CN103044281A - Preparation method of high-purity tigecycline - Google Patents
Preparation method of high-purity tigecycline Download PDFInfo
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Abstract
The invention relates to a preparation method of high-purity tigecycline, which comprises the steps of taking minocycline hydrochloride as an initial raw material, and conducting nitration, hydrogenation, acid conversion, amidation and purification. According to the preparation method, the hydrogenation pressure is reasonable; time used for a purification technology is shorter; the use amount of a solvent is reduced by more than 30%; when the prepared high-purity tigecycline with the purity of over 99.5% is used for a complicated skin and skin texture infected patient, compared with the existing tigecycline, the incidences of nausea and vomit are decreased to 15.1% and 10.2% respectively; and when tigecycline is used for treating a complicated intra-abdominal infected patient, the incidences of the nausea and the vomit are decreased to 15.4% and 11.3% respectively.
Description
Technical field
The invention belongs to Tigecycline class pharmaceutical field, particularly a kind of method for making of high-purity tigecycline.
Background technology
Tigecycline (tigecycline), chemical name: (4S, 4aS, 5Ar, 12aS)-4, two (the dimethyl)-9-[(tertiary butyls of 7-are amino) acetamido]-3,10,12,12a-tetrahydroxy-1,11-dioxo-Isosorbide-5-Nitrae, 4a, 5,5a, 6,11,12a-octahydro tetracene-2-methane amide claims again Tigecycline or tigecycline, obtains the FDA approval in June, 2005 by Hui Shi (WYETH) company, be the first Tigecycline class microbiotic of getting permission to go on the market, its molecular structure is as follows:
Tigecycline: C
29H
39N
5O
8
MW：585.65g/mol
Wyeth requires having about the Tigecycline Chinese patent of right of priority:
CN92112130 in 1992, this patent is take Minocycline HCl as starting raw material, is prepared from through several links such as nitrated, reduction, acid conversion, amidations, reaction process is:
(1) with SODIUMNITRATE as nitrating agent:
(2) with nitrosonitric acid as nitrating agent:
Chinese patent CN200680026438 in 2005, its core technology content is that the nitration reaction rear center body does not separate from reaction mixture, purpose is to obtain the higher Tigecycline of purity.
Chinese patent CN200680026763 in 2005, when disclosing amidate action, reaction medium is for being selected from aqueous medium and at least a basic solvent when not having reactant alkali to exist.
Chinese patent CN200680026792 in 2005 discloses purification process, namely adopts at least a polar aprotic solvent and a kind of polar aprotic solvent mixed solution, carries out purification process in differing temps section, different time sections.
Chinese patent CN200680026962 in 2005 discloses the catalyzer in the hydro-reduction reaction, the actual conditionses such as reaction pressure.
Chinese patent CN2006800064473 in 2005, the composition of open Tigecycline is particularly under without low temperature and low-oxygen environment, by adding carbohydrate, regulating the pH value and reduce the oxidizing reaction of Tigecycline and the generation of epimerization reaction.
There are the following problems at least for Tigecycline in the prior art: 1, the reduction process hydrogen pressure is unreasonable, does not disclose optimal pressure range; 2, use quantity of solvent excessive in the end product Tigecycline treating process, and then it is difficult to cause the three wastes to be processed; 3, product purity is not high, and purifying process is unreasonable, and then the adverse reaction rate that some impurity causes is higher; 4, raw material is when making lyophilized injectable powder, and easily the problem of oxidation and epimerization does not solve at all; 5, the intermediate of Tigecycline is very unstable, and process time is oversize.
Summary of the invention
The invention provides a kind of hydrogenation pressure rationally, the preparation method of the technique time spent is shorter during purifying, solvent load is little high-purity tigecycline, the Tigecycline adverse reaction rate that the method makes is lower.The below makes introductions all round to technical scheme of the present invention.
