CN102453041B - Environment-friendly impurity-removal manufacturing method - Google Patents
Environment-friendly impurity-removal manufacturing method Download PDFInfo
- Publication number
- CN102453041B CN102453041B CN201010524971.8A CN201010524971A CN102453041B CN 102453041 B CN102453041 B CN 102453041B CN 201010524971 A CN201010524971 A CN 201010524971A CN 102453041 B CN102453041 B CN 102453041B
- Authority
- CN
- China
- Prior art keywords
- amino
- mercaptobenzothiazole
- acid
- grams
- filter
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
The invention relates to a method for removing 2-mercaptobenzothiazole which comprises the following steps: reacting 100g of corresponding cephalosporin intermediates, 110-230g of side-chain esters, 1300-1700ml of solvent and 80-100ml of triethylamine at 5-15 DEG C for 3-10 hours, pouring into water, precipitating impurities, filtering, decolorizing, and regulating the pH value to 2.5-2.9 to obtain the product, wherein the corresponding cephalosporin intermediates are (7-amino-3-(triazazincyclo)thiomethyl-4-cephalosporanic acid) and (7-amino-3-vinyl-cephalosporanic acid); the active side-chain esters are (2-methoxyimido-2-(2-amono-4-thiazolyl)-(Z)-thioacetate benzothiazole) and (2-(Z)-(2-aminothiazolyl-4-yl)-2-acetoxyimidoacetic 2-benzothiazole thioester); and the organic solvent is acetonitrile, ethanol, tetrahydrofuran, acetone or methanol. The invention has the advantages of simple technique and environment friendliness, and is suitable for industrial production.
Description
Technical field
The present invention relates to cephalosporin intermediate or 7-amino-cephalosporanic acid and active side chain ester and (use (2,2
,-bis-sulphur are two-benzene thiazole) and the side chain ester prepared) technology of removal by product 2-mercaptobenzothiazole after condensation reaction.
Background technology
In third generation cephalosporin, some kind is through structure of modification, at the C of cephalosporin nucleus
7on-bit amino, introduce 2-(2-amino-4-thiazolyl) group of ethanoyl, this contributes to improve broad spectrum and the efficient resistance to enzyme of cynnematin.Introduce this group, generally use three kinds of methods: 1, chloride method.2, mixed anhydride method.3, active ester method.In three kinds of methods, because active ester method is active strong, reaction conditions gentleness, stable, thus be more suitable for suitability for industrialized production and be much better than chloride method and mixed anhydride method.Generally by side-chain radical R (containing 2-(2-amino-4-thiazolyl) Acetyl Groups) with (2,2
,-bis-sulphur are two-benzene thiazole) and connect to generate and there is the highly active stabilization of solid-side chain active ester that is easy to storage.
The C of this active thioester and cephalosporin intermediate or 7-amino-cephalosporanic acid
7when-bit amino carries out condensation reaction, under alkaline condition, the R-S key of active thioester is easy to disconnect, and R connects C
7the amino of-position, and a large amount of residuing in reaction system as by product.Because 2-mercaptobenzothiazole is soluble in methylene dichloride, ethyl acetate, acetone equal solvent, cannot separate because acetone and water are miscible, therefore conventionally select methylene dichloride or ethyl acetate as extraction 2-mercaptobenzothiazole solvent, make it with water in product separation.As in the condensation reaction of the cephalo product of some third generation, all adopt this method to carry out removal of impurities, this all has report in the literature, as: CN101016365, WO200610368, EP0037380, US20040242557, IN185089, this is all the method for a little more classical removal of impurities 2-mercaptobenzothiazoles.
Although described these class methods have been used the several years, how without the organic solvent removal of impurity, simplify technique, reduce costs, reaching environmental protection production has been the problem that industry technician and pharmaceutical manufacturer have considered.
Summary of the invention
The object of this invention is to provide except 2-mercaptobenzothiazole method, he is that one is suitable for suitability for industrialized production, and technique is simple, avoids with an organic solvent removal of impurities, reaches the object that environmental protection is produced.
