Disclosure of Invention
The technical problem to be solved by the invention is to provide a novel method for synthesizing minocycline hydrochloride, so that the synthesis steps are simplified, the safety risk and the labor hour cost are reduced, and the feasibility of converting the process into industrial mass production is improved.
The invention adopts the technical scheme that: a novel method for synthesizing minocycline hydrochloride, which comprises the following steps: A. taking the demethyl aureomycin hydrochloride as a raw material, and carrying out debenzylation reaction on the raw material to obtain 7-chloromountain cyclamine hydrochloride; B. 7-chloromountain cyclase hydrochloride, sodium iodide or potassium iodide are used as raw materials, and an ultraviolet irradiation method is used for synthesizing the 7-iodomountain cyclase hydrochloride; C. taking 7-iodo-shan-cycline hydrochloride and an organotin reagent as raw materials, and carrying out a coupling reaction under the action of a palladium complex to produce minocycline hydrochloride.
Further, the specific operation of the step A is as follows: adding hydrochloric acid demethyl aureomycin and dichlorodimethyl silane into sodium iodide or potassium iodide solution, reacting at 0-30 ℃ to remove benzyl hydroxyl of hydrochloric acid demethyl aureomycin, and then obtaining 7-chloromountain cyclic extract through acidification, crystallization, washing and drying.
Further, the specific operation of the step B is as follows: dissolving 7-chloromountain cyclamine hydrochloride and sodium iodide (potassium iodide) in a solvent, adding an acetonitrile solution of iodine for reaction, carrying out ultraviolet irradiation in an ultraviolet reactor at a low temperature of between 0 and 30 ℃ and with an ultraviolet wavelength of between 0 and 300nm, and acidizing, crystallizing, washing and drying after the reaction is finished to obtain the 7-iodomountain cyclamine.
Further, the specific operation of the step C is as follows: dissolving 7-iodo-mountain cyclamine hydrochloride in a reaction solvent, adding a palladium complex and an organotin reagent, performing a coupling reaction at a low temperature of 0-30 ℃, and separating by macroporous adsorption resin to obtain minocycline hydrochloride.
Further, in the step A, the chlortetracycline hydrochloride is prepared by: dichlorodimethylsilane: the molar ratio of potassium iodide or sodium iodide is 1 (1-2): 3-5, wherein the solvent used in the sodium iodide or sodium iodide solution in the step A is at least one of acetone and acetonitrile or a mixed solvent of one of acetone and acetonitrile and dichloromethane according to any proportion, and the mixed proportion of solute and solvent in the potassium iodide or sodium iodide solution is as follows: solvent=1:3 to 8 (g: mL).
Further, the ratio of the 7-chloromountain cyclic element to the solvent in the step B is 1:3-10 (g: mL), the solvent is acetonitrile or a mixed solvent of acetonitrile and water, the volume ratio of acetonitrile is 50% -100%, the ratio of sodium iodide (potassium iodide) to iodine solution is 2:1-2 (g: mL), the concentration of the iodine acetonitrile solution is 0.1-0.5M, and the molar ratio of the sodium iodide or potassium iodide to the 7-chloromountain cyclic element hydrochloride is 2-4:1.
Further, the solvent in the step C is one of ethylene glycol dimethyl ether, dimethylpropyleneurea, N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide or 1, 4-dioxane, and the ratio of the 7-iodo-mountain bike hydrochloride to the solvent is 1:3 to 10 (g: mL); the palladium complex is one of diisopropylimidazole palladium chloride, tetra (triphenylphosphine) palladium, bis (triphenylphosphine) palladium dichloride or bis (acetonitrile) palladium dichloride; the organic tin reagent is an organic tin reagent with N, N-dimethyl connected with tin atoms, and is specifically one of 1, 1-tributyl-N, N-dimethyl stannane amine or (dimethyl amine) trimethyl tin; the molar ratio of the materials is 7-iodinated mountain cyclic acid hydrochloride: palladium complex catalyst: organotin reagent=1:0.01 to 0.05:1.03 to 1.2.
Further, the solvent used in the sodium iodide or potassium iodide solution in the step A is acetone.
Further, in the step B, the ultraviolet wavelength is 254nm, the reaction temperature is preferably 25 ℃, and the solvent for dissolving the 7-chloromountain cyclic element is a mixed solvent of acetonitrile and water in a ratio of 1:1.
