Preparation method of minocycline

A technology of minocycline and sancycline, which is applied in the field of preparation of minocycline, can solve problems such as difficult purification, and achieve the effect of simple purification and simple operation

Pending Publication Date: 2020-11-06
卡博金艾美斯医药(上海)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] 4. Azo addition reduction method: under strong acidic conditions (concentrated sulfuric acid, methanesulfonic acid or trifluoroacetic acid), sancycline and dibenzyl azodicarboxylate at C-7 are addition products, the intermedi

Method used

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  • Preparation method of minocycline
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  • Preparation method of minocycline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1 Sancycline 6-protection of ethoxycarbonyl

[0036] The structural formula is as follows:

[0037]

[0038] Sancycline (2 mmol), dichloromethane (5 mL) and triethylamine (3 mmol) were added in a 50 mL flask. The mixture was cooled to 0°C, and ethyl chloroformate (2.2 mmol) was slowly added dropwise, keeping the temperature not exceeding 5°C. The reaction was monitored by TLC, and the conversion was complete within 1 hour. Add 10 ml of water and separate the layers. The organic phase was concentrated to dryness and used directly in the next reaction without purification. ESI-MS m / z: 487.2 (M+H+).

Embodiment 2

[0039] Embodiment 2 Sancycline 6-protection of acetyl group

[0040] The structural formula is as follows:

[0041]

[0042] Shancycline (2 mmol), acetic anhydride (6 mmol) and pyridine (6 mmol) were added to 50 ml of dichloromethane and refluxed for not less than 5 hours. After the reaction is complete, cool down to room temperature, adjust to neutrality with saturated aqueous sodium bicarbonate solution, wash the organic phase with 12% brine, dry over anhydrous sodium sulfate, filter, concentrate to dryness, and directly use in the next reaction without purification . ESI-MS m / z: 457.3 (M+H+).

Embodiment 3

[0043] Embodiment 3 Sancycline 6-protection of benzoyl

[0044] The structural formula is as follows:

[0045]

[0046] Sancycline (2mmol), sodium carbonate (5g) and benzoyl chloride (2.5mmol) were added to 50ml of methanol and stirred at 25-35°C for 4 hours. TLC showed that the reaction was complete, 100 ml of purified water was added, adjusted to neutrality with saturated aqueous sodium bicarbonate solution, the organic phase was washed with 12% brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and used directly for Next reaction. ESI-MS m / z: 518.9 (M+H+).

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PUM

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Abstract

The invention discloses a preparation method of minocycline. The minocycline is (4S,4aS,5aR,12aS)-4,7-dimethylamino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-tetraphenyl-2-formamide. According to the method, sancyline is subjected to protection of a phenolic hydroxyl group via an acyl group, and then selective dimethylamination is conducted on position 6. After a protection strategy is adopted in the process route of the method, generation of 9-position dimethylamination by-products is avoided, and purification is simple. Usage of precious metal is avoided in a reaction, a production unit is simple to operate, safe and environment-friendly, and the method is very suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of minocycline, which belongs to the technical field of medicine synthesis. Background technique [0002] The chemical name of minocycline is: (4S,4aS,5aR,12aS)-4,7-bisdimethylamino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1, 4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, the structural formula is as follows: [0003] [0004] 4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2- Naphthalene carboxamide; Minocycline; 7-Dimethylamino-6-desmethyl-6-deoxytetracycline, CAS: 10118-90-8. [0005] Minocycline, also known as minocycline or minocycline, is a broad-spectrum antibacterial tetracycline antibiotic. Can combine with tRNA to achieve antibacterial effect. Minocycline has a broader antibacterial spectrum than similar drugs and has antibacterial activity. The antibacterial spectrum is similar to that of tetracycline, and it has a strong effect on Gram-positive ...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C237/26
CPCC07C231/12C07C2603/46C07B2200/07C07C237/26Y02P20/55
Inventor 顾开春王希林
Owner 卡博金艾美斯医药(上海)有限公司
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