Sitafloxacin intermediate, preparation method of sitafloxacin and sitafloxacin pharmaceutical composition

A technology for sitafloxacin and intermediates, applied in the field of pharmaceutical compositions containing sitafloxacin, can solve the problems of complex post-processing, poor safety, and low yield, and achieve simple post-processing, low cost, and high yield high effect

Active Publication Date: 2013-10-23
SHENZHEN SALUBRIS PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The purpose of the present invention is to overcome the problems of low yield, complex post-processing, poor safety and high cost of existing sitafloxacin intermediates in the process of preparing sitafloxacin, and provides a sitafloxacin A New Synthetic Method for Intermediates

Method used

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  • Sitafloxacin intermediate, preparation method of sitafloxacin and sitafloxacin pharmaceutical composition
  • Sitafloxacin intermediate, preparation method of sitafloxacin and sitafloxacin pharmaceutical composition
  • Sitafloxacin intermediate, preparation method of sitafloxacin and sitafloxacin pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Preparation of ethyl ester

[0048] Take 3.65g of ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-(1R,2S)-2-fluorocyclopropaneamino]acrylate in 40ml N,N-di In methylformamide (DMF), add 3.18g Na 2 CO 3 , stirred and heated to 40°C, TLC monitored the reaction until the raw material point disappeared to stop the reaction, spin-dried DMF under reduced pressure, added 50ml of water and 100ml of dichloromethane to separate phases, spin-dried the organic layer, and dried to obtain 3.2g of the product, with a yield of 92.7% . Melting point: 179.5-181℃, m / e 346.7[M+H] + , 1 H-NMR (500MHz, DMSO) δ (ppm): 8.64(d,J=2.5, 1H) ,8.13(m,1H), 5.11(m,1H), 4.30(m,2H),4.23(m,1H ), 1.72(m,2H), 1.33(t,J=7.5,3H).

Embodiment 2

[0049] Example 2 8-fluoro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropanyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Preparation of ethyl ester

[0050] Dissolve 3.49 g of 2-(3-fluoro-2,4,5-trifluorobenzoyl)-3-(1R,2S)-2-fluorocyclopropaneamino]ethyl acrylate in 40ml of tetrahydrofuran, and add 2.8 ml triethylamine, stirred and heated to reflux, TLC monitored the reaction until the raw material point disappeared to stop the reaction, spin-dried tetrahydrofuran, added 50ml water and 100ml dichloromethane for phase separation, spin-dried the organic layer, and dried to obtain 2.87g of product, yield 87% , m / e 330.3[M+H] + , 1 H-NMR (500MHz, DMSO) δ (ppm): 8.54(d,J=2.5, 1H) , 8.23(m,1H), 5.21(m,1H), 4.30(m,2H),4.33(m,1H ), 1.82(m,2H), 1.34(t, J=7.5,3H).

Embodiment 3

[0051] Example 3 Preparation of 6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropanyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester

[0052] Dissolve 3.31g of 2-(2,4,5-trifluorobenzoyl)-3-(1R,2S)-2-fluorocyclopropaneamino]ethyl acrylate in 50ml of N,N-dimethylacetamide (DMA), add 9.7g potassium oxalate, stir and heat to 50°C, monitor the reaction by TLC until the raw material point disappears to stop the reaction, spin the DMA to dryness under reduced pressure, add 50ml water and 100ml dichloromethane to separate phases, spin the organic layer to dry, After drying, 2.7g of the product was obtained, with a yield of 86.8%, melting point: 249-251°C, m / e 312.2[M+H] + , 1 H-NMR (500MHz, DMSO)δ(ppm): 8.66(d, J=2.5, 1H), 8.25(m,1H), 8.15(m,1H), 5.13(m,1H), 4.32(m,2H ), 4.25(m,1H), 1.75(m,2H), 1.35(t,J=7.5,3H).

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Abstract

The invention discloses a sitafloxacin intermediate, a preparation method of sitafloxacin and a sitafloxacin pharmaceutical composition. The preparation method can be used for solving the problems of low yield, troublesome aftertreatment, poor safety and higher cost in the existing sitafloxacin preparation. The preparation method disclosed by the invention is simple in process, easily available in raw materials, lower in cost, the solvent after reaction is easy to treat, high yield and quite suitable for large-scale industrial production. The sitafloxacin pharmaceutical composition obtained by virtue of the preparation method provided by the invention can be used for further improving the product dissolution effect, improving the in-vivo bioavailability of the sitafloxacin and enhancing the exertion of medical effect.

Description

technical field [0001] The invention relates to a sitafloxacin intermediate, a preparation method of the sitafloxacin and a pharmaceutical composition containing the sitafloxacin. Background technique [0002] Sitafloxacin (sitafloxacin), the chemical name is 7-[(7S)-amino-5-azaspiro[2.4]hept-5-yl]-8-chloro-6-fluoro-1-[(1R,2S )-cis-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is a fluoroquinolone antibacterial agent developed by Japan's Daiichi Pharmaceutical Company, and its monohydrate is used clinically things. Sitafloxacin is a new oral N-1-fluorocyclopropyl new quinolone antibacterial drug with broad-spectrum antibacterial activity, which is effective against aerobic or anaerobic Gram-positive bacteria and Gram-negative bacteria, and Chlamydia have broad-spectrum antibacterial effect. [0003] Regarding the synthesis of this compound, the synthetic route was first reported by Youichi Kimura et al. in Japan in 1994 (J.Med. Chem. 1994.37(20), 3344-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/56C07D401/04A61K31/4709A61P31/04
Inventor 许文杰邱雪辉华怀杰谭颂德郑加林肖尚志
Owner SHENZHEN SALUBRIS PHARMA CO LTD
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