The method for making of a kind of high-purity tigecycline of the present invention is take minocycline hydrochloride as starting raw material, forms through nitrated, hydrogenation, sour conversion, amidation, purification,
Nitrated referring under protection of inert gas the minocycline hydrochloride concentrated sulfuric acid dissolution extracted system hydrogenchloride out, then with nitrosonitric acid generation nitration reaction, through crystallization and dispersion, gets nitration product; In this nitration reaction, the vitriol oil is 3-8 times of minocycline hydrochloride quality, and temperature of reaction is 0-20 ℃, and the reaction times is 2-7 hour, and the mol ratio of nitrosonitric acid and minocycline hydrochloride is 1.2-1.6:1;
Hydrogenation refers to the nitration product dissolve with ethanol, under palladium/charcoal katalysis, under certain hydrogen pressure hydrogenation occurs, and through crystallization and dispersion, gets hydrogenated products; In this hydrogenation, the mass ratio of ethanol and nitration product is 4-10:1; Reaction times is 8-20 hour; The consumption of Pd/carbon catalyst and nitration product mass ratio are 0.03-0.08:1; Hydrogen pressure is 0.005-0.3MPa;
It is under protection of inert gas hydrogenated products to be dissolved in a certain amount of cold water first that acid transforms, and then regulates pH value, leaves standstill crystallization, filtration, drying etc. and get sour converted product after operating through concentrated hydrochloric acid; In this acid conversion reaction, temperature of reaction is 0-15 ℃, and the pH value is 3.0-6.0, and leaving standstill the crystallization time is 12-24 hour, and the mass ratio of cold water and hydrogenated products is 2-10:1;
Amidation refers under protection of inert gas sour converted product is dissolved in the cold water, adds the amino glycyl chloride hydrochloride of uncle's N-fourth stirring reaction under the low temperature, gets the Tigecycline crude product after extraction step; In this amidate action, cold water is that the 2-10 of sour converted product consumption doubly measures, and temperature of reaction is 0-10 ℃, and the reaction times is 2-5 hour; Extraction step refers under the condition of the pH to 6.0-9.0 of conditioned reaction liquid before each extraction and afterwards, add and filter after extraction agent and methyl alcohol stir, filtrate is used the extraction agent extracted several times, merge and to add an amount of methyl alcohol after the organic phase and wash with water, then adding anhydrous sodium sulphate in organic phase stirs dry, filter, filtrate decompression has been concentrated into solid again to add extraction agent and be concentrated into when separating out has solid to separate out again, stirred 1 hour, filter, filter cake is drained with the extraction agent washing for several times, the filter cake drying under reduced pressure gets the Tigecycline crude product;
Purifying refers to one or more solvents the Tigecycline crude product be carried out recrystallization under protection of inert gas and certain temperature, makes the Tigecycline sterling; In this purification reaction, solvent comprises one or more mixed solvent of ethanol, methyl alcohol, acetone, butanone, and temperature range refers at 0-30 ℃, and mixing solutions is that the 2-6 of Tigecycline crude product quality doubly measures.
Realizing in the purpose situation of the present invention, below is further preferred technical scheme:
In the nitration reaction, the vitriol oil is 4-6 times of minocycline hydrochloride quality, and temperature of reaction is 0-5 ℃, and the reaction times is 4-6 hour, and the molar equivalent of nitrosonitric acid and minocycline hydrochloride is 1.3-1.5:1;
In the hydrogenation, the mass ratio of ethanol and nitration product is 6-8, and the reaction times is 9-11 hour, and the consumption of Pd/carbon catalyst and nitration product mass ratio are 0.04-0.06:1, and hydrogen pressure is 0.05-0.25MPa;
In the acid conversion reaction, temperature of reaction is 0-5 ℃, and the pH value is 3.0-5.0, and leaving standstill the crystallization time is 12-15 hour, and the mass ratio of cold water and hydrogenated products is 3-4:1;
In the amidate action, cold water is that the 4-7 of sour converted product consumption doubly measures, and temperature of reaction is 0-5 ℃, and the reaction times is 2.5-3.5 hour; In the extraction step, pH value scope is 7.0-7.8, and extraction agent comprises ethyl acetate, methylene dichloride or trichloromethane;
In the purification reaction, mixing solutions is that mass ratio is methyl alcohol and the acetone of 1:5-5:1, and temperature range refers at 15-25 ℃, and mixing solutions is that the 3-5 of Tigecycline crude product quality doubly measures.
