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A kind of preparation method of prazogamicin antibiotic

A technology of antibiotics and sisomicin, which is applied in the fields of medicinal chemistry and pharmaceutical engineering, can solve problems such as difficult industrial production, and achieve the effect of increasing yield

Active Publication Date: 2020-05-05
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] However, the existing synthesis methods of plazomicin antibiotics are difficult to be applied to industrial production

Method used

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  • A kind of preparation method of prazogamicin antibiotic
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  • A kind of preparation method of prazogamicin antibiotic

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0032] A typical implementation of the present application provides

[0033] A kind of preparation method of prazogamicin antibiotic, its step is:

[0034] (1) Sisomicin is removed from the sulfuric acid molecule to obtain the free base shown in formula 1; (2) under the catalysis of Lewis acid, the free base shown in formula 1 carries out nucleophilic substitution reaction with the compound containing PNZ protecting group to obtain The compound shown in formula 2; (3) under the catalysis of Lewis acid and organic base, the compound shown in formula 2 carries out nucleophilic substitution reaction with the compound containing Boc protecting group to obtain the compound shown in formula 3; (4) the compound shown in formula 3 The shown compound first carries out nucleophilic substitution reaction with the compound containing the FOMC protecting group, and then under the action of base catalysis, carries out the nucleophilic substitution reaction with the compound containing the B...

Embodiment 1

[0080] Proceed as follows:

[0081] (1) Synthesis of compound shown in formula 1

[0082]

[0083] Add NaOH (14.52 g, 363 mmol) to a stirred methanol solution (600 mL) of sisomicin sulfate (50.06 g, 72.59 mmol) at room temperature, stir at room temperature for 5 h, filter, concentrate, and dry in vacuo to obtain formula The compound shown in 1 (31.53g, 70.45mmol), yield 97%.

[0084] (2) Synthesis of compound shown in formula 2

[0085]

[0086] In the stirred MeOH (600mL) solution of the compound shown in Formula 1 (33.64g, 70.45mmol) was added Zn(OAc) 2 (38.78 g, 211.36 mmol), and the reaction mixture was stirred for 2 hours until all the zinc went into solution (one spot by TLC). Then a solution of PNZ-ONB (22.26 g, 62.12 mmol) in DCM (400 mL) was added dropwise within 2 hours, and reacted at room temperature for 10 h. After the completion of the reaction monitored by TCL, the reactant was concentrated to dryness to obtain a crude product. The crude product was s...

Embodiment 2

[0126] Embodiment 2: This embodiment is a further enlargement of Embodiment 1.

[0127] (1) Synthesis of compound shown in formula 1

[0128] To a stirred solution of sisomicin sulfate (200 g, 0.29 mol) in methanol (2 L) was added NaOH (57.99 g, 1.45 mol) at room temperature, and the reaction mixture was stirred for 5 h. Concentrate by filtration and dry in vacuo to obtain the compound represented by Formula 1 (125.31 g, 0.28 mol) with a yield of 97%.

[0129] (2) Synthesis of compound shown in formula 2

[0130] Add Zn(OAc) in the MeOH (1.5L) solution of compound (125.31g, 0.28mol) shown in the formula 1 that stirs 2 (154.12 g, 0.84 mol) and the reaction mixture was stirred for 2 hours until all the zinc went into solution (one spot by TLC). Then a solution of PNZ-ONB (85.99 g, 0.24 mol) in DCM (1 L) was added dropwise, and the reaction was stirred at room temperature for 10 h (reaction monitored by TCL). The reaction mixture was concentrated to dryness to give crude prod...

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Abstract

The invention provides a preparation method of pradimicin antibiotics, belonging to the field of pharmaceutical chemistry and pharmaceutical engineering. The preparation method comprises the followingsteps: freeing of sisomicin, protection of amino, selective introduction of protective groups, deprotection of amino, and the like. The preparation method is suitable for industrial production, thushaving good market prospects.

Description

technical field [0001] The invention belongs to the technical fields of medicinal chemistry and pharmaceutical engineering, and relates to a preparation method for the industrial production of plazomicin antibiotics. Background technique [0002] Plazomicin (Prazomicin in Chinese) was developed by Achaogen Corporation in South San Francisco, USA, for the treatment of severe infections caused by multidrug-resistant Enterobacteriaceae, including carbapenem antibiotic-resistant Enterobacteriaceae. Plazomicin is a novel aminoglycoside antibiotic that acts on the 16S rRNA of the 30S ribosomal subunit and inhibits the protein translation process in bacteria. Plazomicin is obtained by chemical modification on the basis of sisomicin, which avoids being destroyed by aminoglycoside antibiotic inactivating enzymes (Aminoglycoside modifying enzymes, AME) and loses its activity. In 2012, Plazomicin obtained the FDA fast-track designation, and in 2014, the FDA obtained the FDA Qualified ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H15/26C07H1/00
CPCC07H1/00C07H15/26Y02P20/55
Inventor 马淑涛蔡小康
Owner SHANDONG UNIV
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