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Synthesis method of minocycline hydrochloride

A technology of minocycline hydrochloride and its synthesis method, which is applied in the field of minocycline hydrochloride, can solve the problems of easy explosion in diazotization reaction, cumbersome operation, and difficulty in removal, so as to improve environmental friendliness and operability, Reduce environmental pollution and reduce the effect of hydrogenation times

Active Publication Date: 2021-03-30
南京仁为医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Direct nitration method: 7-nitroshancycline and 9-nitroshancycline are synthesized after nitration of sancycline with mixed acid, and the yield of 9-nitroshancycline is higher than that of 7-nitroshancycline and 7-nitroshancycline Minocycline hydrochloride is obtained through sulfate separation and reductive amination. This route requires nitrification, which is more polluting and dangerous for nitrification.
[0008] 2. Tert-butyl protected nitration method: Sancycline reacts with tert-butanol under the catalysis of strong acid, protects the 9-position to obtain 9-tert-butyl sancycline, and then nitrates to obtain 7-nitro-9- Tert-butylshancycline, and then through reductive ammoniation, acid deprotection, to obtain minocycline hydrochloride, which needs to be protected and deprotected, the operation is cumbersome, the cost is high, the yield is low, and the trifluoroformic acid used has strong corrosion resistance, limiting the application in mass production
This process uses dibenzyl azodicarboxylate, which is not common in the market, as an azoamination intermediate, which has high cost and is easy to decompose, resulting in unqualified product purity and related substances, and is difficult to apply in industrial production.
[0010] 4. Chlorine protection diazonium method: first protect the 11a position with a halogenating agent, and then react with a substituted phenyl diazonium salt to obtain the 7-position addition product, and the product is subjected to catalytic hydrogenation and methylation to obtain minocycline; The method requires NCS to protect the 11th position additionally, as well as the instability of diazo and azo compounds, the product needs column purification and other disadvantages, and the diazotization reaction is prone to explosion risks
[0011] 5. CN201911190466 .1 protects a method for preparing minocycline hydrochloride using sancycline hydrochloride as a starting material. After protection, minocycline hydrochloride is combined with O-benzoyl-N,N-dimethylhydroxylamine Minocycline is synthesized under the catalysis of ferric chloride, and the steps are relatively short. Although the use of heavy metals is avoided, the ammoniation reaction under the catalysis of ferric chloride is easy to produce the 9-amminated isomer, which is difficult to remove. And O-benzoyl-N , N-dimethylhydroxylamine is difficult to buy
[0013] 1. Minocycline hydrochloride is prepared by dechlorination, dehydroxylation reaction, chlorination protection of 11a position, 7-azotization reaction, and reductive amination of demethylaureomycin hydrochloride. The reaction steps are long and column chromatography is required. Method separation, diazotization reaction has a certain risk and the impurities produced are difficult to remove, so it is not suitable for industrial production
[0014] 2. Huang Kai, Le Zhanxian, Zhuang Hong, Xie Lijun. Research on the synthesis process of minocycline hydrochloride[J]. Haixia Pharmacy, 2017,29(05):247-249. The raw material is dechlorinated and dehydroxylated to obtain sancycline hydrochloride, then iodized to obtain 7-iodosancycline hydrochloride, and finally ammoniated to obtain minocycline hydrochloride. This route is relatively short and more expensive Palladium carbon is used as a dechlorination catalyst, and the dechlorination reaction produces more impurities. The expensive rhodium carbon is used as a catalyst, and the iodination reaction is easy to produce 9-position iodo isomers, which are difficult to remove

Method used

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  • Synthesis method of minocycline hydrochloride
  • Synthesis method of minocycline hydrochloride
  • Synthesis method of minocycline hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0039] In a stainless steel hydrogenation autoclave, add 20g of demethylaureomycin hydrochloride and 120ml of methanol, add 30g of p-toluenesulfonic acid, add 2g of Raney nickel, replace nitrogen three times, then flush with hydrogen to a pressure of 2Mpa, react at 40°C for 6h, and detect by HPLC The reaction is considered to be complete when the content of desmethylchlortetracycline in hydrochloric acid is ≤2%. Cool down to 0°C, add 300ml of water, add aqueous sodium bicarbonate solution to adjust the pH to about 8, and precipitate a solid, which can be obtained by suction filtration to obtain Intermediate I, a light yellow solid 17g, yield 88%, HPLC purity 97.5%. 1 H NMR (500 MHz, DMSO ) δ 7.53 (s, 1H), 7.31 (s, 2H), 6.84 (s, 1H), 3.68 (s, 1H), 3.28 (s, 1H), 3.07 – 2.76 (m, 3H), 2.61 (s, 1H), 2.26 (s, 6H), 1.74 (s, 2H).

Embodiment 2

[0041] In a stainless steel hydrogenation autoclave, add 20g of demethylaureomycin hydrochloride and 200ml of ethanol, add 15g of methanesulfonic acid, add 6g of Raney nickel, replace with nitrogen three times, then flush with hydrogen to a pressure of 3.5Mpa, react at 45°C for 8h, and detect by HPLC The reaction is considered to be complete when the content of desmethylchlortetracycline in hydrochloric acid is ≤2%. Cool down to 0°C, add 300ml of water, add aqueous sodium bicarbonate solution to adjust the pH to about 8, and precipitate a solid, which can be obtained by suction filtration to obtain Intermediate I, a light yellow solid 16.5g, yield 85%, HPLC purity 97.8%.

Embodiment 3

[0043]In a stainless steel hydrogenation autoclave, add 20g of demethylaureomycin hydrochloride and 280ml of methanol, add 15g of methanesulfonic acid, add 10g of Raney nickel, replace nitrogen three times, then flush with hydrogen to a pressure of 5Mpa, react at 50°C for 5h, and detect the reaction by HPLC The reaction is considered complete when the content of desmethylchlortetracycline hydrochloride is ≤2%. Cool down to 0°C, add 300ml of water, add aqueous sodium bicarbonate solution to adjust the pH to about 8, precipitate a solid, and obtain intermediate I by suction filtration, a light yellow solid of 18.2 g, yield 94%, HPLC purity 95.6%.

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Abstract

The invention discloses a preparation method of minocycline hydrochloride. The preparation method is characterized by comprising the following steps: with demeclocycline hydrochloride as an initial raw material, carrying out a dehydroxylation reaction to obtain 6-deoxy-6-demeclocycline (intermediate I for short); carrying out acetyl protection on the intermediate I to obtain 3,10,12,12a-tetraacetyl-6-deoxy-6-demeclocycline (intermediate II for short); carrying out the BuchwaldHartwig reaction on the intermediate II to obtain 3,10,12,12a-tetraacetylminocycline (intermediate III for short); hydrolyzing the intermediate III to obtain minocycline free alkali (intermediate IV for short); and salifying the intermediate IV to obtain minocycline hydrochloride. According to the invention, nitrification, diazotization and azo reactions used in traditional minocycline hydrochloride synthesis processes are avoided, so dangerous factors in the production process are reduced, operation is simple, environmental pollution is avoided, and the method has industrial production prospects.

Description

technical field [0001] The present invention relates to a synthesis method of minocycline hydrochloride, in particular to the synthesis of 3,10,12,12a-tetraacetyl minocycline by means of Buchwald-Hartwig reaction, followed by hydrolysis and salt formation to obtain minocycline hydrochloride . . 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] 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 bacteria, including tetracycline-r...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C237/26A61P31/04
CPCC07C231/12A61P31/04C07C2603/46C07C237/26
Inventor 陈杰任燕陈怡然
Owner 南京仁为医药科技有限公司
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