More a step is preferably:
In the nitration reaction, the vitriol oil is 5.3-5.8 times of minocycline hydrochloride quality; Reaction times is 4.5-5.5 hour, and the molar equivalent of nitrosonitric acid and minocycline hydrochloride is 1.40-1.46:1;
In the hydrogenation, the mass ratio of ethanol and nitration product is 6.5-7.5, and the reaction times is 10 hours, and the consumption of Pd/carbon catalyst and nitration product mass ratio are 0.05:1, and hydrogen pressure is 0.005MPa;
In the acid conversion reaction, the pH value is 4.0-4.4, and leaving standstill the crystallization time is 13-14 hour, and the mass ratio of described cold water and hydrogenated products is 3.5-4:1;
In the amidate action, cold water is that the 4.5-5 of sour converted product consumption doubly measures, and the reaction response time is 3 hours; In the extraction step, pH value scope is 7.0-7.4, and extraction agent is methylene dichloride;
In the purification reaction, temperature of reaction is 20 ℃, and the mass ratio of methyl alcohol and acetone is 1:2-2:1, and mixing solutions is 4 times of amounts of Tigecycline crude product quality.
The dispersion agent that above-mentioned " crystallization and dispersion " is selected and crystallization agent comprise a kind of solvent among normal heptane, normal hexane, hexanaphthene, Virahol, the isopropylcarbinol or the mixture of several solvents, preferably mass ratio is the normal heptane of 3-11 and the mixture of Virahol, it is 6-8:1 that the Virahol of choosing and the mass ratio of normal heptane are more arranged, and preferred mass ratio is 6.5-7.5:1.
Surprisingly, comprise also in the mixture of Virahol and normal heptane that mass parts is hexanaphthene or the normal hexane of 3-5, comprise also that perhaps effect more when mass parts was the isopropylcarbinol of 6-10.Rare gas element used herein is preferred but be not limited to nitrogen; Each step of drying is vacuum-drying, and between temperature 40-68 ℃, wherein the drying temperature of nitration product, hydrogenated products, sour converted product is 40 ℃, and the drying temperature of Tigecycline crude product and sterling is 65 ℃.
Better purification step provided by the invention is that the Tigecycline crude product is added to first in the acetone, and wherein the mass ratio of Tigecycline crude product and acetone is 1:2-1:1, the rotating speed strong stirring take rotating speed as 2000-5000 rev/min 5-10 minute; Adding and the anhydrous methanol of acetone quality than 1:1, the rotating speed strong stirring take rotating speed as 2000-5000 rev/min 5-10 minute; Filter, the filter cake mass ratio is the anhydrous methanol of 1:1 and the drip washing of acetone mixed solution 3 times, and the mass ratio of mixed solution and Tigecycline crude product is 0.2-0.3:1, drain, and the filter cake drying under reduced pressure, and get final product.
Each step reaction of the present invention is carried out under infrared lamp avoiding visible light, and each goes on foot intermediate product and uses tinfoil parcel cryopreservation.
Tigecycline preparation method's of the present invention beneficial effect is, hydrogenation pressure is reasonable, the purifying process time spent is shorter, solvent load reduces more than 30%, the high-purity Tigecycline more than 99.5% that makes is when being used for complicated skin and skin texture infected patient, with respect to existing Tigecycline, the incidence of its nausea and vomiting reduces respectively 15.1% and 10.2%, when infected patient was used the Tigecycline treatment in the complicated abdomen, the incidence of its nausea and vomiting was reduced to respectively 15.4% and 11.3%.
Embodiment
Embodiment 1:
Under the nitrogen protection, 0 ℃, minocycline hydrochloride 10.0g is dissolved in 28ml(51.52g) in the vitriol oil; HCl in the most system is taken out in stirring; Slowly drip nitrosonitric acid 1.9g, stirring reaction 5 hours; Reaction slowly adds to reaction solution among Virahol/normal heptane (mass ratio 7:1) mixed solution 250g stirring at room 1 hour after finishing; Filter, filter cake is drained with the washing of Virahol/normal heptane (mass ratio 7:1) mixed solution (16g * 3 time); 40 ℃ of drying under reduced pressure of filter cake 5 hours get yellow powder 12.66 grams, yield 89.5%.
Embodiment 2:
Under the nitrogen protection, 0 ℃, minocycline hydrochloride 4.85kg is dissolved in the 15L vitriol oil; HCl in the most system is taken out in stirring; Slowly drip nitrosonitric acid 1.07kg, 0 ℃ stirring reaction 4.5-5.5 hour; Reaction slowly adds to reaction solution among Virahol/normal heptane (volume ratio 7:1) mixed solution 160L stirring at room 1-1.5 hour after finishing; Filter, filter cake is drained with the washing of Virahol/normal heptane (volume ratio 7:1) mixed solution (10L * 3 time); 40 ℃ of drying under reduced pressure of filter cake 5 hours get yellow powder 6.24kg, yield 90.9%.
