CN102911228A - Refining method and preparation method of erythromycin thiocyanate - Google Patents
Refining method and preparation method of erythromycin thiocyanate Download PDFInfo
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Abstract
The invention provides a refining method of erythromycin thiocyanate and a preparation method of the erythromycin thiocyanate. The refining method of the erythromycin thiocyanate comprises the following steps of: (1) dissolving an erythromycin thiocyanate coarse product in a solvent, performing alkaline treatment, filtering off insoluble matters, adding thiocyanate and then adding acid to regulate pH (Potential of Hydrogen) to be 5.5-8.3; and (2) separating a solid matter out, washing and drying to obtain an erythromycin thiocyanate finished product, wherein the solvent in the step (1) is methanol, ethanol or isopropyl alcohol; or the solvent is mixed solvent of more than two of methanol, ethanol, isopropyl alcohol, water, acetone, dichloroethane, ethyl acetate and butyl acetate; and the content of the methanol, the ethanol or the isopropyl alcohol is over 30 percent w/w in the mixed solvent. According to the refining method and the preparation method of the erythromycin thiocyanate, the technical bias that the erythromycin impurity cannot be reduced because of mixing of the solvent and the water existing in the conventional method is overcome, the purity and the yield of the erythromycin thiocyanate finished product are not reduced, the solvent cost is also obviously saved, and the technological steps are also obviously simplified.
Description
Technical field
The present invention relates to a kind of refining and preparation method of Matachrom.
Background technology
Matachrom (being called for short sulphur red) is the thiocyanate-of erythromycin, initial Matachrom is a kind of veterinary drug, development and application along with semisynthetic antibiotics, Matachrom becomes a kind of important medicine intermediate, be used for the synthesis of erythromycin oxime, erythromycin oxime can get clarithromycin, Roxithromycin and Azythromycin etc. by chemosynthesis.In recent years clarithromycin, Roxithromycin and Azythromycin three more than half synthesis of erythromycin at home and abroad the demand on the market rise rapidly, also in rising trend as the demand of the Matachrom of its synthesis material.The erythromycin main active ingredient is Erythromycin A, and impurity composition mainly contains berythromycin, Erythromycin C, Erythromycin E, ErF etc., and the content of each impurity composition that different strain and different fermentations condition obtain is also different.Present most enterprise classifies to product according to erythromycin and foreign matter content, in regulation " acceptable end product ", and berythromycin≤1.5%, Erythromycin C≤2%, other impurity≤3%.Erythromycin A content is higher, foreign matter content is fewer, and its product price is higher.Therefore, preparation contains the related products of high purity Erythromycin A, has a good application prospect.
Patent application: CN201110396176.x, a kind of preparation method of Matachrom is disclosed: prepare first the Matachrom crude product, use again the Matachrom crude product, the refining Matachrom finished product that obtains, process for purification is as follows: the Matachrom crude product, add acetone, regulating pH with sodium hydroxide solution is 9.5～10.5, Matachrom is changed into erythromycin, standing separation; get acetone soln; add sodium thiocyanate solution, transfers pH to 5.5～7.5 with acetum, adds 45～60 ℃ of purified water; 20～35 ℃ of crystallization control temperature; slowly stirred 10 minutes, lowers the temperature to enter whizzer in 0.5～2 hour and separate and to get the Matachrom product that wet again, and drip washing; drying namely gets the Matachrom finished product.In this patent application, use acetone to be solvent, the researchist all thinks at present, and the method can be utilized the principle of acetone and water stratification, water-soluble impurity is taken away by separating water layer, thus the purity of raising finished product.If use Virahol, n-propyl alcohol, ethanol as solvent, demixing phenomenon does not then occur, water-soluble impurity fails to remove, the existence of these impurity may impel the impurity such as berythromycin, C, D, E to crystallize out together with Erythromycin A, this will be unfavorable for the purifying of erythromycin finished product (" former solvent is on the impact research of its brilliant habit and purity in the erythromycin dilution crystallization process ", China's microbiotic magazine, in December, 1999).
But during take acetone as solvent, water and acetone have certain miscible ratio, when taking away impurity by water layer, have also lost the part erythromycin composition in the solution; Moreover, the required thiocyanate-of follow-up generation Matachrom also dissolves in water, therefore, separate water layer and also can take away greatly thiocyanate-, later stage also needs again to add the thiocyanate-consumption of loss when the crystallization of Matachrom salify, cause production cost to increase.
Summary of the invention
The object of the present invention is to provide a kind of new Matachrom process for purification.Another object of the present invention is to provide a kind of preparation method of Matachrom.
