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Fluoroquinolone compounds and synthesis method thereof

A technology of fluoroquinolones and compounds, which is applied in the field of preparation of fluoroquinolones and can solve urgent problems such as

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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

With the widespread use of antibiotics, especially the abuse of antibiotics, the emergence of multidrug-resistant bacteria has resulted in the emergence of many existing Gram-positive bacteria resistant to antibiotics, such as methicillin-resistant grape aureus cocci (MRSA), vancomycin-resistant Enterococci (VRE), penicillin-resistant Streptococcus pneumoniae (PRSP), etc.; the emergence and continued spread of these multidrug-resistant bacteria has become a global problem
Although a new generation of fluoroquinolone antibiotics such as gatifloxacin, moxifloxacin, and gemifloxacin are available for the treatment of Gram-positive bacteria, as bacteria become more resistant to fluoroquinolone antibiotics, Especially with the emergence of methicillin-resistant and fluoroquinolone-resistant Staphylococcus aureus (QMMRSA), the development of a new generation of fluoroquinolone antibiotics with high efficacy, broad spectrum and resistance to Gram-positive bacteria has become an urgent task without delay.

Method used

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  • Fluoroquinolone compounds and synthesis method thereof
  • Fluoroquinolone compounds and synthesis method thereof
  • Fluoroquinolone compounds and synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1a

[0023] Example 1a: Synthesis of (Z)-3-[[2,2-difluoro-1-(hydroxymethyl)ethyl]amino]-2-(2,3,4,5-tetrafluorobenzoyl)propane -Ethyl 2-enoate (3a)

[0024] Ethyl 2,3,4,5-tetrafluorobenzoylacetate (1) (100 g, 0.378 mol), triethoxyorthoformate (63 mL, 0.567 mol), and acetic anhydride (89 ml, 0.945 mol) mixture was heated to 115-120°C and stirred for three hours, then concentrated in vacuo; the concentrate was diluted with 455ml of ethanol, and the diluted solution was cooled to zero in an ice bath, and the solution was added dropwise with (2S)-2-amino -3,3-Difluoropropanol (33.7 grams, 0.416mol) and 410ml ethanol generated solution; The resulting mixture was stirred at room temperature for one hour, then concentrated in vacuo; The concentrate was further purified on a silica gel column with dichloromethane / The methanol mixture was eluted to give 94 g of a pale yellow solid in a 62% yield.

[0025] 3a: 1 HNMR (CDCl 3 )δ: 1.26(t, J=6.9Hz, 3H), 3.13-3.36(m, 2H), 3.48-3.53(dd, J=12....

Embodiment 1b

[0026] Example 1b: Synthesis of (Z)-3-[[2,2-difluoro-1-(hydroxymethyl)ethyl]amino]-2-(2,3,4,5-tetrafluorobenzoyl)propane -2-enoic acid ethyl ester (3b)

[0027] The intermediate (2) was reacted with (2S)-2-amino-3,3,3-trifluoropropanol in the same way as in the synthesis of (3a) to obtain 26 g of the compound with a yield of 18%.

[0028] 3b: 1 HNMR (CDCl 3 )δ: 1.29(t, J=7.0Hz, 3H), 3.48-3.53(m, 2H), 3.86(dd, J=9.0, 7.0Hz, 1H), 4.20(q, J=7.0Hz, 2H), 8.20(m, 1H), 10.9(s, 1H); MS(ES + ): MW+H + = 404.1.

Embodiment 2a

[0029] Example 2a Synthesis of (3R)-9,10-difluoro-2,3-dihydro-3-difluoromethyl-7-oxidation-7hydropyrido[1,2,3-de][1,4 ]Benzoxazine-6-carboxylic acid ethyl ester (4a)

[0030] A mixture of intermediate (3a) (66 g, 0.172 mol), anhydrous potassium fluoride (spray-dried, 35 g, 0.60 mol) and anhydrous dimethyl sulfone (300 ml) was heated to 115-120 °C for five hours After cooling to room temperature, 150ml of methanol was added; the resulting mixture was stirred in an ice bath for two hours, then filtered; the collected precipitate was resuspended in 250ml of methanol and stirred for 30 minutes, and filtered; the collected precipitate was resuspended in 250 Stir in mL of water for 30 minutes, filter, wash with 125 mL of methanol, suck dry, and dry in vacuo to obtain 33 g of light yellow solid (4a); the yield is 56%.

[0031] 4a: 1 HNMR (CDCl 3)δ: 1.28(t, J=6.8Hz, 3H), 3.76(m, 1H), 4.03(dd, J=12.4, 7.2Hz, 1H), 4.18-4.30(m, 3H), 5.85(td, J =57.3, 7.0Hz, 1H), 7.63(dd, J=10.8, 7.8H...

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Abstract

The invention discloses novel fluoroquinolone compounds shown in a structural general formula (I). R1 is difluoromethyl or trifluoromethyl; R2 is a substituted piperazine (1), piperidine (2), pyrrolidine (3), (5) or 3-aminopyrrole (4) derivative which is connected with carbostyril through a C-N bond; and the chiral center of 2-bit carbon in the formula (I) can have laevorotatory, dextral and racemic configurations. The invention also relates to a method for preparing the compounds and application of the compounds and a medicinal composition to the treatment of diseases of urinary tracts, intestinal tracts, respiratory tracts, skin soft tissues and enterocoelia.

Description

technical field [0001] The invention relates to a fluoroquinolone compound, and also provides a preparation method of the fluoroquinolone compound. Background technique [0002] Since the first fluoroquinolone antibiotic norfloxacin (norfloxacin) came out, fluoroquinolone antibiotics have become broad-spectrum high-efficiency antibiotics widely used in clinical practice. With the widespread use of antibiotics, especially the abuse of antibiotics, the emergence of multidrug-resistant bacteria has resulted in the emergence of many existing Gram-positive bacteria resistant to antibiotics, such as methicillin-resistant grape aureus cocci (MRSA), vancomycin-resistant Enterococci (VRE), penicillin-resistant Streptococcus pneumoniae (PRSP), etc.; the emergence and continued spread of these multidrug-resistant bacteria has become a global problem. Although a new generation of fluoroquinolone antibiotics such as gatifloxacin, moxifloxacin, and gemifloxacin are available for the trea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/04A61K31/5383A61K9/20A61K9/48A61P13/02A61P1/00A61P11/00A61P17/00A61P19/02A61P31/00A61P31/04A61P31/16A61P31/12A61P35/00A61P31/18A61P9/00
Inventor 周崇科肖晓羽
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