Embodiment 3:
Substantially the same manner as Example 2, difference is that dispersion agent and crystallization agent are Virahol/normal heptane/hexanaphthene (volume ratio 7:1:4), final yellow powder 6.49kg, the yield 94.5% of getting.
Embodiment 4:
Substantially the same manner as Example 2, difference is that dispersion agent and crystallization agent are Virahol/normal heptane/isopropylcarbinol (volume ratio 7:1:8), final yellow powder 6.39kg, the yield 93.1% of getting.
Embodiment 5:
9-nitro Minocycline HCl dithionate 30.0g, 10% palladium/charcoal 1.5g, methyl alcohol 250ml, water 25ml are added hydrogenation reaction cauldron; Pass into hydrogen, control hydrogen pressure 0.15MPa, room temperature catalyzed reaction 10 hours; After reaction finishes, filter, filter cake is with methanol wash (45ml * 2 time); To react gained solution under stirring and add among Virahol/normal heptane (volume ratio 6:1) mixed solution 660ml stirring at room 0.5 hour; Filter, filter cake is drained with Virahol/normal heptane mixed solution (volume ratio 6:1) washing (35ml * 2 time); 40 ℃ of drying under reduced pressure of filter cake 5 hours get yellow-green colour powder 8.16 grams, yield 71%.
Embodiment 6:
9-nitro Minocycline HCl dithionate 6.20kg, 10% palladium/charcoal 0.38kg, methyl alcohol 50L, water 5L are added to hydrogenation reaction cauldron; Pass into hydrogen, control hydrogen pressure 0.15MPa; Room temperature catalyzed reaction 10 hours.After reaction finishes, filter, filter cake is with methanol wash (5L * 2 time); Filtrate is added among Virahol/normal heptane (volume ratio 6:1) mixed solution 160L stirring at room 1 hour under stirring; Filter, filter cake is drained with Virahol/normal heptane mixed solution (volume ratio 6:1) washing (7L * 2 time); 40 ℃ of dryings of filter cake 5 hours get 4.27 kilograms in yellow-green colour powder, yield 72%.
Embodiment 7:
Substantially the same manner as Example 6, difference is that dispersion agent and crystallization agent are Virahol/normal heptane/hexanaphthene (volume ratio 7:1:4), final yellow powder 4.98kg, the yield 84.0% of getting.
Embodiment 8:
Substantially the same manner as Example 6, difference is that dispersion agent and crystallization agent are Virahol/normal heptane/isopropylcarbinol (volume ratio 7:1:8), final yellow powder 5.03kg, the yield 84.8% of getting.
Embodiment 9:
Under the nitrogen protection, 0 ℃, 9-amino minocycline ring element dithionate 20.0g, sodium sulphite anhydrous 99.3 0.30g are dissolved in 60ml water; After solution stirring is even, drip concentrated hydrochloric acid 12.5ml, stirring reaction 1 hour; Regulate pH to 4.2 ± 0.2,0 ℃ stirring 1 hour (maintenance pH value 4.2 ± 0.2) with ammoniacal liquor, leave standstill more than 12 hours; Filter, filter cake is drained with isopropanol water solution washing (20ml * 2 time); 40 ℃ of drying under reduced pressure of filter cake 5 hours get yellow-green colour powder 10.65 grams, yield 69.8%.
Embodiment 10:
Nitrogen protection, 0 ℃ are dissolved in 15L water with 9-amino minocycline ring element dithionate 4.25kg, sodium sulphite anhydrous 99.3 0.25kg, are cooled to; Stir after 15 minutes and to add concentrated hydrochloric acid 1.7L, 0 ℃ stirring reaction 1-2 hour; Regulate pH to 4.2 ± 0.2,0 ℃ stirring 1.5 hours (maintenance pH value 4.2 ± 0.2) with ammoniacal liquor, 0 ℃ left standstill more than 12 hours; Filter, filter cake is drained with isopropanol water solution washing (3L * 2 time); 40 ℃ of drying under reduced pressure of filter cake 5 hours get 2.9 kilograms in yellow-green colour powder, yield 70.8%.