The invention provides a kind of process for purification of Matachrom, it comprises following operation steps:
(1) get the Matachrom crude product, after the dissolving, alkaline purification removes by filter insolubles in solvent, behind the adding thiocyanate-, adds acid for adjusting pH to 5.5～8.3 again;
(2) separate out solid substance, washing, drying namely gets the Matachrom finished product;
Wherein, solvent is methyl alcohol, ethanol or Virahol described in the step (1); Or described solvent is mixed solvent two or more in methyl alcohol, ethanol, Virahol, water, acetone, methylene dichloride, ethyl acetate, the butylacetate; In the described mixed solvent, the content of methyl alcohol, ethanol or Virahol is more than 30%w/w.
Methyl alcohol, ethanol, three kinds of solvents of Virahol, miscible with water, and price is low than acetone, be applicable to the inventive method, but the invention is not restricted to the independent use of above-mentioned three kinds of solvents, if with the methyl alcohol that also contains significant quantity in the miscible mixed solvent of water, ethanol or/and Virahol then also can be realized technique effect of the present invention.Aborning, the cost of methyl alcohol, ethanol is lower, and therefore, in order further to save cost, in the described mixed solvent, the content of methyl alcohol or ethanol is more than 90%w/w.
Further, in the step (1), described solvent is methyl alcohol or ethanol; Or described solvent is mixed solvent two or more in water, methyl alcohol, the ethanol.
Further preferably, in the step (1), described solvent is that methyl alcohol, ethanol or the alcohol amount of containing are preferably greater than 95%v/v greater than 90%v/v() methanol aqueous solution or aqueous ethanolic solution.
Still more preferably, described solvent is methyl alcohol or contains the alcohol amount greater than the methanol aqueous solution of 90%v/v.
Wherein, in the step (1), the volumetric usage of the solvent that every BOU erythromycin is corresponding is 1～10 liter.
Further, in the step (1), the volumetric usage of the solvent that every BOU erythromycin is corresponding is 1.5～4 liters.
Further, in the step (1), add acid for adjusting pH to 6.5～7.8.
Among the present invention, the temperature of reaction in the step (1) all can realize with interior (comprising boiling point) in the solvent boiling point temperature.But, in order to save production energy consumption, further reduce production costs, can selective solvent in temperature at 10 ℃～65 ℃; Preferably, the interior temperature of solvent is at 30～50 ℃.
Wherein, in the step (1), described alkaline purification is to regulate pH to 8.4～11 with one or more the mixture in yellow soda ash, salt of wormwood, ammoniacal liquor, sodium hydroxide, potassium hydroxide, sodium bicarbonate, saleratus or the triethylamine solution.
Further, in the step (1), pH to 9.0～10.5 are transferred in alkaline purification.
Wherein, step (in 1), the mole charging capacity of thiocyanate-are 0～0.9 times of erythromycin molar weight in the Matachrom crude product.
Further preferably, in the step (1), the mole charging capacity of thiocyanate-is 0.2 ~ 0.5 times of erythromycin molar weight in the Matachrom crude product, more preferably 0.2 ~ 0.4 times.
Wherein, in the step (1), described thiocyanate-is one or more the mixture in Sodium Thiocyanate 99, potassium sulfocyanate, the ammonium thiocyanate; Described acid is one or more the mixture in acetic acid, formic acid, the phosphoric acid.
Wherein, described alkali is aqueous sodium hydroxide solution; Described thiocyanate-is Sodium Thiocyanate 99; Described acid is acetic acid.
Among the present invention, after adding acid for adjusting pH, the dissolubility difference of the Matachrom of generation in solvent separated out in the solid substance mode.In order to guarantee that solid substance separates out fully, can adopt the synthetic known cooling in field, add the modes such as poor solvent and carry out.That is, among the present invention, also can be by adding water or/and solid substance be separated out in cooling.
Wherein, the content of Erythromycin A is counted 63～83%w/w with dry product in the described Matachrom crude product.
The present invention also provides a kind of preparation method of Matachrom, and it comprises following operation steps:
A, get the erythromycin crude product, in solvent, after the dissolving, remove by filter insolubles, add thiocyanate-after, add again acid for adjusting pH to 5.5～8.3;
B, separate out solid substance, washing, drying namely gets the Matachrom finished product;
Wherein, described solvent is methyl alcohol, ethanol or Virahol; Or described solvent is mixed solvent two or more in methyl alcohol, ethanol, Virahol, water, acetone, methylene dichloride, ethyl acetate, the butylacetate; In the described mixed solvent, the content of methyl alcohol, ethanol or Virahol is more than 30%w/w.
Wherein, the mole charging capacity of thiocyanate-is 1.1～2 times of erythromycin molar weight in the erythromycin crude product.
Wherein, the content of Erythromycin A is counted 56～83%w/w with dry product in the described Matachrom crude product.
In order to save cost, in the described mixed solvent, the content of methyl alcohol or ethanol is more than 90%w/w.
