Preparation method and intermediate of minocycline

A technology of minocycline and tetracycline, which is applied in the preparation of organic compounds, carboxylic acid amide preparation, chemical instruments and methods, etc., and can solve the problems of high price and difficult availability of 7-aminocycline

Active Publication Date: 2013-11-13
CHENGDU CHEMPARTNER
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This patent has done the improvement that yield increases, but, the raw material 7-aminosancycline used is not easy to obtain, and the price is expensive

Method used

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  • Preparation method and intermediate of minocycline
  • Preparation method and intermediate of minocycline
  • Preparation method and intermediate of minocycline

Examples

Experimental program
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Effect test

Embodiment 1

[0054] In a 1000ml three-necked flask, add 50g of demethylaureomycin hydrochloride (content greater than 99%, mass percentage), add 500ml of DMF, add 10g of diisopropylimidazolium palladium chloride, and stir to dissolve at room temperature. Cool in an ice-water bath, add 30ml of 40% dimethylamine aqueous solution, and stir and react at 10°C to 15°C for 8 hours. HPLC detects the reaction solution, and the demethylactetracycline is 1.22%, and the reaction is terminated.

[0055] Add the above reaction solution into 6000ml of isopropanol, stir to precipitate a solid, then put it into a -20°C freezer, and freeze it for 8 to 10 hours. Filter, and wash the filter cake with 50 ml of isopropanol at -20°C. The filtrate is collected in a separate recovery bucket. The filter cake was dried under reduced pressure at 30°C-40°C for 8 hours to obtain 43.6 g of the product 7-dimethylamino-6-nortetracycline (M-M), yield: 91.1%, the product 7-dimethylamino- 6-nortetracycline (M-M) purity: 9...

Embodiment 2

[0060] In a 1000ml three-necked flask, add 50g of desmethyltetracycline hydrochloride (content greater than 99%), add 500ml of N-methylpyrrolidone, add 8g of tetrakis(triphenylphosphine)palladium, stir and dissolve at room temperature. Add 30ml of 40% dimethylamine aqueous solution, and stir the reaction at 45-55°C for 5 hours. HPLC detects the reaction solution, and the demethylactetracycline is 0.74%, and the reaction is terminated.

[0061]Add the above reaction solution into 6500ml of isopropanol, stir to precipitate a solid, then put it into a -20°C freezer, and freeze it for 8 to 10 hours. Filter and wash the filter cake with 50 ml of frozen isopropanol. The filtrate is collected in a separate recovery bucket. The filter cake was dried under reduced pressure at 30-40°C for 8 hours to obtain 44.3 g of the product 7-dimethylamino-6-nortetracycline (M-M), yield: 90.2%, the product 7-dimethylamino-6 - Nortetracycline (M-M) purity: 95.9%.

[0062] Add 44.3 g of 7-dimethyl...

Embodiment 3

[0066] In a 1000ml three-neck flask, add 50g of demethylaureomycin hydrochloride (content greater than 99%), add 500ml of DMPU, add 10g of bistriphenylphosphinepalladium dichloride, stir and dissolve at room temperature. Add 35ml of 40% dimethylamine aqueous solution, and stir and react at 20-25°C for 9 hours. HPLC detects reaction solution, and demethylactetracycline is 0.97%, finishes reaction.

[0067] Add the above reaction solution into 6000ml of isopropanol, stir to precipitate a solid, then put it into a -20°C freezer, and freeze it for 8 to 10 hours. Filter and wash the filter cake with 50 ml of frozen isopropanol. The filtrate is collected in a separate recovery bucket. The filter cake was dried under reduced pressure at 30-40°C for 8 hours to obtain 45.2 g of the product 7-dimethylamino-6-nortetracycline (M-M), yield: 92.3%, the product 7-dimethylamino-6 - Nortetracycline (M-M) purity: 96.8%.

[0068] Add 45.2 g of 7-dimethylamino-6-nortetracycline (M-M) into 550...

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Abstract

The invention discloses a preparation method and an intermediate of minocycline. A preparation method for the intermediate M-M is to subject demethylated aureomycin and dimethylamine to reactions as described in the specification in an amine solvent or amide solvent under the catalysis of a palladium complex. The preparation method for minocycline comprises the following steps: (1) subjecting demethylated aureomycin and dimethylamine to the reactions in the amine solvent or amide solvent under the catalysis of the palladium complex so as to prepare the compound M-M; and (2) subjecting the compound M-M prepared in step (1) to hydrogenation and dehydroxylation in an alcohol solvent including an acid under the catalysis of a catalyst. The preparation method provided by the invention has the advantages of easily available raw materials, low cost, simple two-step reaction operation, high product yield, good product quality, recoverability and reusability of the solvents and easy industrial production.

Description

technical field [0001] The present invention specifically relates to a preparation method of minocycline and its intermediate. Background technique [0002] Minocycline, English name: Minocycline, chemical name: (4S–(4α,4aα,5aα,12aα))-4,7-bis(dimethylamino)-1,4,4a,5,5a,6, 11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide; (4S–(4α,4aα,5aα,12aα))-4,7 -Bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarbox-amide. Trade name: Demecycline, Minocycline, Connie. Its chemical structural formula: [0003] [0004] Minocycline MW:457 [0005] Minocycline is a second-generation semi-synthetic tetracycline broad-spectrum antibiotic with high efficiency and long-term effect. Among tetracycline antibiotics, this product has a stronger antibacterial effect. The antibacterial spectrum is similar to that of tetracycline. It has a strong effect on Gram-positive bacteria, including tetracycline-resistant ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/26C07C231/12
Inventor 李英富陈元伟谈平忠
Owner CHENGDU CHEMPARTNER
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