Embodiment 11:
Under the nitrogen protection, 0 ℃, 9-amino minocycline ring element hydrochloride 10.0g is dissolved in 50ml water; Add the amino glycyl chloride hydrochloride of uncle's N-fourth 11.0g, 0 ℃ of stirring reaction 3 hours; After reaction finishes, regulate pH to 7.2 ± 0.2 with ammoniacal liquor, the 75ml that adds methylene chloride, methyl alcohol 100ml stirred 0.5 hour, regulated pH to 7.2 ± 0.2 with ammoniacal liquor; Filter, filtrate is regulated pH to 7.2 ± 0.2 with ammoniacal liquor with dichloromethane extraction (150ml * 1 time, 75ml * 4 time) before each extraction; Merge organic phase, add methyl alcohol 50ml, wash with water (2.5ml * 3 time); Stirred dry 0.5 hour with anhydrous sodium sulphate 50g; Filter, 35 ℃ of filtrates have been evaporated to solid and have separated out, and add methylene dichloride 150ml to residuum, have been concentrated into solid and have separated out, and 0 ℃ of residuum stirred 1 hour; Filter, filter cake is drained with washed with dichloromethane (25ml * 3 time); 65 ℃ of drying under reduced pressure of filter cake 6 hours get orange crystalline powder 8.05 grams, yield 70.1%.
Embodiment 12:
Under the nitrogen protection, 0 ℃, with the water-soluble 10L of 9-amino minocycline ring element hydrochloride 2.25kg; Add the amino glycyl chloride hydrochloride of uncle's N-fourth 2.48kg, 0 ℃ of stirring reaction 3-4 hour afterreaction finishes; Ammoniacal liquor with 25% is regulated pH to 7.2 ± 0.2, adds methylene dichloride 20L, methyl alcohol 30L, stirs 30 minutes, and the ammoniacal liquor with 25% is regulated pH to 7.2 ± 0.2; Filter, filtrate is regulated pH to 7.2 ± 0.2 with ammoniacal liquor with dichloromethane extraction (20L * 1 time, 10L * 4 time) before each extraction; Merge organic phase, add methyl alcohol 10L, wash with water (4L * 3 time); Organic phase stirred dry 30 minutes with anhydrous sodium sulphate 5kg; Filter, 35 ℃ of filtrates have been evaporated to solid and have separated out, and add methylene dichloride 20L to residuum, have been concentrated into solid and have separated out, and 0 ℃ was stirred 1 hour; Filter, filter cake is drained with washed with dichloromethane (5L * 3 time); 65 ℃ of drying under reduced pressure of filter cake 6 hours get 1.86 kilograms of orange crystalline powders, yield 71.8%.
Embodiment 13:
Under the nitrogen protection, Tigecycline crude product 15g is added among the acetone 30g, the control temperature is 20 ℃, stirs 10 minutes; Add anhydrous methanol 30g, stirred 2 hours; Filter, filter cake is drained with anhydrous methanol/acetone solution (mass ratio 1:1) drip washing (15ml * 3 time); 65 ℃ of drying under reduced pressure of filter cake 8 hours.Get orange crystalline powder 10.2 grams, yield 68.0%.
Embodiment 14:
Under the nitrogen protection, Tigecycline crude product 1.85kg is added among the acetone 3.7kg control temperature to 20 ℃; Stirred 10 minutes; Add anhydrous methanol 3.7kg, stirred 2-3 hour; Filter, filter cake is drained with anhydrous methanol/acetone mixed solution (mass ratio 1:1) drip washing (0.5kg * 3 time); 65 ℃ of drying under reduced pressure of filter cake 8 hours.Get 1.31 kilograms of orange crystalline powders, yield 70.6%.
Embodiment 15:
Under the infrared lamp, Tigecycline crude product 1.85kg is added among the acetone 3.7kg control temperature to 20 ℃, take rotating speed as 3000 rev/mins rotating speed strong stirring 5-10 minute; Add anhydrous methanol 3.7kg, take rotating speed as 3000 rev/mins rotating speed strong stirring 5-10 minute; Filter, the filter cake mass ratio is the anhydrous methanol of 1:1 and the drip washing of acetone mixed solution 3 times, and the mass ratio of mixed solution and Tigecycline crude product is 0.2-0.3:1, drains 65 ℃ of drying under reduced pressure of filter cake 4 hours.Get 1.42 kilograms of orange crystalline powders, yield 76.7%.