Technical solution of the present invention is, first by 100 grams of corresponding cephalosporin intermediates or 7-amino-cephalosporanic acid, 110 to 230 grams of active side chain esters, 1300 to 1700 milliliters of organic solvents, 80～100 milliliters of triethylamines were 5 to 30 DEG C of reactions 3 to 10 hours, afterwards feed liquid is poured in 1600 to 3000 ml waters, extremely neutral with salt acid for adjusting pH, there is yellow impurity 2-mercaptobenzothiazole to separate out, stir 1 hour, filter, with 600 ml water washing impurity, the filtrate of containing product is after activated carbon decolorizing, adjusting pH with hydrochloric acid is 2.5 to 2.9, separate out solid, growing the grain 1 hour, filter, washing, dry, obtain product, the above corresponding cephalosporin intermediate is (7-amino-3-(tri-azepine piperazine rings) thiomethyl-4-Cephalosporanic acid) and (7-amino-3-vinyl-Cephalosporanic acid), the above active side chain ester is (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole ester), (2-(Z)-(thiazolamine-4-yl)-2-acetoxyl group acetimidic acid 2-[4-morpholinodithio thioesters) or ((Z)-2-(thiazolamine-4-yl)-2-methoxycarbonyl methoxyimino thioacetic acid-2-[4-morpholinodithio thioesters), the above organic solvent is acetonitrile, ethanol, tetrahydrofuran (THF), acetone, methyl alcohol.
Of the present invention first by 100 grams of (7-amino-3-(tri-azepine piperazine rings) thiomethyl-4-Cephalosporanic acids), 110 grams of (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole esters), 1300 milliliters of acetonitriles, 5～7 DEG C, drip 100 milliliters of triethylamines, add, 5～7 DEG C of reactions 8 hours, react complete, feed liquid is poured in 1600 ml waters, adjust pH=7.2 to separate out flaxen solid 2-mercaptobenzothiazole, stir 1 hour, filter, with 600 ml water washings, filtrate hydrochloric acid with 2N after activated carbon decolorizing is adjusted pH to 2.5, separate out solid, growing the grain 1 hour, filter, washing, can obtain (the 6R of white, 7R)-7-{ (Z)-2-(2-amino-4-thiazolyl)-2-(methoxy imino) kharophen }-3-{ ((2, 5-dihydro-6-hydroxy-2-methyl-5-oxygen-1, 2, 4-triazine-3-yl) sulphur) methyl }-8-oxygen-5-sulphur-1-azepine a word used for translation (4, 2, 0) oct-2-ene-2-formic acid.
Above-described first by 100 grams of 7-amino-cephalosporanic acids, 110 grams of (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole esters), 1200 milliliters of acetone, 5～7 DEG C, drip 100 milliliters of triethylamines, add, 5～7 DEG C of reactions 10 hours, react complete, feed liquid is poured in 3000 ml waters, adjust pH=5.0 to separate out jonquilleous solid 2-mercaptobenzothiazole, stir 1 hour, filter, with 600 ml water washings, filtrate hydrochloric acid with 2N after activated carbon decolorizing is adjusted pH to 2.5, separate out solid, growing the grain 1 hour, filter, washing, can obtain (the 6R of white, 7R)-7-((2-amino-4-thiazolyl)-(methoxyimino) kharophen)-3-((acetoxyl group) methyl)-8-oxo-5-thia-1-azabicyclo (4, 2, 0) oct-2-ene-2-formic acid.