Further, in the steps A, described solvent is methyl alcohol or ethanol; Or described solvent is mixed solvent two or more in water, methyl alcohol, the ethanol.
Further preferably, in the steps A, described solvent is methyl alcohol, ethanol or contains the alcohol amount greater than methanol aqueous solution or the aqueous ethanolic solution of 90%v/v.
Still more preferably, described solvent is methyl alcohol or contains the alcohol amount greater than the methanol aqueous solution of 90%v/v.
Wherein, in the steps A, the volumetric usage of the solvent that every BOU erythromycin is corresponding is 1～10 liter.
Further, in the steps A, the volumetric usage of the solvent that every BOU erythromycin is corresponding is 1.5～4 liters.
Further, in the steps A, add acid for adjusting pH to 6.5～7.8.
Among the present invention, the temperature of reaction in the steps A is in solvent boiling point or comprise that boiling point all can realize.But, in order to save production energy consumption, can selective solvent in temperature at 10 ℃～65 ℃; Preferably, the interior temperature of solvent is at 30～50 ℃.
Wherein, in the steps A, described alkaline purification is to regulate pH to 8.4～11 with one or more the mixture in yellow soda ash, salt of wormwood, ammoniacal liquor, sodium hydroxide, potassium hydroxide, sodium bicarbonate, saleratus or the triethylamine solution.
Further, in the steps A, pH to 9.0～10.5 are transferred in alkaline purification.
Wherein, in the steps A, described thiocyanate-is one or more the mixture in Sodium Thiocyanate 99, potassium sulfocyanate, the ammonium thiocyanate; Described acid is one or more the mixture in acetic acid, formic acid, the phosphoric acid.
Wherein, described alkali is aqueous sodium hydroxide solution; Described thiocyanate-is Sodium Thiocyanate 99; Described acid is acetic acid.
Methyl alcohol, ethanol, Virahol equal solvent, they and water are miscible, although traditional method thinks that these solvents can not reduce erythromycin impurity, but, the present invention is after with this type of solvent replacing acetone or part acetone, not only do not reduce purity and the yield of Matachrom finished product, also significantly saved solvent cost, simplified processing step, bring huge economic benefit for industrial production, shown the refining or preparation method of Matachrom of the present invention, overcome conventional art prejudice, more be applicable to industrialized production, have a good application prospect.
Embodiment
The present invention is described in further detail below in conjunction with test example and embodiment.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment, all technology that realizes based on content of the present invention all belong to scope of the present invention.
The process for purification of embodiment 1 Matachrom of the present invention
The Matachrom crude product wets, and (it is 580 unit/milligrams that water content 30%, erythromycin are tired to product; The HPLC external standard method detects, contain 73% Erythromycin A in dry product, contain 2.8% berythromycin, contain 3% Erythromycin C, contain 3% Erythromycin E), add methyl alcohol (every BOU erythromycin adds 3 liters of methyl alcohol), with concentration be 20% sodium hydroxide solution to regulate pH be 9.5, Matachrom is changed into erythromycin, remove by filter insolubles, the sodium thiocyanate solution (per 1 mole of erythromycin adds 0.4 molar sulphur Zassol) of adding 20%, transfer pH to 7.5 with 50% glacial acetic acid solution, 1 times that presses the lysate volume adds purified water, 25～30 ℃ of crystallization control temperature, slowly stirred 10 minutes, left standstill again 1 hour, and filtered to get the wet product of Matachrom, use respectively methyl alcohol, purified water drip washing, drying namely gets the Matachrom finished product.The yield of Matachrom A is 93%; The HPLC external standard method detects, and in dry product, contains 86.5% Erythromycin A in the product, contains 1.0% berythromycin, contains 1.7% Erythromycin C, contains 2.2% Erythromycin E.Among the present invention, the percentage composition unit of acid, alkali and thiocyanate salt solution is in w/w; The percentage composition unit of solvent is in volume/volume.
Among the present invention, used Matachrom crude product can obtain by buying the commercially available prod, also can adopt existing method preparation, such as Chinese patent application 201110396176.x, 201110097249.5.The present invention adopts following method preparation:
It is 7.6 that erythromycin fermentation liquid is transferred pH with 20% sodium hydroxide solution, adopts the ceramic membrane filter in 50nm～100nm aperture, and filtered liquid concentrates with the nanofiltration membrane of 200 molecular weight, obtains the erythromycin concentrated solution; The erythromycin concentrated solution is placed crystallizer, it is 6.7 that glacial acetic acid solution with 40% is regulated pH, the sodium thiocyanate solution (amount that every BOU erythromycin adds Sodium Thiocyanate 99 is 0.2kg) that adds 20% concentration, the crystallization Matachrom, solidliquid mixture gets the Matachrom crude product through centrifugation.