The above; only for the better embodiment of the present invention, but protection scope of the present invention is not limited to this, anyly is familiar with those skilled in the art in the technical scope that the present invention discloses; the variation that can expect easily or replacement all should be encompassed within protection scope of the present invention.Therefore, protection scope of the present invention should be as the criterion with the protection domain of claim.
Claims (10)
1. the method for making of a high-purity tigecycline take minocycline hydrochloride as starting raw material, forms through nitrated, hydrogenation, sour conversion, amidation, purification,
Described nitrated referring under protection of inert gas the minocycline hydrochloride concentrated sulfuric acid dissolution extracted system hydrogenchloride out, then with nitrosonitric acid generation nitration reaction, through crystallization and dispersion, gets nitration product;
Described hydrogenation refers to the nitration product dissolve with ethanol, under palladium/charcoal katalysis, under certain hydrogen pressure hydrogenation occurs, and through crystallization and dispersion, gets hydrogenated products;
It is under protection of inert gas hydrogenated products to be dissolved in a certain amount of cold water first that described acid transforms, and then regulates pH value, leaves standstill crystallization, filtration, drying etc. and get sour converted product after operating through concentrated hydrochloric acid;
Described amidation refers under protection of inert gas sour converted product is dissolved in the cold water, adds the amino glycyl chloride hydrochloride of uncle's N-fourth stirring reaction under the low temperature, gets the Tigecycline crude product after extraction step;
Described purifying refers to one or more solvents the Tigecycline crude product be carried out recrystallization under protection of inert gas and certain temperature, makes the Tigecycline sterling;
It is characterized in that,
In the described nitration reaction, the vitriol oil is 3-8 times of minocycline hydrochloride quality, and temperature of reaction is 0-20 ℃, and the reaction times is 2-7 hour, and the mol ratio of described nitrosonitric acid and minocycline hydrochloride is 1.2-1.6:1;
In the described hydrogenation, the mass ratio of ethanol and nitration product is 4-10:1; Reaction times is 8-20 hour; The consumption of Pd/carbon catalyst and nitration product mass ratio are 0.03-0.08:1; Hydrogen pressure is 0.005-0.3MPa;
In the described sour conversion reaction, temperature of reaction is 0-15 ℃, and the pH value is 3.0-6.0, and leaving standstill the crystallization time is 12-24 hour, and the mass ratio of described cold water and hydrogenated products is 2-10:1;
In the described amidate action, cold water is that the 2-10 of sour converted product consumption doubly measures, and temperature of reaction is 0-10 ℃, and the reaction times is 2-5 hour; Described extraction step is under the condition of the pH to 6.0-9.0 of rear conditioned reaction liquid before each extraction, add and filter after extraction agent and methyl alcohol stir, filtrate is used the extraction agent extracted several times, merge and to add an amount of methyl alcohol after the organic phase and wash with water, then adding anhydrous sodium sulphate in organic phase stirs dry, filter, filtrate decompression has been concentrated into solid again to add extraction agent and be concentrated into when separating out has solid to separate out again, stirred 1 hour, filter, filter cake is drained with the extraction agent washing for several times, the filter cake drying under reduced pressure gets the Tigecycline crude product;
In the described purification reaction, solvent comprises one or more mixed solvent of ethanol, methyl alcohol, acetone, butanone, and temperature range refers at 0-30 ℃, and described mixing solutions is that the 2-6 of Tigecycline crude product quality doubly measures.
2. method for making as claimed in claim 1 is characterized in that,
In the described nitration reaction, the vitriol oil is 4-6 times of minocycline hydrochloride quality, and temperature of reaction is 0-5 ℃, and the reaction times is 4-6 hour, and the molar equivalent of nitrosonitric acid and minocycline hydrochloride is 1.3-1.5:1;
In the described hydrogenation, the mass ratio of ethanol and nitration product is 6-8, and the reaction times is 9-11 hour, and the consumption of Pd/carbon catalyst and nitration product mass ratio are 0.04-0.06:1, and hydrogen pressure is 0.05-0.25MPa;
In the described sour conversion reaction, temperature of reaction is 0-5 ℃, and the pH value is 3.0-5.0, and leaving standstill the crystallization time is 12-15 hour, and the mass ratio of described cold water and hydrogenated products is 3-4:1;
In the described amidate action, cold water is that the 4-7 of sour converted product consumption doubly measures, and temperature of reaction is 0-5 ℃, and the reaction times is 2.5-3.5 hour; In the described extraction step, pH value scope is 7.0-7.8, and extraction agent comprises ethyl acetate, methylene dichloride or trichloromethane;
In the described purification reaction, described mixing solutions is that mass ratio is methyl alcohol and the acetone of 1:5-5:1, and temperature range refers at 15-25 ℃, and mixing solutions is that the 3-5 of Tigecycline crude product quality doubly measures.