Of the present inventionly in reaction flask, add 100 grams (7-amino-3-vinyl-Cephalosporanic acids), 230 grams (2-(Z)-(thiazolamine-4-yl)-2-acetoxyl group acetimidic acid 2-[4-morpholinodithio thioesters), 1600 milliliters of tetrahydrofuran (THF)s, 5～10 DEG C drip 80 milliliters of triethylamines, add, 10～15 DEG C are reacted 10 hours, feed liquid is poured in 2000 ml waters, adjust pH=7.5, stir 1 hour, separate out luteotestaceous solid 2-mercaptobenzothiazole, filter, with 600 ml water cleaning products, reaction solution adds carbon decoloring, filter, in filtrate, add 50% sodium carbonate water liquid 30 DEG C of hydrolysis 35 minutes, adjusting pH with 6N hydrochloric acid is 2.5, obtain flaxen (6R, 7R)-7-{ ((2-amino-4-thiazolyl)-(oximido) ethanoyl) amino }-3-vinyl-8-oxo-5-thia-1-azabicyclo (4, 2, 0) oct-2-ene-2-carboxylic acid.
Above-describedly in reaction flask, add 100 grams (7-amino-3-vinyl-Cephalosporanic acids), 220 grams ((Z)-2-(thiazolamine-4-yl)-2-methoxycarbonyl methoxyimino thioacetic acid-2-[4-morpholinodithio thioesters), 1700 milliliter of 95% ethanol, be cooled to 10～15 DEG C, slowly drip 90 milliliters of triethylamines, molten clear after, 30 DEG C of reactions 3 hours, react complete, feed liquid is poured in 1800 ml waters, adjust pH=7.2, stir 1 hour, separate out yellow solid 2-mercaptobenzothiazole, filter, with 600 ml water cleaning products, reaction solution adds carbon decoloring, filter, with 6N hydrochloric acid crystallization, terminal pH is 2.9, growing the grain, filter, washing, obtain the { (6R of white, 7R)-7-{(2Z)-(thiazolamine-4-yl) ((2-methoxyl group-2-oxo oxyethyl group) imino-) acetamido }-3-vinyl-8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-ene-2-carboxylic acid }.
A kind of new 2-mercaptobenzothiazole method of removing provided by the invention is: after cephalosporin intermediate or 7-amino-cephalosporanic acid and side chain active ester are carried out condensation reaction, need not use methylene dichloride or ethyl acetate abstraction impurity removal, need only adopt simple adding water (feed liquid is poured into water or directly adds water in feed liquid), adjust the method for pH can reach same impurity-eliminating effect, the 2-mercaptobenzothiazole amount of separating out reaches 99.7-100%, can obtain after filtration highly purified yellow solid 2-mercaptobenzothiazole, this 2-mercaptobenzothiazole particle is thick, loose, easily air-dry voluntarily in air, be 172-177 DEG C through surveying its fusing point.Can be used for as industrial raw material.
The water yield using is: the weight ratio of intermediate or 7-amino-cephalosporanic acid and water is: 1:5-1:200, preferably 1:8-30.
The scope of pH is: 3-10, preferably: pH=7.5-7.0.
Advantage of the present invention:
1, reduce raw materials cost.Need not additionally use other organic solvents except 2-mercaptobenzothiazole, a water can reach removal of impurities object.
2, work simplification, reduce production costs.Need not extracting and demixing, greatly simplify technique.
Having shortened the production cycle reaches 5 hours, has saved the usage quantity of retort, thereby the energy consumption of making, production cost, labour intensity all decrease.If use methylene dichloride and ethyl acetate extraction, for reducing costs, will carry out solvent recovery, but this recovery can not adopt simple distillation method, otherwise after solvent evaporate to dryness, the 2-mercaptobenzothiazole that is mixed with other impurity becomes hard bulk, at the bottom of being firmly bonded in retort and cannot take out, the recovery of solvent cannot be implemented.For efficient recovery solvent, must carry out comparatively loaded down with trivial details pre-treatment, after being removed, 2-mercaptobenzothiazole carries out again Distillation recovery, increase production process, be unfavorable for the reduction of production cost.And recovery mother liquor is mixed solvent, increases recovery difficult, also reduces the rate of recovery of solvent.
