- Synthesis method of minocycline hydrochloride
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The invention relates to a synthesis method of minocycline hydrochloride, which comprises the following steps of: (1) reacting demeclocycline with an amination reagent in a first organic solvent in the presence of a palladium metal complex to obtain 7-amino-6-demethyltetracycline; (2) carrying out a dehydroxylation reaction on the 7-amino-6-demethyltetracycline in a second organic solvent in the presence of a first acid reagent and a first catalyst, so as to obtain 7-amino-6-demethyl-6-deoxytetracycline; and (3) in a third organic solvent, in the presence of a second acid reagent and a second catalyst, carrying out alkylation reaction on the 7-amino-6-demethyl-6-deoxytetracycline and an alkylation reagent to obtain minocycline hydrochloride. The minocycline hydrochloride prepared by the method disclosed by the invention has the advantages of simple synthesis process, high yield, high purity and easiness in large-scale production.
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- Synthesis method of minocycline hydrochloride
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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.
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Paragraph 0024; 0052-0053
(2021/03/31)
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- Preparation method of 7-amino-6-demethylation-6-deoxy tetracycline and minocycline hydrochloride
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The invention relates to a preparation method of 7-amido-6-demethylation-6-deoxy tetracycline and minocycline hydrochloride, and particularly provides a preparation method of 7-amido-6-demethylation-6-deoxy tetracycline. The preparation method comprises the following steps: (1) carrying out chlorination reaction on 6- preparation method-6-deoxy tetracycline and a chlorination reagent, and obtaining a chlorination product; carrying out azo reaction on the chlorination product and an azo reagent to obtain a reaction solution containing 7-p-benzenesulfonic acid azo group-11a-chloro-6-demethylation-6-deoxy tetracycline; and (2) adding a reducing reagent into the reaction solution containing the 7-p-benzenesulfonic acid azo group-11a-chloro-6-demethylation-6-deoxy tetracycline obtained in the step (1), and carrying out a reaction to obtain the 7-amido-6-demethylation-6-deoxy tetracycline. The synthesis method of minocycline hydrochloride has the advantages of simple synthesis process, high yield, high purity, easiness in large-scale production and the like.
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Paragraph 0326-0329; 0336; 0337
(2021/04/14)
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- Preparation method of minocycline
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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.
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Paragraph 0026
(2020/11/23)
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- A robust platform for the synthesis of new tetracycline antibiotics
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Tetracyclines and tetracycline analogues are prepared by a convergent, single-step Michael-Claisen condensation of AB precursor 1 or 2 with D-ring precursors of wide structural variability, followed by removal of protective groups (typically in two steps). A number of procedural variants of the key C-ring-forming reaction are illustrated in multiple examples. These include stepwise deprotonation of a D-ring precursor followed by addition of 1 or 2, in situ deprotonation of a D-ring precursor in mixture with 1 or 2, and in situ lithium-halogen exchange of a benzylic bromide D-ring precursor in the presence of 1 or 2, followed by warming. The AB plus D strategy for tetracycline synthesis by C-ring construction is shown to be robust across a range of different carbocyclic and heterocyclic D-ring precursors, proceeding reliably and with a high degree of stereochemical control. Evidence suggests that Michael addition of the benzylic anion derived from a given D-ring precursor to enones 1 or 2 is quite rapid at -78 °C, while Claisen cyclization of the enolate produced is rate-determining, typically occurring upon warming to 0 °C. The AB plus D coupling strategy is also shown to be useful for the construction of tetracycline precursors that are diversifiable by latter-stage transformations, subsequent to cyclization to form the C ring. Results of antibacterial assays and preliminary data obtained from a murine septicemia model show that many of the novel tetracyclines synthesized have potent antibiotic activities, both in bacterial cell culture and in vivo. The platform for tetracycline synthesis described gives access to a broad range of molecules that would be inaccessible by semisynthetic methods (presently the only means of tetracycline production) and provides a powerful engine for the discovery and, perhaps, development of new tetracycline antibiotics.
- Sun, Cuixiang,Wang, Qiu,Brubaker, Jason D.,Wright, Peter M.,Lerner, Christian D.,Noson, Kevin,Charest, Mark,Siegel, Dionicio R.,Wang, Yi-Ming,Myers, Andrew G.
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supporting information; experimental part
p. 17913 - 17927
(2009/07/18)
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- Isolation and recovery of calcium chloride complex of 7-dimethylamino-6-dimethyl l-6-deoxytetracycline hydrochloride
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This disclosure describes a process for the recovery of 7-dimethylamino-6-demethyl-6-deoxytetracycline from an aqueous solution thereof by means of a calcium chloride complex of 7-dimethylamino-6-demethyl-6-deoxy-tetracycline hydrochloride.
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