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Preparation of cephamycine intermediate compound

A compound and intermediate technology, which is applied in the new preparation field of cephamycin key intermediate compound, can solve problems such as difficult production, easy explosion, and large yield loss

Active Publication Date: 2008-11-12
QILU ANTIBIOTICS PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] But as far as we know, the general methods with industrialized production value at present or the use of particularly unstable and explosive tert-butyl hypochlorite at extremely low temperatures such as -78 ° C or even -90 ° C, etc., the actual production is still very difficult. It is very difficult; or it is necessary to first protect the 4-position carboxyl group into an ester such as diphenylmethyl ester, and then use aluminum trichloride / anisole to remove the 4-position protecting group after introducing the 7α-position methoxyl group. The steps are cumbersome , a large yield loss

Method used

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  • Preparation of cephamycine intermediate compound
  • Preparation of cephamycine intermediate compound
  • Preparation of cephamycine intermediate compound

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preparation example Construction

[0018] A preparation method of cephamycin intermediate, comprising the following steps:

[0019] 1) prepare the compound of formula (VII) from formula (XI) compound

[0020] (i) in the presence of an organic solvent, the silylating agent reacts with the compound of formula (XI) or its hydrochloride at a temperature ranging from -10°C to 60°C to generate a feed solution rich in the compound of formula (X),

[0021]

[0022] where R 1 Represents 1-methyl-1H-tetrazol-5-ylsulfanyl that is R 2 Represents H or trimethylsilyl.

[0023] The above organic solvent is selected from one or a combination of halogenated hydrocarbons, nitriles, ketones, ethers, esters, amides.

[0024] The above-mentioned silylating agent is selected from one or a combination of hexamethyldisilazane, hexamethyldisilazane, N, O-bistrimethylsilylacetamide, trimethylchlorosilane, and trimethyliodosilane.

[0025] The above-mentioned halogenated hydrocarbons, preferably dichloromethane, chloroform or ca...

Embodiment 1

[0076] 7β-Dibromoacetamide-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid as triethylamine salt

[0077] 7β-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid 33.2g (content 99.0%, 0.100mol) and hexamethyl 20.9 ml (0.100 mol) of disilazane was sequentially added to 300 ml of dichloromethane, and refluxed at normal pressure for 4 to 5 hours.

[0078] Then the temperature was lowered to -20~10°C, and 30.9 g (0.110 mol) of dibromoacetyl bromide was slowly added, and the reaction was completed for 30 minutes. Cool down to 0-5°C.

[0079] Then pour it into 300ml of ice water, stir for 20 minutes and let stand for 30 minutes, then discard the water phase.

[0080] The organic phase was washed with 100 g of 30% sodium chloride solution, and the aqueous phase was discarded after standing for separation.

[0081] Add 3.0 g of activated carbon to the organic phase, stir for 30 minutes, filter, wash with 100 ml of dichloromethane, and drain. ...

Embodiment 2

[0085] 7β-Dibromoacetamide-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

[0086] 7β-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid 33.2g (content 99.0%, 0.100mol) and hexamethyl 20.9 ml (0.100 mol) of disilazane was sequentially added to 300 ml of dichloromethane, and refluxed at normal pressure for 4 to 5 hours.

[0087] Then the temperature was lowered to -20~10°C, and 30.9 g (0.110 mol) of dibromoacetyl bromide was slowly added, and the reaction was completed for 30 minutes. Cool down to 0-5°C.

[0088] Then pour it into 300ml of ice water, stir for 20 minutes and let stand for 30 minutes, then discard the water phase.

[0089] The organic phase was washed with 100 g of 30% sodium chloride solution, and the aqueous phase was discarded after standing for separation.

[0090] Add 3.0 g of activated carbon to the organic phase, stir for 30 minutes, filter, wash with 100 ml of dichloromethane, and drain.

[0091] Collect the f...

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Abstract

The invention relates to a cephamycines intermediate compound formula (I) and a method for making the free acid of the same. According to the formula (I), X1 represents halogen atom C1 or Br, and L<+> represents counter ion which is formed into salt in the presence of alkali and solvent. The method does not need an extremely low temperature and column purification, and has relatively simple operation and ideal product purity; therefore, the method is easy to use in industrial scale. The cephamycines intermediate compound made by the method can be widely used to make cephamycines antibiotics such as cefminox, cefmetazole and cefotetan and so on.

Description

technical field [0001] The invention relates to a new preparation method of a compound of formula (I), a key intermediate of cephamycin. Background of the invention [0002] Cephamycins refer to cephalosporins with a trans-methoxy group at the C7 position of the β-lactam ring. The presence of methoxy prevents the approach of the lactam ring and the enzyme molecule, enhances the stability of the drug against β-lactamase, and improves the activity against anaerobic bacteria, making this class of antibiotics more resistant to β-lactamase It has strong antibacterial effect on some bacteria producing β-lactamase. [0003] The difficulty in the synthesis of cephamycin mainly lies in the introduction of the methoxyl group at the 7α position. In the 1970s and 1980s, this difficulty has attracted widespread attention, and a variety of synthetic routes have been studied, among which the more representative ones are: [0004] 1) Acylimine Process: In the presence of a strong base, 7...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D501/36
CPCY02P20/55
Inventor 汤沸董付敏王勇进
Owner QILU ANTIBIOTICS PHARMA