The process for purification of embodiment 2 Matachroms of the present invention
(it is 580 unit/milligrams that water content 30%, erythromycin are tired to get 1 kilogram of Matachrom crude product; The HPLC external standard method detects, contain 73% Erythromycin A in dry product, contain 2.8% berythromycin, contain 3% Erythromycin C, contain 3% Erythromycin E), add ethanol (every BOU erythromycin adds 2.5 liters of ethanol), stir, it is 10 that the sodium hydroxide solution with 20% is regulated pH, and be warming up to 40 ± 3 ℃, remove by filter insolubles, washing with alcohol filter cake (every BOU erythromycin is washed with 0.2 liter of ethanol) merges washing lotion and filtrate, add 100 ml waters, be warming up to 45 ± 3 ℃, add 40% sodium thiocyanate solution (per 1 mole of erythromycin adds 0.9 molar sulphur Zassol), add 20% aqueous acetic acid accent pH to 7.3, filter to get the wet product of Matachrom, with the purified water washing, 45 ℃ of vacuum-dryings namely get the Matachrom finished product.The yield that gets Matachrom A is 93%; The HPLC external standard method detects, and in dry product, contains 87% Erythromycin A in the product, contains 1.2% berythromycin, contains 1.7% Erythromycin C, contains 2.4% Erythromycin E.Detect with vapor-phase chromatography, gained dissolvent residual of the present invention is ethanol.
The process for purification of embodiment 3 Matachroms of the present invention
(it is 580 unit/milligrams that water content 30%, erythromycin are tired to 20 kilograms of Matachrom crude products; The HPLC external standard method detects, contain 73% Erythromycin A in dry product, contain 2.8% berythromycin, contain 3% Erythromycin C, contain 3% Erythromycin E), the methyl alcohol of adding 99% stirred in (the BOU erythromycin that whenever feeds intake adds 2.5 liters of methyl alcohol), added 30% sodium hydroxide solution accent pH to 9.6, be warming up to 35 ℃ of stirrings, filter methanol wash filter cake (whenever feed intake BOU erythromycin with 0.1 liter of methanol wash), filtrate and washing lotion merging, be warming up to 35 ℃, the sodium thiocyanate solution (per 1 mole of erythromycin adds 0.3 molar sulphur Zassol) of adding 40% slowly adds Glacial acetic acid to pH=7.1, is cooled to 25 ± 3 ℃, 0.6 times by methanol usage adds purified water, be cooled to again 15 ℃, filter to get the wet product of Matachrom, wash with purified water, 50 ℃ of vacuum-dryings namely get the Matachrom finished product.The yield that gets Matachrom A is 94.5%; The HPLC external standard method detects, and in dry product, contains 86% Erythromycin A in the product, contains 1.4% berythromycin, contains 1.9% Erythromycin C, contains 2.7% Erythromycin E.
The process for purification of embodiment 4 Matachroms of the present invention
(it is 740 unit/milligrams that water content 20%, erythromycin are tired to 20 kilograms of Matachrom crude products; The HPLC external standard method detects, contain 86% Erythromycin A in dry product, contain 2% berythromycin, contain 2% Erythromycin C, contain 2% Erythromycin E), the middle stirring of mixed solvent (the BOU erythromycin that whenever feeds intake adds 4 liters of solvents) that adds methyl alcohol: acetone=3:7, add 30% sodium hydroxide solution accent pH to 9.8, be warming up to 45 ℃ of stirrings, filter, add 40% sodium thiocyanate solution (per 1 mole of erythromycin adds 0.9 molar sulphur Zassol) in the filtrate, slowly add Glacial acetic acid to pH=7.4, be cooled to 25 ± 3 ℃, 1 times of adding purified water by methanol usage is cooled to 15 ℃ again, filter to get the wet product of Matachrom, with the purified water washing, 50 ℃ of vacuum-dryings namely get the Matachrom finished product.The yield that gets Matachrom A is 94.5%; The HPLC external standard method detects, and in dry product, contains 91% Erythromycin A in the product, contains 0.4% berythromycin, contains 1% Erythromycin C, contains 0.6% Erythromycin E.
The process for purification of embodiment 5 Matachroms of the present invention
Get the wet product (water content 27%) of 1 kilogram of Matachrom, add 96% methyl alcohol (every BOU erythromycin adds 2.5 liter of 96% methyl alcohol), stirring also is warming up to 35 ± 3 ℃, and regulate pH to 9.4 with 25% sodium hydroxide, remove by filter insolubles, 96% methanol aqueous solution washing leaching cake (every BOU erythromycin is washed with 0.5 liter of 96% methyl alcohol), merge washing lotion and filtrate, 35 ± 3 ℃ of insulations, the sodium thiocyanate solution (per 1 mole of erythromycin adds 0.4 molar sulphur Zassol) of adding 40%, the acetate methanol solution of adding 65% is transferred pH to 7.1, is cooled to 25 ± 3 ℃, 0.65 times by methanol usage adds purified water, be cooled to again 15 ℃, filter to get the wet product of Matachrom, wash with purified water, 55 ℃ of vacuum-dryings namely get the Matachrom finished product.
