microporous membrane to pass the clarity. Cool to -10-5°C, stir and crystallize for 2-3 hours, filter, and dry under reduced pressure at 40°C to obtain 5.3Kg of biapenem sterile powder with a yield of 84.8%.

Embodiment 3

[0058] Example 3 Preparation of Biapenem Aseptic Powder

[0059] In the aseptic workshop, first heat 125Kg of water for injection adjusted to pH = 4 with acetic acid to 40°C, then add 6.25Kg of crude biapenem, stir to dissolve, if it is not clear, add water for injection until clear, add activated carbon to keep warm After 15 minutes, filter out the active carbon, filter the filtrate with a 0.22 μm microporous membrane, check the clarity of the filtrate, and add ethanol that is 2 times the volume of water for injection after passing through a 0.22 μm microporous membrane to pass the clarity. Cool to -10-5°C, stir and crystallize for 2-3 hours, filter, and dry under reduced pressure at 40°C to obtain 5.09Kg of biapenem sterile powder with a yield of 81.5%.

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Abstract

The invention relates to a preparation method of biapenem aseptic powder. Specifically, in a preparation process of a biapenem crude product, an alkaline substance of 2,6-lutidine is used so that post-reaction treatment is simple and a yield is high. In a preparation process of biapenem aseptic powder, acetic acid is utilized for adjustment of a pH value of water so that dissolvability and stability of biapenem in water are improved. Biapenem aseptic powder prepared through the preparation method has a high yield and controllable quality.

Description

technical field [0001] The invention relates to a preparation method of biapenem and sterile powder thereof. Background technique [0002] Biapenem is a new generation of carbapenem antibiotics, its chemical name is: 6-[(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-2 -Carboxy-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]thio-6,7-dihydro-5H-pyrazolo[1,2-α ][1,2,4]triazol-4-ium inner salt, the structure of which is shown in formula I. It has a broad antibacterial spectrum and has good bactericidal activity against Gram-negative, Gram-positive, aerobic and anaerobic bacteria; it is stable to human DHP-I and does not need to be used in combination with DHP-I inhibitors. And it is stable to β-lactamase; it has excellent pharmacokinetic properties and low toxicity, and plays an important role in the field of treating infectious diseases. [0003] At present, the preparation method of biapenem is mainly obtained by using the compound of formula V as a raw material and removing the prot...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/06
Inventor 张爱明夏春光张喜全
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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