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Preparation method of amikacin and intermediate activated thioester thereof

A technology of active thioester and amikacin, applied in the field of medicine, can solve the problems of poor acylation reaction selectivity, many side reactions and high cost, and achieve the effects of high selectivity, easy separation and purification, and reduction of synthesis cost.

Active Publication Date: 2015-03-25
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In order to solve many problems such as poor selectivity of acylation reaction, many side reactions, low yield and high cost in the synthesis of amikacin under the existing technical conditions, the invention provides a preparation method of amikacin, which acylation The reaction has the remarkable characteristics of high selectivity and less side reactions

Method used

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  • Preparation method of amikacin and intermediate activated thioester thereof
  • Preparation method of amikacin and intermediate activated thioester thereof
  • Preparation method of amikacin and intermediate activated thioester thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0054] Embodiment 1: the preparation of active thioester

[0055] In a 1000ml dry flask, feed in sequence: 200ml of dichloromethane, 50g of PHBA and 100g of DM, and stir thoroughly for 30 minutes; then slowly add dropwise a mixture of 30ml of pyridine, 50ml of triethylamine and 60ml of triethyl phosphite at 5-10°C. Mixed solution, control the rate of addition to drop after 2 hours. Continue to keep warm at 5-10°C for 3-5 hours, then filter the reaction solution, wash the filter cake with dichloromethane; distill off the solvent from the filtrate under reduced pressure, and dry it in vacuum at 50°C to obtain a yellow solid; place the solid in 80ml of methanol Slurry in medium for 1 hour, filter, and vacuum dry at 50° C. to obtain 78 g of a light yellow active thioester solid with a content of >98% and a molar yield of 98%. The mp of the product: 168-172°C. MS (m / z): 398.4; 1 HNMR (DMSO, 300MHz): 2.18(m,2H), 3.381(t,2H), 4.44(t,1H), 5.56(s,1H), 7.58~7.64(d,2H), 7.91~7.91(s, ...

Embodiment 2

[0056] Embodiment 2: the preparation of active thioester

[0057] Add 35g DM, 25g PHBA and 350ml 1,2-dichloroethane into a dry 500ml flask, stir at room temperature for 30 minutes, then cool to 0°C, add 30ml triethylamine dropwise, after the addition is complete, within 2 hours Add 31.5g triphenylphosphine in batches, continue to react for 4 hours after adding, filter, wash the filter cake with 1,2-dichloroethane, distill the solvent from the filtrate under reduced pressure to obtain a yellow solid; add the yellow solid to In 50ml of methanol, stirred at 0°C for 1 hour, filtered, washed with cold methanol, and vacuum-dried at 50°C to obtain 36.5g of light yellow active thioester solid, content>99%, yield 92%.

Embodiment 3

[0058] Embodiment 3: the preparation of active thioester

[0059] Add a mixture of 7.5g PHBA, 12.5g DM, 40g toluene and 60g acetonitrile into a dry flask, stir at room temperature for 30 minutes, then cool down to 10-15°C, add 5ml triethylamine and 7g phosphorous acid within 2 hours The mixed solution of triethyl ester was incubated and reacted for 4 hours; the reaction was completed, the feed liquid was filtered, the filter cake was washed with toluene until colorless, the solvent was distilled under reduced pressure, and then the gained solid was placed in 30ml methanol for beating for 1 hour, filtered to obtain Yellow active thioester solid 11.8g, content>99%, yield 98%.

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Abstract

The invention discloses a preparation method of amikacin and an intermediate activated thioester thereof. The activated thioester has the structural formula (I). The preparation method comprises the following steps: using PHBA and DM as raw materials, under the condition that organic alkali is used as a catalyst, performing condensation reaction on the raw materials and a water absorbent triphenylphosphine or phosphite ester to obtain the activated thioester; using the activated thioester as the intermediate, performing acylation reaction on the activated thioester and kanamycin A silanized derivative, de-protecting by using an alcohol reagent, performing hydrazinolysis and crystallizing to obtain the amikacin. The preparation method is suitable for industrialized production; by the preparation method, the synthesis cost of the amikacin can be greatly reduced.

Description

technical field [0001] The invention relates to a preparation method of amikacin and an intermediate thereof, belonging to the technical field of medicine. Background technique [0002] Aminoglycoside antibiotics (Aminoglycoside antibiotics) have the structure of aminosugar and aminocyclic alcohol, and are composed of aminosugar molecules and aglycones in non-sugar parts. They have strong antibacterial ability, wide antibacterial spectrum, stable chemical properties, easy absorption and At the same time, they also have common characteristics in terms of antibacterial spectrum, antibacterial mechanism, serum protein binding rate, gastrointestinal absorption, renal excretion and adverse reactions. This type of antibiotic is an important class of broad-spectrum anti-infective drugs clinically, and is mainly used in the treatment of Gram-negative bacteria, Pseudomonas aeruginosa and other infections in clinical practice. It is still the first drug for the treatment of bacterial...

Claims

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Application Information

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IPC IPC(8): C07D417/12C07H15/234C07H1/00
CPCY02P20/55C07D417/12C07H1/00C07H15/234
Inventor 王树鹏常宝磊秦春霞刘荣旺李保勇吴柯樊长莹张兆珍董廷华柏明士李德才
Owner 山东安信制药有限公司
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