The process for purification of embodiment 6 Matachroms of the present invention
Get the wet product (water content 5%) of 1 kilogram of Matachrom, add 90% methyl alcohol (every BOU erythromycin adds 2.5 liter of 90% methyl alcohol), stirring also is warming up to 30 ℃, and regulate pH to 9.4 with 25% sodium hydroxide, remove by filter insolubles, 90% methanol aqueous solution washing leaching cake (every BOU erythromycin is washed with 0.5 liter of 90% methyl alcohol), merge washing lotion and filtrate, 30 ℃ of insulations, the sodium thiocyanate solution (per 1 mole of erythromycin adds 0.4 molar sulphur Zassol) of adding 40%, the acetate methanol solution of adding 65% is transferred pH to 5.8, be cooled to 25 ± 3 ℃, filter to get the wet product of Matachrom, wash with purified water, 55 ℃ of vacuum-dryings namely get the Matachrom finished product.
The process for purification of embodiment 7 Matachroms of the present invention
(it is 790 unit/milligrams that water content 12%, erythromycin are tired to get 1 kilogram of Matachrom crude product; The HPLC external standard method detects, contain 73% Erythromycin A in dry product, contain 2.8% berythromycin, contain 3% Erythromycin C, contain 3% Erythromycin E), add mixed solvent (methyl alcohol: ethanol: Virahol=1:1:1v/v/v, every BOU erythromycin adds 2 liters of mixed solvents), stir and be warming up to 45 ℃, add 20% sodium hydroxide solution to pH=9.5, filter, insulation adds 30% sodium thiocyanate solution (per 1 mole of erythromycin adds 0.5 molar sulphur Zassol) at 45 ℃, slowly adds 55% acetate methanol pH value of solution to 8.0, add purified water, separate out solid substance, filter to get the wet product of Matachrom, wash with purified water, 50 ℃ of vacuum-dryings namely get the Matachrom finished product.
The process for purification of embodiment 8 Matachroms of the present invention
(it is 790 unit/milligrams that water content 5%, erythromycin are tired to get 1 kilogram of Matachrom crude product; The HPLC external standard method detects, contain 73% Erythromycin A in dry product, contain 2.8% berythromycin, contain 3% Erythromycin C, contain 3% Erythromycin E), add methyl alcohol (every BOU erythromycin adds 1.7 liters of methyl alcohol), stirring also is warming up to 40 ℃, add 30% sodium hydroxide solution to pH=9.8, filter, insulation is at 40 ℃, the sodium thiocyanate solution (per 1 mole of erythromycin adds 0.2 molar sulphur Zassol) of adding 40%, slowly add 65% acetate methanol pH value of solution to 6.8, add purified water, separate out solid substance, filter to get the wet product of Matachrom, with the purified water washing, 50 ℃ of vacuum-dryings namely get the Matachrom finished product.The yield that gets Matachrom A is 93%; The HPLC external standard method detects, and in dry product, contains 86% Erythromycin A in the product, contains 1.4% berythromycin, contains 1.8% Erythromycin C, contains 2.8% Erythromycin E.Detect with vapor-phase chromatography, gained dissolvent residual of the present invention is methyl alcohol.
The preparation method of embodiment 9 Matachroms of the present invention
(it is 730 unit/milligrams that water content 5%, erythromycin are tired to get 200 clarithromycin alkali crude products; The HPLC external standard method detects, contain 67% Erythromycin A in dry product, contain 2% berythromycin, contain 3% Erythromycin C, contain 3% Erythromycin E), add Virahol (every BOU erythromycin adds 3 liters of Virahols), add 20 ml waters, stir, it is 9.6 that the sodium hydroxide solution with 30% is regulated pH, and is warming up to 46 ± 3 ℃, remove by filter insolubles, Virahol alcohol washing filter cake (every BOU erythromycin with 0.2 liter of isopropyl alcohol wash) merges washing lotion and filtrate, is incubated at 45 ± 3 ℃, add potassium sulfocyanate solid (per 1 mole of erythromycin adds 1.1 molar sulphur potassium cyanates) and add 20% phosphate aqueous solution accent pH to 7.2, be cooled to 25 ± 3 ℃, 0.8 times that presses the Virahol consumption adds purified water, is cooled to 15 ℃ again, filter to get the wet product of Matachrom, with the purified water washing, 60 ℃ of vacuum-dryings namely get the Matachrom finished product.The yield that gets Matachrom A is 91%; The HPLC external standard method detects, and in dry product, contains 86% Erythromycin A in the product, contains 1.4% berythromycin, contains 1.8% Erythromycin C, contains 2.8% Erythromycin E.
