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Method for preparing moxifloxacin or its medicinal salt and its intermediate

A technology of medicinal salt and cyclopropyl, which is applied in the field of compound preparation, can solve the problems of product moxifloxacin color influence, intermediate product color deepening, equipment and human injury, etc., and achieve low requirements for reaction equipment and good reproducibility , easy-to-operate effect

Active Publication Date: 2012-08-01
SHENZHEN SALUBRIS PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The above-mentioned reaction using boric acid as a chelate will generate a large amount of acid mist during the reaction, which will cause damage to equipment and human body; the reaction between acetic anhydride and boric acid disclosed in WO2010052726 is carried out at the reflux internal temperature of 140°C, and this temperature requires a special Experimental equipment to achieve, it is difficult to achieve through simple steam temperature heating, WO2005012285 and WO2010052726 use 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo- Ethyl 3-carboxylate and triacetoxyboron B(OAc) 3 The reaction is carried out at a high temperature of about 100°C. The two-step high temperature will cause the color of the intermediate product to deepen and affect the color of the final product moxifloxacin or its pharmaceutically acceptable salt.

Method used

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  • Method for preparing moxifloxacin or its medicinal salt and its intermediate
  • Method for preparing moxifloxacin or its medicinal salt and its intermediate

Examples

Experimental program
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Embodiment 1

[0031] Example 1: 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid-O 3 , O 4 -Preparation of boron diacetate (compound II)

[0032] Dissolve powdery boron trioxide (63.9g, or 0.918mol) in acetic anhydride (511.2mL) and acetic acid (319.5mL), then react at 90-100°C for 2h, then cool, and add quinolinecarboxylic acid Cyclic ester (Compound I) (517g, namely 1.6mol), reacted at 50-60°C for 5h, then cooled to 40°C, added anisole (1.1L), cooled to 15-20°C while stirring, and then Stirring at this temperature for 2 hours, a large amount of solid precipitated out, filtered, washed with anisole, and dried to obtain the compound II product (576 g, yield 91.1%, HPLC purity 99.5%).

Embodiment 2

[0033] Example 2: 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid-O 3 , O 4 -Preparation of boron diacetate

[0034] Dissolve powdery boron trioxide (63.9g, ie 0.918mol) in acetic anhydride (958.5mL) and acetic acid (511.2mL), then react at 95-105°C for 4h, then cool to 60-70°C, add formula (I) Compound quinolinecarboxylic acid cyclic ester (790g, namely 2mol), reacted at 60-70°C for 8h, then cooled to 40-50°C, added isopropyl ether (1.2L), and cooled to 15-20°C, and then stirred at this temperature for 2 hours, a large amount of solid precipitated, filtered, washed with isopropyl ether, and dried in vacuo to obtain Compound II (668g, yield 92.0%, HPLC purity 99.8%).

Embodiment 3

[0035] Example 3: 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid-O 3 , O 4 -Preparation of boron diacetate

[0036] Dissolve powdery boron trioxide (63.9g, namely 0.918mol) in acetic anhydride (639mL) and acetic acid (400mL), then react at 110-120°C for 3h, then cool to 70-80°C, add formula (I ) Compound quinoline carboxylic acid cyclic ester (711g, namely 1.8mol), reacted at 70-80°C for 6h, then cooled to 40-50°C, added methyl tert-butyl ether (1L), cooled while stirring to 15-20°C, then stirred at this temperature for 2h, a large amount of solid precipitated out, filtered, washed with methyl tert-butyl ether, and dried in vacuo to obtain compound II product (652g, yield 91.6%, HPLC purity 99.6%).

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Abstract

The invention provides a novel method for preparing moxifloxacin or its medicinal salt and its intermediate, which comprises the following steps: dissolving boron trioxide in a certain amount of acetic anhydride and an acetate mixing solution, reacting under the temperature of 90-120 DEG C, cooling a reaction solution; adding cyclized quinolinecarboxylic ester in the reaction solution and reacting at the reaction temperature of 50-80 DEG C, cooling, adding a certain amount of an ether solvent, stirring and then filtering, washing by the ether solvent, drying to obtain the product; reacting with (4aR, 7aR)-octahydropyrrolo[3,4-b]pyridine to obtain the moxifloxacin or its medicinal salt. The reaction method of the invention is mild and controllable, the common equipments enable production, the obtained product has the advantages of high purity and good color, boron oxide substitutes boric acid for chelating to reduce the damage of equipments and human body caused by acid mist in the reaction.

Description

technical field [0001] The invention relates to a method for preparing a compound, especially a method for preparing moxifloxacin or its pharmaceutically acceptable salt and its intermediate. Background technique [0002] Moxifloxacin hydrochloride, the chemical name is 1-cyclopropyl-7-(S,S-2,8-diaza-bicyclo[4.3.0]nonan-8-yl)-6- Fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinoline carboxylic acid hydrochloride, is the fourth generation of extended-spectrum quinolone antibacterial drugs, used for the treatment of patients with upper respiratory tract and lower Adults with respiratory infections such as acute sinusitis, acute exacerbation of chronic bronchitis, community-acquired pneumonia, and skin and soft tissue infections. [0003] The currently published literature on the preparation of moxifloxacin hydrochloride is mostly prepared after chelation with boric acid, such as the patent literature: [0004] WO2005012285 discloses a preparation method of moxifloxacin. After reacti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02C07D471/04
Inventor 张昌中郑加林
Owner SHENZHEN SALUBRIS PHARMA CO LTD
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