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Method for industrial production of moxifloxacin side chain

A moxifloxacin side chain and organic solvent technology, which is applied in the field of industrial preparation of chemically synthesized drugs, can solve the problems of great impact on product quality, troublesome production operations, and low product purity, and achieve the effect of low market price

Inactive Publication Date: 2013-09-04
SUZHOU MICRODIAG BIOLOGICALS
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The purity of the products obtained by the above three routes is not high, especially the content of a single impurity does not meet the requirements, which has a great impact on the quality of the product, the production operation is troublesome, and the cost is relatively high. industrial production of

Method used

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  • Method for industrial production of moxifloxacin side chain
  • Method for industrial production of moxifloxacin side chain
  • Method for industrial production of moxifloxacin side chain

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041]

[0042]In a 1000mL autoclave, add 40g (0.265mol) of 3-formylpyridine-2-carboxylic acid, 70.9g (0.66mol) of benzylamine, 4g of 10% Pd / C, and 450mL of methanol into the autoclave. React at 60°C and 90 atm for 15 hours. After the reaction is complete, distill methanol and water out, add ethylene glycol for vacuum distillation, and add 50 mL of water to obtain the mother liquor, extract with ethyl acetate 200 mL×3, combine the organic layers, and anhydrous sodium sulfate Drying and rotary evaporation gave 54.8 g of 6-benzyl-hexahydropyrrolo[3,4-b]pyridin-7-one, with a yield of 90.1%.

[0043] NMR C 14 h 18 N 2 O( 1 H NMR, 400MHz, CDCl 3 ) δppm: 7.34(m, 5H), 4.54(dd, J 1 =9.8Hz,J 2 =23.8Hz, 2H), 3.57(d, J=4.4Hz, 1H), 3.23(m, 1H), 2.81(m, 1H), 2.77(m, 1H), 2.59(m, 1H), 2.44(s , -NH, 1H), 2.38(m, 1H), 1.73(m, 1H), 1.54(m, 1H), 1.46(m, 1H), 1.15(m, 1H).

[0044] C 14 h 18 N 2 O( 13 C NMR, 400MHz, CDCl 3 ) δppm: 173.8, 136.0, 128.5, 128.1, 127.5, 77.5, 76.7, 58....

Embodiment 2

[0046]

[0047] In a 1000L autoclave, add 40kg (264.7mol) of 3-formylpyridine-2-carboxylic acid, 70.9kg (661.7mol) of benzylamine, 4kg of 10% Pd / C, and 450L of methanol into the autoclave. React at 70°C and 70atm for 36 hours. After the reaction is complete, distill methanol and water out, add ethylene glycol for vacuum distillation, and add 50L of water to the mother liquor, extract with ethyl acetate 200L×3, combine the organic layers, and anhydrous sodium sulfate Drying and rotary evaporation gave 55.6 kg of 6-benzyl-hexahydropyrrolo[3,4-b]pyridin-7-one, with a yield of 91.3%.

[0048] Synthetic Example 1 of 6-benzyl-octahydro-pyrrolo[3,4-b]pyridine in this example:

[0049]

[0050] In a 1L three-necked flask, add THF 400mL, 25g (0.11mol) 6-benzyl-hexahydropyrrolo[3,4-b]pyridin-7-one, add 12.5g (0.33mol) hydroboration under stirring Sodium, at 65°C, reflux for 8h, and add 300mL of saturated ammonium chloride solution to quench the reaction. Then the solvent was eva...

Embodiment 7

[0062] Example 7, Synthesis of (s,s)-6-benzyl-hexahydropyrrolo[3,4-b]pyridine:

[0063]

[0064] In a 250mL three-necked flask, 5.26g (24.3mmol) of 6-benzyl-octahydro-pyrrolo[3,4-b]pyridine was dissolved in 50mL of anhydrous methanol, and D-(-)-tartaric acid ( 3.65g, 24.3mmol), heated to 80°C, reacted for 0.5h, then slowly cooled to 20°C, and stirred overnight at this temperature. The reaction solution was filtered, the obtained crystals were washed with 10 mL of absolute ethanol, and dried to obtain white (S, S)-5 tartrate (3.82 g, 85.7%), melting point: 122-126 ° C, [α] = -26.4° (c=1, H 2 O).

[0065] (S, S)-5 tartrate (3.82g, 10.4mmol) was dissolved in 10mL of water, 3mL of 35% NaOH solution was added under stirring, stirred at room temperature for 2h, extracted with 30mL×3 cyclohexane, the organic layers were combined, and no Dry over sodium sulfate and rotary evaporate to obtain 2.15g of (s,s)-6-benzyl-hexahydropyrrolo[3,4-b]pyridine as a yellow liquid with a yield...

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Abstract

The invention discloses a method for industrial production of moxifloxacin side chain. The method comprises the steps of A, dissolving 3-aldehyde pyridine-2-carboxylic acid and benzylamine in a mixed solvent of distilled water and an organic solvent, putting the above solution into an autoclave to carry out catalytic hydrogenation, and thus 6-benzyl-hexahydro-pyrrolo[3,4-b] pyridine-7-one is obtained; B. dissolving 6-benzyl-hexahydro-pyrrolo[3,4-b] pyridine-7-one in an organic solvent, adding a reducing agent in the solution to carry out a reduction reaction, and thus 6-benzyl-octahydro pyrrolo[3,4-b]pyridine is obtained; C. dissolving 6-benzyl-octahydro pyrrolo[3,4-b]pyridine in an organic solvent, adding D-(-)-tartaric acid to carry out resolution, and thus (s, s)-6-benzyl-octahydro-pyrrolo[3,4-b]pyridine is obtained; and D. dissolving (s, s)-6-benzyl-octahydro-pyrrolo[3,4-b]pyridine in an organic solvent, putting the solution in the autoclave to carry out catalytic hydrogenation for debenzylation, and thus (S,S)-2,8-diazabicyclo[4.3.0]nonane is obtained. The technical solution provided by the invention is simple and practical, low in cost and high in production efficiency, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to a method for industrial production of moxifloxacin side chains, in particular to a method for industrial production of moxifloxacin side chains which is simple and practical, low in cost and high in production yield, and belongs to the technical field of industrial preparation methods of chemically synthesized drugs. Background technique [0002] Moxifloxacin is a new generation of fluoroquinolone antibacterial drugs. Its chemical structure is significantly different from other fluoroquinolones. A methoxy group is introduced into the 8-position carbon atom of its molecular structure. This structural feature makes it not only have the antibacterial activity of other quinolones against Gram-negative bacteria, but also enhance the antibacterial effect against Gram-resistant bacteria and atypical pathogenic bacteria. In addition, one of its outstanding contributions is the enhanced antibacterial activity against anaerobic bacteria....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
Inventor 张健张燕飞沈宗旋王一广
Owner SUZHOU MICRODIAG BIOLOGICALS
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