Among the present invention, the erythromycin crude product of use can obtain by buying the commercially available prod, also can adopt existing method preparation, such as CN200810179653.The present invention adopts following method preparation:
The abomacetin fermentation filtered liquid is processed with decolouring impurity elimination resin, rear is that 200 rolling organic membrane concentrates with molecular weight, be concentrated into 18000u/ml～22000u/ml, add 20% sodium hydroxide when again concentrated solution being heated to 54～56 ℃, control pH:9.5～10.0, transfer 30～45 minutes alkali time, crystal solution gets the erythromycin crude product behind the suction filtration while hot.
The preparation method of embodiment 10 Matachroms of the present invention
(it is 580 unit/milligrams that water content 25%, erythromycin are tired to get 1 kilogram of erythromycin crude product; The HPLC external standard method detects, contain 67% Erythromycin A in dry product, contain 2% berythromycin, contain 3% Erythromycin C, contain 3% Erythromycin E), the mixed solvent (every BOU erythromycin adds 2 liters of mixed solvents) that adds methyl alcohol: N-BUTYL ACETATE=50:1, stirring also is warming up to 45 ± 3 ℃, remove by filter insolubles, methanol wash filter cake (every BOU erythromycin is washed with 0.1 liter of mixed solvent) merges washing lotion and filtrate, 45 ± 3 ℃, add ammonium thiocyanate solid (per 1 mole of erythromycin adds 1.4 molar sulphur ammonium cyanates), add glacial acetic acid solution and transfer pH to 6.8, be cooled to 25 ± 3 ℃, filter to get the wet product of Matachrom, with the purified water washing, 55 ℃ of vacuum-dryings namely get the Matachrom finished product.The yield that gets Matachrom A is 92%; The HPLC external standard method detects, and in dry product, contains 86% Erythromycin A in the product, contains 1.2% berythromycin, contains 1.7% Erythromycin C, contains 2.5% Erythromycin E.
Below specify beneficial effect of the present invention by test example.
Test example 1 process for purification of the present invention and existing methodical comparison
(1) comparison of product yield, purity
Getting with batch Matachrom crude product is raw material, prepares respectively the Matachrom finished product according to the process for purification of embodiment 1 among the method for embodiment 1 and the number of patent application 201110396176.x, and both product is compared, and the results are shown in Table 1:
Table 1
| Patent application 201110396176.x | Process for purification of the present invention | |
| Erythromycin A component yield | 89% | 93% |
| Erythromycin A content (HPLC external standard method) | 85.8% | 86.5% |
| Berythromycin foreign matter content (HPLC external standard method) | 1.5% | 1.0% |
| Erythromycin C foreign matter content (HPLC external standard method) | 1.8% | 1.7% |
| Erythromycin E foreign matter content (HPLC external standard method) | 2.9% | 2.2% |
As seen from the above table, compare with disclosed process for purification among the patent application 201110396176.x, process for purification of the present invention has not only significantly improved the yield (4%) of Erythromycin A, also guaranteed the high purity of Erythromycin A, even foreign matter content also is lower than prior art.
Brief summary:
In the process for purification of the present invention, use the solvents miscible with water such as methyl alcohol, ethanol, Virahol, although not with the water generates layering, can't remove impurity by layering, but this process for purification has but guaranteed high yield and the high purity of product, even better than existing process for purification.This just shows, the method has not only been avoided the loss of effective constituent after adopting improved solvent to make with extra care, and has also guaranteed good purification effect.
(2) comparison of production technique, cost
(1) solvent that adopts of the inventive method, its cost is more cheap than acetone, has significantly saved raw materials cost, below is the remarkable reduction that example illustrates cost by methanol/ethanol:
Table 2
| Solvent market unit price (adding transportation cost) | 1 ton of Matachrom finished product solvent cost | Solvent cost saving rate | |
| Acetone | 9000 yuan/tons | 28400 yuan | / |
| Ethanol | 7000 yuan/tons | 22100 | 22% |
| Methyl alcohol | 3000 yuan/tons | 9500 yuan | 67% |
According to upper table as can be known, as to use methyl alcohol instead be solvent, produces 10000 tons of Matachroms per year in the whole nation, and this solvent cost just can produce 1.89 hundred million yuan benefit.As to use ethanol instead be solvent, produces 10000 tons of Matachroms per year in the whole nation, and this solvent cost just can produce 0.63 hundred million yuan benefit.
(2) process for purification of the present invention, the solvent of use can to carry out arbitrary proportion miscible with water, and the later stage need not to carry out the step of layering removal of impurities again, so that production technique is easier.