Further, the solvent in the step C is N, N-dimethylformamide; the palladium complex is bis triphenylphosphine palladium dichloride; the organotin reagent is (dimethylamine) trimethyltin.
The beneficial effects obtained by the invention are as follows: the method simplifies the step of synthesizing minocycline hydrochloride, has no participation of hydrogen reduction reaction, improves the safety of the reaction, reduces the labor hour cost and improves the feasibility of industrialized mass production.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments.
Example 1
A. Synthesis of 7-chloromountain-Cycloxine hydrochloride
131.4g of sodium iodide is dissolved in 700mL of acetonitrile, the temperature is reduced to 0 ℃ under the protection of argon, 54mL of dichlorodimethylsilane and 110g of hydrochloric acid desmethylaureomycin are added into the stirred reaction solution to start the reaction, the reaction is monitored by TLC, saturated sodium thiosulfate solution is added for washing after the reaction is finished, and 103.1g of 7-chloromountain cyclidine hydrochloride is obtained through acidification, crystallization, washing and drying, and the single-step yield is 96.8%.
B. Synthesis of 7-iodo-shan-cycline hydrochloride
127.2g of sodium iodide was dissolved in 500mL of acetonitrile-water (volume ratio 1:1), 103.1g of 7-chloromountain cyclamine was added thereto, stirred until complete dissolution, and I was added dropwise2 Continuously stirring until the color is not changed, cooling in liquid nitrogen until the reaction liquid is completely frozen, vacuumizing by an oil pump, taking out the reaction bottle, placing in the air, slowly melting the feed liquid, replacing again, repeating the operation for 4 times, and finally filling argon. And (3) placing the reaction bottle into an ultraviolet irradiation reactor, irradiating with an ultraviolet lamp with the wavelength of 254nm at room temperature to initiate a reaction, monitoring the reaction by TLC, adding sodium thiosulfate to neutralize excessive iodine simple substance after the reaction is finished for 42 hours, and obtaining 100.1g of 7-iodo mountain cyclist through acidification, crystallization, washing and drying, wherein the single-step yield is 81.6%.
C. Synthesis of minocycline hydrochloride
100.1g of 7-iodo-shan-cycline is dissolved in 650mL of N, N-dimethylacetamide, 2.39g of tetra (triphenylphosphine) palladium is added, the mixture is stirred and dissolved at room temperature, 25mL of triethylamine, 61.2g of 1, 1-tributyl-N, N-dimethylstannanamine are added, the mixture is stirred at room temperature, TLC monitors the reaction, and after the reaction is finished, 62.0g of minocycline hydrochloride is obtained by eluting through macroporous adsorption resin, the single-step yield is 72.4%, and the total yield is 57.2%.
Example 2
A. Synthesis of 7-chloromountain-Cycloxine hydrochloride
178.5g of potassium iodide is dissolved in 550mL of acetone, the temperature is reduced to 0 ℃ under the protection of argon, 60mL of dichlorodimethylsilane and 108g of hydrochloric acid desmethylaureomycin are added into the stirred reaction solution to start the reaction, TLC monitors the reaction, saturated solution of sodium thiosulfate is added for washing after the reaction is finished, and 101.7g of 7-chloromountain cyclidine is obtained through acidification, crystallization, washing and drying, and the yield is 97.3%.
B. Synthesis of 7-iodo-shan-cycline hydrochloride
104.2g of potassium iodide is dissolved in 600mL of acetonitrile-water (volume ratio is 3:1), 101.7g of 7-chloromountain cyclic hydrochloride is added, stirring is carried out until the potassium iodide is completely dissolved, 60mL of acetonitrile solution of 0.3M iodine is dropwise added, stirring is continued until the color is not changed any more, a reaction bottle is placed into an ultraviolet irradiation reactor, ultraviolet irradiation with the wavelength of 254nm at room temperature is carried out for initiating reaction, TLC monitoring reaction is carried out, after 39h, sodium thiosulfate is added for neutralizing excessive iodine simple substance, 95.9g of 7-iodomountain cyclic hydrochloride is obtained through acidification, crystallization, washing and drying, and the yield is 79.2%.
