Preparing method of 8-bromo-5,6-difluoro-2-methylquinoline

A technology of methylquinoline and difluoroacetanilide, which is applied to 8-bromo-5, can solve the problems of low yield in the cyclization reaction step, large consumption of alkali for neutralization, consumption of solvent, etc., and achieves low cost and reduced medium And the amount of alkali used, the effect of safe and easy operation

Active Publication Date: 2007-08-15
CHANGZHOU YABANG PHARMA
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Problems solved by technology

[0006] This synthetic route adopts in the cyclization step of synthesizing 8-bromo-5,6-difluoro-2-methylquinoline (D) by 3,4-difluoro-6-bromoacetanilide (C) The oxidizing agent is sodium m-nitrobenzenesulfonate. This oxidizing agent is not only expensive, but also because it is a solid, it will consume a part of the solvent, so that the amount of acidic solvent (concentrated hydrochloric acid) required in the cyclization reaction is relatively large, resulting in a large amount of waste in the aftertreatment process. The consumption of alkali for neutralization is relatively large, and the cost is relatively high; more importantly, the yield of the cyclization reaction step is low (less than 60%), so it is still desired to have a more improved method

Method used

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  • Preparing method of 8-bromo-5,6-difluoro-2-methylquinoline
  • Preparing method of 8-bromo-5,6-difluoro-2-methylquinoline
  • Preparing method of 8-bromo-5,6-difluoro-2-methylquinoline

Examples

Experimental program
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Effect test

Embodiment 1

[0060] (1) Preparation of 3,4-difluoroacetanilide (B)

[0061] In a 1000ml four-neck round bottom flask equipped with mechanical stirring, thermometer and condenser, add 200ml of acetic acid solution containing 65g3,4-difluoroaniline (A) and 0.5g of anhydrous aluminum chloride, and cool to below 10°C. Add 90ml of acetic anhydride dropwise, gradually heat up to 60-65°C within 1 hour, react for 3 hours, cool to room temperature, add 10% dilute hydrochloric acid, stir for complete crystallization, filter with suction, wash with water, and dry to obtain 3,4- Difluoroacetanilide (B) 78.2g (mp: 124.5~106.0°C, yield 90%)

[0062] (2) Preparation of 3,4-difluoro-6-bromoacetanilide (C)

[0063] In a 1000ml four-neck flask equipped with mechanical stirring, thermometer and condenser tube, add 320ml acetic acid solution containing 77g 3,4-difluoroacetanilide (B) and 0.3g iodine, stir at room temperature, add bromine dropwise 75g, gradually heated up to 35-40°C, reacted for 12 hours, th...

Embodiment 2

[0071] (1) Preparation of 3,4-difluoroacetanilide (B)

[0072] In a 1000ml four-neck round bottom flask equipped with mechanical stirring, thermometer and condenser tube, add 300ml acetic acid solution containing 65g 3,4-difluoroaniline and 0.8g anhydrous zinc chloride, cool to below 10°C, dropwise add Acetyl chloride 95ml, gradually heated up to 75-80°C within 1 hour, reacted for 2 hours, cooled to room temperature, added 10% dilute hydrochloric acid, stirred to crystallize completely, suction filtered, washed with water, and dried to obtain 3,4-difluoro Acetanilide (B) 78.2g (mp: 124.5~126.0°C, yield 87.1%)

[0073] (2) Preparation of 3,4-difluoro-6-bromoacetanilide (C)

[0074] In a 1000ml four-necked bottle, equipped with mechanical stirring, thermometer and condenser,

[0075] Add 77g of 3,4-difluoroacetanilide (B) and 0.6g of anhydrous magnesium chloride in 300ml of acetic acid solution, stir at room temperature, add 78g of bromine dropwise, gradually raise the tempera...

Embodiment 3

[0081] Preparation of 8-bromo-5,6-difluoro-2-methylquinoline

[0082] (The oxidizing agent is concentrated nitric acid, without catalyst)

[0083] Step (1), the preparation of 3,4-difluoroacetanilide (B) and step (2), the preparation of 3,4-difluoro-6-bromoacetanilide (C), are all the same as in Example 1 is the same, only step (3), ie the preparation of 8-bromo-5,6-difluoro-2-methylquinoline (D), is different from Example 1.

[0084] Add 95g of 3,4-difluoro-6-bromoacetanilide (C), 25ml of concentrated nitric acid, 10g of ferric sulfate, 100g of boric acid, 350ml of concentrated hydrochloric acid and 45g of trans-crotonaldehyde into a 2000ml four-necked flask with a stirring bar and a condenser , heated up to 90°C within 1 hour, reacted for 2 hours, cooled, added about 300ml of 40% sodium hydroxide, adjusted the pH to neutral, filtered, washed, and dried to obtain 8-bromo-5,6-difluoro-2-methanol Quinoline (D) 66.4g (mp: 101.1-103.2°C, yield 67.8%).

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Abstract

The invention discloses a making method of 8-bromine-5, 6-difluo-2-methyl quinoline as key intermediate of broad spectrum antibiotic nafuxacin, which comprises the following steps: adopting 3, 4-difluo-6-difluo phenylamine as original raw material; acylating to produce 3, 4-difluo aceto phenylamine; bromidizing to make 3, 4-difluo-6-difluo aceto phenylamine as cyclic starting material; ringing 3, 4-difluo-6-difluo aceto phenylamine, oxidizer, alleviator, condensed sulfuric acid, ferric sulfate, trans-crotonaldehyde; selecting condensed sulfuric acid and condensed nitric acid as oxidizer; fitting for industrial manufacturing with low cost and high receiving rate.

Description

technical field [0001] The invention relates to a preparation method of 8-bromo-5,6-difluoro-2-methylquinoline, a key pharmaceutical intermediate of the novel broad-spectrum antibacterial drug nafloxacin. Background technique [0002] The formal chemical name of Nafloxacin is 9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidinyl)-5-methyl-1-oxo-1H,5H-benzene And [i, j] quinozine-2-carboxylic acid, whose English name is nadifloxacin, is a broad-spectrum antibacterial drug developed and developed by Otsuka Co., Ltd. of Japan, which was first listed in Japan in 1993 for the treatment of Acne; it is effective against Gram-positive bacteria, especially Propionibacterium acnes, Staphylococcus surface and Pseudomonas aeruginosa, and can be used for common acne and other skin infections. 8-bromo-5,6-difluoro-2-methylquinoline is a very key pharmaceutical intermediate for the synthesis of nafloxacin. [0003] Koji Hashimto et al. (Chem.Pharm.Bull.1996.44 (4): 642-645) use 3,4-difluoro-6-...

Claims

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Application Information

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IPC IPC(8): C07D215/18A61P31/00
Inventor 颜文革石卫兵郭彦彰张虹
Owner CHANGZHOU YABANG PHARMA
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