(3) dissolvent residual
Among the refining or preparation method of the present invention, adopt methyl alcohol, ethanol is solvent more, and in the Matachrom for preparing, dissolvent residual is methyl alcohol, ethanol.When using Matachrom to prepare erythromycin oxime, the solvent of these residual solvents and Oximation is compatible, can not produce side reaction.And (such as number of patent application: 201110396176.x), residual acetone in the products obtained therefrom has carbonyl in the acetone molecules, in Oximation, has the risk with oxammonium hydrochloride generation side reaction in the existing method.
In sum, methyl alcohol, ethanol, Virahol equal solvent, they and water are miscible, although traditional method thinks that these solvents can not reduce erythromycin impurity, but, the present invention does not only reduce purity and the yield of Matachrom finished product after replacing acetone or part acetone with this kind solvent, also significantly having saved solvent cost is that industrial production has been brought huge economic benefit; Simultaneously, after the present invention replaces acetone or part acetone with this kind solvent, need not to carry out the separatory operation, not only simplified processing step, the erythromycin composition of also having avoided separating water layer and having caused and the loss of thiocyanate-, improve the Matachrom product yield, when later stage Matachrom salify crystallization, also further reduced the production cost that produces because adding thiocyanate-.Refining or the preparation method that these have all shown Matachrom of the present invention has overcome conventional art prejudice, more is applicable to industrialized production, has a good application prospect.
Claims (18)
1. the process for purification of a Matachrom, it is characterized in that: it comprises following operation steps:
(1) get the Matachrom crude product, after the dissolving, alkaline purification removes by filter insolubles in solvent, behind the adding thiocyanate-, adds acid for adjusting pH to 5.5～8.3 again;
(2) separate out solid substance, washing, drying namely gets the Matachrom finished product;
Wherein, solvent is methyl alcohol, ethanol or Virahol described in the step (1); Or described solvent is mixed solvent two or more in methyl alcohol, ethanol, Virahol, water, acetone, methylene dichloride, ethyl acetate, the butylacetate; In the described mixed solvent, the content of methyl alcohol, ethanol or Virahol is more than 30%w/w.
2. the process for purification of Matachrom according to claim 1, it is characterized in that: in the described mixed solvent, the content of methyl alcohol or ethanol is more than 90%w/w.
3. the process for purification of Matachrom according to claim 1 and 2, it is characterized in that: in the step (1), described solvent is methyl alcohol or ethanol; Or described solvent is mixed solvent two or more in water, methyl alcohol, the ethanol.
4. the process for purification of Matachrom according to claim 3 is characterized in that: in the step (1), described solvent is methyl alcohol, ethanol or contains the alcohol amount greater than methanol aqueous solution or the aqueous ethanolic solution of 90%v/v.
5. the process for purification of Matachrom according to claim 1 and 2, it is characterized in that: in the step (1), the volumetric usage of the solvent that every BOU erythromycin is corresponding is 1～10 liter.
6. the process for purification of Matachrom according to claim 5, it is characterized in that: in the step (1), the volumetric usage of the solvent that every BOU erythromycin is corresponding is 1.5～4 liters.
7. the process for purification of Matachrom according to claim 1 and 2 is characterized in that: in the step (1), add acid for adjusting pH to 6.5～7.8.
8. the process for purification of Matachrom according to claim 1 and 2 is characterized in that: in the step (1), temperature is at 10 ℃～65 ℃ in the solvent.
9. the process for purification of Matachrom according to claim 8 is characterized in that: in the step (1), temperature is at 30～50 ℃ in the solvent.
10. the process for purification of Matachrom according to claim 1 and 2, it is characterized in that: in the step (1), described alkaline purification is to regulate pH to 8.4～11 with one or more the mixture in yellow soda ash, salt of wormwood, ammoniacal liquor, sodium hydroxide, potassium hydroxide, sodium bicarbonate, saleratus or the triethylamine solution; Described thiocyanate-is one or more the mixture in Sodium Thiocyanate 99, potassium sulfocyanate, the ammonium thiocyanate; Described acid is one or more the mixture in acetic acid, formic acid, the phosphoric acid.
11. the process for purification of Matachrom according to claim 10 is characterized in that: in the step (1), pH to 9.0～10.5 are transferred in alkaline purification; Described alkali is aqueous sodium hydroxide solution; Described thiocyanate-is Sodium Thiocyanate 99; Described acid is acetic acid.
12. the process for purification of Matachrom according to claim 1 and 2 is characterized in that: in the step (1), the mole charging capacity of thiocyanate-is 0～0.9 times of erythromycin molar weight in the Matachrom crude product.
13. the process for purification of Matachrom according to claim 1 and 2 is characterized in that: in the step (1), the mole charging capacity of thiocyanate-is 0.2 ~ 0.5 times of erythromycin molar weight in the Matachrom crude product.
