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Preparation method of sitafloxacin side chain intermediate

A sitafloxacin and side chain technology, applied in the field of biopharmaceuticals, can solve the problems of long preparation time, difficult processing, and only a total yield, and achieve high product yield, high process amplification safety, and small environmental impact. Effect

Inactive Publication Date: 2014-12-24
SUZHOU NACHI BIOTECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] (1) There are many intermediate products in this route, the preparation time is long, the utilization rate of atoms is low, and there are many side reactions, and the total yield has only 8%;
[0011] (2) The second step will use a large amount of bromine, and there is no bromine in the intermediate, so after the reaction, the bromine enters the waste water in the form of acid, which is difficult to handle and has a great impact on the environment;
[0013] (4) The LiAlH4 reagent used in the sixth step will react explosively when it encounters water, and it will be very dangerous to enlarge the production

Method used

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  • Preparation method of sitafloxacin side chain intermediate
  • Preparation method of sitafloxacin side chain intermediate
  • Preparation method of sitafloxacin side chain intermediate

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preparation example Construction

[0033] A method for preparing a sitafloxacin side chain intermediate, comprising the steps of:

[0034] ①Synthesis of a three-membered ring: Dissolve every 1kg of methyl 4-chloroacetoacetate in 5-6L of acetonitrile, add 38-40g of proline, then add 1.25kg of 1,2-dibromoethane, and add 2.3kg of potassium carbonate while stirring -2.5kg, then the reaction solution was stirred at a controlled temperature of 30-36°C for 30-36 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a three-membered carbocyclic compound A;

[0035] ②Synthesis of nitrogen heterocycles: Slowly add the obtained A into 5L of ammonia water with a concentration of 25%, stir at room temperature for 2.5-3 hours, then heat up to 38-40° and react for 8-10 hours, then suction filter, wash and dry to obtain Five-membered nitrogen heterocyclic compound B;

[0036] ③Generation of chiral carbon: Dissolve B in 2-2.5L toluene, add R-1-phenylethylamine with 111% of the mass of B...

Embodiment 1

[0042] ①Dissolve 1kg of methyl 4-chloroacetoacetate in 6L of acetonitrile, add 38g of proline and 1.25kg of 1,2-dibromoethane, add a total of 2.3kg of potassium carbonate in 10 times under stirring, and then the reaction solution is heated at 35°C Stir for 36 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain three-membered carbocyclic compound A as a colorless oil.

[0043] ②Continuously add the above A into 5L of 25% ammonia water, stir for 3 hours, then raise the temperature to 40°C, and continue the reaction for 10 hours. Suction filtration, washing the solid with water, and drying to obtain 300 g of five-membered nitrogen-heterocyclic compound B in the form of white solid powder.

[0044] ③Dissolve the above powder B in 2L of toluene, then add 333g of R-1-phenylethylamine, and reflux for 10 hours while stirring. Cooled, concentrated to dryness under reduced pressure to obtain solid chiral compound C.

[0045] ④ Add the above solid C...

Embodiment 2

[0049] ① Dissolve 10kg of methyl 4-chloroacetoacetate in 50L of acetonitrile, add 400g of proline and 12.5kg of 1,2-dibromoethane, add a total of 24kg of potassium carbonate in 9 times under stirring, and then stir the reaction solution at 30°C 36 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain three-membered carbocyclic compound A as a colorless oil.

[0050] ②The above three-membered carbocyclic compound was continuously added to 5L of 25% ammonia water, stirred for 2.5 hours, then heated to 38°C, and continued to react for 8 hours. Suction filtration, washing the solid with water, and drying to obtain 3078 g of five-membered nitrogen heterocyclic compound B in the form of white solid powder.

[0051] ③ Dissolve the above powder B in 25L of toluene, then add 3.4kg of R-1-phenylethylamine, stir and reflux to separate water for 12 hours. Cooled, concentrated to dryness under reduced pressure to obtain solid chiral compound C.

[0052]...

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Abstract

The invention relates to a preparation method of a sitafloxacin side chain intermediate. The preparation method comprises the following steps: synthesizing 4-methyl acetoacetate with 1,2-dibromoethane into a three-membered ring, synthesizing the three-membered ring with ammonia water into nitrogen heterocycle, synthesizing nitrogen heterocycle with R-1-phenyl ethylamine to generate chiral carbon, reducing through sodium borohydride, adding ditertbutyl dicarbonate to generate a protecting group, and finally performing carbonyl reduction to borane-dimethyl sulfide to obtain an intermediate. According to the preparation method, the atom utilization rate can be improved, the use of toxic reagents can be reduced, and the amplification of the technology can be facilitated.

Description

【Technical field】 [0001] The invention relates to the technical field of biopharmaceuticals, in particular to a method for preparing a sitafloxacin side chain intermediate which is simple, environment-friendly and easy to scale up. 【Background technique】 [0002] The chemical name of sitafloxacin (sitafloxacin hydrate) is 7-[(7S)-7-amino-5-azaspiro[2.4]heptane-5-yl]-8-chloro-6-fluoro-1-[( 1R,2S)-cis-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, its structure is as follows: [0003] [0004] The compound is a broad-spectrum quinolone antibacterial drug developed by Japan's Daiichi Pharmaceutical Sankyo Co., Ltd., and its monohydrate is used clinically. It is an anti-infection drug, a new oral quinolone antibiotic, and has strong antibacterial activity against methicillin-resistant Staphylococcus aureus and Pseudomonas bacteria. It also has good pharmacokinetic properties, can reduce adverse reactions, and its antibacterial activity in vitro is signif...

Claims

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Application Information

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IPC IPC(8): C07D209/96
CPCY02P20/55C07D209/54
Inventor 吴天俊
Owner SUZHOU NACHI BIOTECH CO LTD
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