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Preparation method of intermediate

A compound and reaction technology, applied in the field of preparation of intermediates, can solve the problems of difficulty in obtaining a single configuration

Pending Publication Date: 2021-03-30
YICHANG HEC CHANGJIANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] There is (S,S)-2,8-diazabicyclo-(4,3,0)-nonyl in the structure of moxifloxacin, and the two chiral centers in its structure lead to its single structure Difficult to obtain

Method used

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  • Preparation method of intermediate
  • Preparation method of intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Embodiment 1 prepares compound C

[0078] Add 20.0g of L-hydroxyproline, 32.0g of sodium bicarbonate and 300.0mL of water into a 500mL one-necked flask, and stir evenly at room temperature; add dropwise 60.0mL of toluene solution containing 30.0g of benzyl chloroformate, after the addition is complete, stir at room temperature for 16h . Stop the reaction, let the layers rest, separate the organic phase, wash the aqueous phase twice with 50mL ether, adjust the pH of the system to 2 with concentrated hydrochloric acid, extract three times with 250mLEA, combine the organic phases, dry with anhydrous sodium sulfate, and filter Concentration under reduced pressure gave 37.3 g of oily compound A, HPLC content: 97.8%; yield 90.2%.

[0079] 7.82g of Compound A (HPLC content: 97.8%) was dissolved in 420mL of acetone, 12mL of prepared 2mol / L Jones reagent was added dropwise, stirred at room temperature for 0.5h, after the reaction was completed, concentrated to dryness under red...

Embodiment 2

[0081] Embodiment 2 prepares compound D

[0082]

[0083] 3.83g of compound C (HPLC content: 98.4%) was dissolved in 100mL of toluene, and 1.76g of S-methylbenzylamine was added dropwise. After the dropwise addition, the temperature was raised to 110°C, and kept stirring for 18h. After cooling to room temperature, the reaction system was concentrated under reduced pressure to obtain an oil compound D: 4.89 g, HPLC content: 96.7%, yield 96.9%.

[0084] LC-MS: [M+1]=457.1; 1 H-NMR(400MHZ):δ7.37-7.23(m,15H),5.31(s,2H),5.13(s,2H),4.43-4.53(m,1H),3.52-3.69(m,5H), 1.32(m,3H).

Embodiment 3

[0085] Embodiment 3 prepares compound E

[0086]

[0087] 3.97g of compound D (HPLC content: 96.7%) was dissolved in 40mL of THF, 7.50g of pyridine was added, and after stirring at room temperature for 30min, 2.26g of acryloyl chloride was added dropwise. After the dropwise addition, the system was heated to 70°C and kept stirring 2h. The reaction system was concentrated to dryness under reduced pressure, then dissolved in 100 mL of ethyl acetate, washed with 1 mol / L dilute hydrochloric acid (100 mL×4), dried the organic phase, filtered, and the filtrate was concentrated to give an oil compound E: 4.02 g, HPLC content : 96.3%; Yield: 90.2%.

[0088] LC-MS: [M+1]=511.2; 1 H-NMR (400MHZ): δ7.39-7.21(m,15H),5.3(s,2H),5.1(s,2H),4.63(s,1H),4.53-4.48(m,1H),3.69( s,2H), 2.34-2.23(m,4H), 1.31(m,3H).

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Abstract

The invention relates to a preparation method of an intermediate, and belongs to the field of medicinal chemistry. The preparation method comprises at least one reaction step of an addition elimination reaction, a cyclization reaction, a reduction reaction, a decarboxylation reaction and a hydrogenation reaction. According to the method disclosed by the invention, the target intermediate with a single configuration can be simply and conveniently obtained, chiral resolution is effectively avoided, the yield is improved, the cost is reduced, and industrial production is facilitated.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of an intermediate. Background technique [0002] Moxifloxacin is a quinolone antibacterial drug with a broad antibacterial spectrum. It has strong antibacterial activity against common respiratory bacteria. It is clinically used to treat acute sinus adenitis, acute exacerbation of chronic bronchitis, community-acquired pneumonia, and Skin and skin soft tissue infection, etc.; its structure is shown in the following formula: [0003] [0004] There is (S,S)-2,8-diazabicyclo-(4,3,0)-nonyl in the structure of moxifloxacin, and the two chiral centers in its structure lead to its single structure Types are more difficult to obtain. Therefore, facile access to single-configuration (S,S)-2,8-diazabicyclo-(4,3,0)-nonane is critical and important for the preparation of moxifloxacin; research is needed The preparation method of (S,S)-2,8-diazabicyclo-(4,3,0)-n...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04C07B2200/07Y02P20/55
Inventor 王仲清黎利军郑金付漆春辉范文进肖毅罗忠华黄芳芳
Owner YICHANG HEC CHANGJIANG PHARMA CO LTD
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