14. the process for purification of Matachrom according to claim 1 and 2 is characterized in that: step (2), separate out solid substance by adding water or/and lower the temperature.
15. the process for purification of Matachrom according to claim 1 and 2 is characterized in that: the content of Erythromycin A is counted 63～83%w/w with dry product in the described Matachrom crude product.
16. the preparation method of a Matachrom is characterized in that: it comprises following operation steps:
A, get the erythromycin crude product, in solvent, after the dissolving, remove by filter insolubles, add thiocyanate-after, add again acid for adjusting pH to 5.5～8.3;
B, separate out solid substance, washing, drying namely gets the Matachrom finished product;
Wherein, described solvent is methyl alcohol, ethanol or Virahol; Or described solvent is mixed solvent two or more in methyl alcohol, ethanol, Virahol, water, acetone, methylene dichloride, ethyl acetate, the butylacetate; In the described mixed solvent, the content of methyl alcohol, ethanol or Virahol is more than 30%w/w.
17. preparation method according to claim 16 is characterized in that: the mole charging capacity of thiocyanate-is 1.1～2 times of erythromycin molar weight in the erythromycin crude product.
18. according to claim 16 or the preparation method of 17 described Matachroms, it is characterized in that: the content of Erythromycin A is counted 56～83%w/w with dry product in the described Matachrom crude product.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201210434104 CN102911228A (en) | 2012-11-02 | 2012-11-02 | Refining method and preparation method of erythromycin thiocyanate |
| CN201310053835.9A CN103275150B (en) | 2012-11-02 | 2013-02-19 | A kind of refining and preparation method of erythromycin thiocyanate |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 201210434104 CN102911228A (en) | 2012-11-02 | 2012-11-02 | Refining method and preparation method of erythromycin thiocyanate |
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| CN 201210434104 Withdrawn CN102911228A (en) | 2012-11-02 | 2012-11-02 | Refining method and preparation method of erythromycin thiocyanate |
| CN201310053835.9A Active CN103275150B (en) | 2012-11-02 | 2013-02-19 | A kind of refining and preparation method of erythromycin thiocyanate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113201038A (en) * | 2021-04-13 | 2021-08-03 | 宜昌东阳光生化制药有限公司 | Method for reducing erythromycin thiocyanate solvent residue |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105348340A (en) * | 2015-11-27 | 2016-02-24 | 宁夏启元药业有限公司 | Preparation method of erythromycin thiocyanate |
| CN105622690A (en) * | 2016-03-25 | 2016-06-01 | 伊犁川宁生物技术有限公司 | Method for preparing high-purity erythrocin A |
| CN105601687B (en) * | 2016-03-28 | 2019-05-24 | 四川新迪医药化工有限公司 | A kind of refining methd of erythromycin thiocyanate |
| CN110950918A (en) * | 2019-12-31 | 2020-04-03 | 伊犁川宁生物技术有限公司 | Method for recovering erythromycin thiocyanate from erythromycin thiocyanate secondary crystallization mother liquor |
| CN113150044B (en) * | 2021-04-28 | 2022-03-18 | 宜昌东阳光生化制药有限公司 | Purification method of erythromycin thiocyanate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR1367842A (en) * | 1963-07-24 | 1964-07-24 | Pierrel Spa | Process for making a new water-soluble erythromycin salt |
| CN1500799A (en) * | 2002-11-15 | 2004-06-02 | 凯能高科技工程（上海）有限公司 | Method for extracting erythromycin using membrane separation |
| CN101624412B (en) * | 2008-07-10 | 2012-07-04 | 刘力 | Derivative of macrolides, method for preparing same and application thereof |
| CN101407533B (en) * | 2008-11-28 | 2011-06-08 | 宁夏启元药业有限公司 | Method for producing abomacetin rhodanate |
| CN102731599B (en) * | 2011-04-15 | 2015-08-12 | 天方药业有限公司 | A kind of preparation method of Matachrom |
| CN102408462B (en) * | 2011-12-02 | 2014-10-22 | 伊犁川宁生物技术有限公司 | Preparation method of erythromycin thiocyanate |
| CN102659881B (en) * | 2012-04-28 | 2014-12-17 | 安徽丰原发酵技术工程研究有限公司 | Method for preparing erythromycin thiocyanate |
-
2012
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113201038A (en) * | 2021-04-13 | 2021-08-03 | 宜昌东阳光生化制药有限公司 | Method for reducing erythromycin thiocyanate solvent residue |
| CN113201038B (en) * | 2021-04-13 | 2022-07-26 | 宜昌东阳光生化制药有限公司 | Method for reducing erythromycin thiocyanate solvent residue |
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| CN103275150B (en) | 2016-05-18 |
| CN103275150A (en) | 2013-09-04 |
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