3. method for making as claimed in claim 2 is characterized in that,
In the described nitration reaction, the vitriol oil is 5.3-5.8 times of minocycline hydrochloride quality; Reaction times is 4.5-5.5 hour, and the molar equivalent of nitrosonitric acid and minocycline hydrochloride is 1.40-1.46:1;
In the described hydrogenation, the mass ratio of ethanol and nitration product is 6.5-7.5, and the reaction times is 10 hours, and the consumption of Pd/carbon catalyst and nitration product mass ratio are 0.05:1, and hydrogen pressure is 0.005MPa;
In the described sour conversion reaction, the pH value is 4.0-4.4, and leaving standstill the crystallization time is 13-14 hour, and the mass ratio of described cold water and hydrogenated products is 3.5-4:1;
In the described amidate action, cold water is that the 4.5-5 of sour converted product consumption doubly measures, and the reaction response time is 3 hours; In the described extraction step, pH value scope is 7.0-7.4, and extraction agent is methylene dichloride;
In the described purification reaction, temperature of reaction is 20 ℃, and the mass ratio of methyl alcohol and acetone is 1:2-2:1, and mixing solutions is 4 times of amounts of Tigecycline crude product quality.
4. such as the described arbitrary method for making of claim 1-3, it is characterized in that, described crystallization and disperse selected dispersion agent and crystallization agent to comprise a kind of solvent among normal heptane, normal hexane, hexanaphthene, Virahol, the isopropylcarbinol or the mixture of several solvents comprises that preferably mass ratio is the Virahol of 3-11:1 and the mixture of normal heptane.
5. method as claimed in claim 4 is characterized in that, the mass ratio of described Virahol and normal heptane is 6-8:1, and preferred mass ratio is 6.5-7.5:1.
6. method as claimed in claim 4 is characterized in that, comprises also in the mixture of described Virahol and normal heptane that mass parts is hexanaphthene or the normal hexane of 3-5.
7. method as claimed in claim 4 is characterized in that, comprises also in the mixture of described Virahol and normal heptane that mass parts is the isopropylcarbinol of 6-10.
8. such as the described either method of claim 1-3, it is characterized in that, described rare gas element is nitrogen; Described drying is vacuum-drying, and between temperature 40-68 ℃, the drying temperature of described nitration product, hydrogenated products, sour converted product is 40 ℃, and the drying temperature of Tigecycline crude product and sterling is 65 ℃.
9. such as the described either method of claim 1-3, it is characterized in that described purification step is to add to first the Tigecycline crude product in the acetone, wherein the mass ratio of Tigecycline crude product and acetone is 1:2-1:1, the rotating speed strong stirring take rotating speed as 2000-5000 rev/min 5-10 minute; Adding and the anhydrous methanol of acetone quality than 1:1, the rotating speed strong stirring take rotating speed as 2000-5000 rev/min 5-10 minute; Filter, the filter cake mass ratio is the anhydrous methanol of 1:1 and the drip washing of acetone mixed solution 3 times, and the mass ratio of mixed solution and Tigecycline crude product is 0.2-0.3:1, drain, and the filter cake drying under reduced pressure, and get final product.
10. such as the described either method of claim 1-3, it is characterized in that, each step reaction is carried out under infrared lamp avoiding visible light, and each goes on foot intermediate product and uses tinfoil parcel cryopreservation.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| WO2020239696A1 (en) | 2019-05-24 | 2020-12-03 | Stichting Katholieke Universiteit | Improved administration of glycylcyclines by inhalation |
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| CN105085311A (en) * | 2015-08-13 | 2015-11-25 | 江苏豪森药业股份有限公司 | Efficient purification method of tigecycline or salt of tigecycline |
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| WO2020239696A1 (en) | 2019-05-24 | 2020-12-03 | Stichting Katholieke Universiteit | Improved administration of glycylcyclines by inhalation |
| CN114685302A (en) * | 2022-02-17 | 2022-07-01 | 河北圣雪大成制药有限责任公司 | Method for continuously synthesizing 9-amino minocycline by microreactor |
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