C. Synthesis of minocycline hydrochloride
95.8g of 7-iodo-shan-cyclic acid hydrochloride is added to 700mLN, N-dimethylformamide, 1.9g of bis (triphenylphosphine) palladium dichloride is added, stirring and dissolving are carried out at room temperature, 20mL of triethylamine and 41.7g of 1, 1-trimethyl-N, N-dimethylstannanamine are added, stirring is carried out at room temperature, TLC monitoring reaction is carried out, and after the reaction is finished, 58.7g of minocycline hydrochloride is obtained through macroporous adsorption resin elution, crystallization, filtration, washing and drying, the yield is 71.5%, and the total yield is 55.1%.
Comparative examples:
A. synthesis of 7-dechlorinated desmethyl aureomycin hydrochloride
120g of desmethylaureomycin hydrochloride is added into 500mL of aqueous solution of urea at room temperature, the pH value is regulated to 8.5 by a sodium hydroxide solution, palladium carbon (Pd, wt percent and 5 percent) is added, hydrogen is introduced into a high-pressure reaction kettle at 0.95MPa and 25 ℃ for reaction, reaction feed liquid is treated after the reaction is finished, 107.5g of 7-dechlorinated desmethylaureomycin hydrochloride is obtained through acidification, crystallization, washing and drying, and the single-step yield is 96.1 percent.
B. Synthesis of mountain cyclic extract hydrochloride
At room temperature, after 7-dechlorinated and demethylated aureomycin hydrochloride 107.5g is dissolved in 400mL of methanol, 44.4g of methanesulfonic acid is added, stirring is carried out until the mixture is dissolved, rhodium-carbon Rh/C catalyst and DMF6.3mL are added, hydrogen is introduced into a high-pressure reaction kettle under the pressure of 1.50MPa at the temperature of 30 ℃ for reaction, the reaction liquid is treated after the reaction is finished, and 66.7g of the shancyclic hydrochloride is obtained through acidification, crystallization, washing and drying, and the single-step yield is 64.3%.
C. Synthetic intermediate 1
66.7g of mountain bike hydrochloride is dissolved in 200mL of purified water at 20 ℃, and after the mixture is stirred until the mixture is dissolved, 21.8g of chlorating reagent NCS is slowly added in batches at 25 ℃, and the mixture is stirred and reacted for 1h to obtain brown reaction liquid. The reaction feed liquid is treated, the temperature is controlled at 15-20 ℃, 56.8g of intermediate 1 is obtained through acidification, crystallization, washing and drying, and the single-step yield is 79.2%.
D. Preparation of diazonium salts
400mL of purified water, 30mL of concentrated hydrochloric acid and 40.7g of sulfanilic acid are sequentially added into a reaction kettle, 20mL of 40% sodium nitrite solution is slowly added dropwise at 0 ℃ for about 1 hour, the pH value is controlled below 3.0 by hydrochloric acid in the reaction process, and a white emulsion of diazonium salt is obtained after the reaction is finished.
E. Synthesis of intermediate 2
To the diazonium salt reaction solution was added a total of 56.8g of intermediate 1 in portions at 0℃and stirred for 1h. Slowly dripping 10% sodium carbonate solution at 0 ℃, adjusting the pH to 4.5-4.7, and stirring and reacting for 30min to obtain the hawthorn red emulsion. Continuously and slowly dripping saturated sodium bicarbonate solution at 0 ℃, regulating the pH value to 6.7-7.0, stirring and reacting for 1.5h to obtain a viscous dark brown emulsion, and obtaining 52.5g of intermediate 2 through acidification, crystallization, washing and drying, wherein the single-step yield is 84.3%.
F. Synthesis of minocycline hydrochloride
52.5g of intermediate 2 is dissolved in a mixed solvent of 50mL of ethylene glycol monomethyl ether, 50mL of concentrated sulfuric acid and 100mL of DMF at 15 ℃, the temperature is controlled below 25 ℃, and after uniform stirring, methanol solution of formaldehyde and formic acid is added. Transferring the feed liquid into an autoclave at 15 ℃, introducing hydrogen, reacting at 15 ℃ under 1.1Mpa under the catalysis of palladium-carbon, filtering and washing the reaction feed liquid after the reaction is finished, purifying by macroporous adsorption resin, crystallizing, washing and drying to obtain 38.3g of minocycline hydrochloride, wherein the single-step yield is 78.6%, and the total yield is 32.4%.
The foregoing is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art, who is within the scope of the present invention, should make equivalent substitutions or modifications according to the technical scheme of the present invention and the inventive concept thereof, and should be covered by the scope of the present invention.