3, quality product increases, and is embodied in: reduced the residual quantity of organic solvent kind, the residual more difficult thorough removal of ethyl acetate solvent, the more difficult standard that meets 10 editions Chinese Pharmacopoeias of residual quantity; The removing effect of 2-mercaptobenzothiazole of the present invention is better than extraction process, and reason is that methylene dichloride and ethyl acetate are more or less water-soluble, separate not thorough, in addition in suitability for industrialized production, due to the limitation of equipment, layered effect be difficult to as lab scale thoroughly.Through HPLC analysis verification, the 2-mercaptobenzothiazole residual quantity in product of the present invention is less than 0.03%, and the 2-mercaptobenzothiazole residual quantity of extraction process is between 0.08-0.2%.The stability of the product of producing with the present invention through product stability test is obviously better than the product that extraction process is produced.
4, yield improves.Use extraction process, more or less product is dissolved in extraction liquid and runs off.With the present invention produce product yield can improve several percentage points.
5, reduce and pollute.The present invention has reduced the use of the methylene dichloride that toxicity is larger, to protection of the environment with ensure the healthy significant of workman, be suitable for the demand for development of society.
This technique is compared with former Technology:
Embodiment:
Embodiment 1
Preparation (6R, 7R)-7-{ (Z)-2-(2-amino-4-thiazolyl)-2-(methoxy imino) kharophen }-3-{ ((2,5-dihydro-6-hydroxy-2-methyl-5-oxygen-1,2,4-triazine-3-yl) sulphur) methyl }-8-oxygen-5-sulphur-1-azepine a word used for translation (4,2,0) oct-2-ene-2-formic acid
In reaction flask, add 100 grams of (7-amino-3-(tri-azepine piperazine rings) thiomethyl-4-Cephalosporanic acids), 110 grams of (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole esters), 1300 milliliters of acetonitriles, 5-7 DEG C, drip 100 milliliters of triethylamines, add, 5-7 DEG C of reaction 8 hours, react complete, feed liquid is poured in 1600 ml waters, adjust pH=7.2, separate out flaxen solid 2-mercaptobenzothiazole, stir 1 hour, filter, with 600 ml water washings, filtrate hydrochloric acid with 2N after activated carbon decolorizing is adjusted pH to 2.5, separate out solid, growing the grain 1 hour, filter, washing, can obtain white product.Yield is 96%, and product purity reaches 99%, 2-mercaptobenzothiazole residual 0.01%.
Embodiment 2
Preparation (6R, 7R)-7-{ (Z)-2-(2-amino-4-thiazolyl)-2-(methoxy imino) kharophen }-3-{ ((2,5-dihydro-6-hydroxy-2-methyl-5-oxygen-1,2,4-triazine-3-yl) sulphur) methyl }-8-oxygen-5-sulphur-1-azepine a word used for translation (4,2,0) oct-2-ene-2-formic acid
In reaction flask, add 100 grams of (7-amino-3-(tri-azepine piperazine rings) thiomethyl-4-Cephalosporanic acids), 110 grams of (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole esters), 1300 milliliters of acetonitriles, 5-7 DEG C, drip 100 milliliters of triethylamines, add, 5-7 DEG C of reaction 8 hours, react complete, feed liquid is poured in 1600 ml waters, adjust pH=8.0, separate out flaxen solid 2-mercaptobenzothiazole, stir 1 hour, filter, with 600 ml water washings, filtrate hydrochloric acid with 2N after activated carbon decolorizing is adjusted pH to 2.5, separate out solid, growing the grain 1 hour, filter, washing, can obtain white product.Yield is 98%, and product purity is 94%, 2-mercaptobenzothiazole residual 0.7%.
Embodiment 3
Preparation (6R, 7R)-7-{ (Z)-2-(2-amino-4-thiazolyl)-2-(methoxy imino) kharophen }-3-{ ((2,5-dihydro-6-hydroxy-2-methyl-5-oxygen-1,2,4-triazine-3-yl) sulphur) methyl }-8-oxygen-5-sulphur-1-azepine a word used for translation (4,2,0) oct-2-ene-2-formic acid
In reaction flask, add 100 grams of (7-amino-3-(tri-azepine piperazine rings) thiomethyl-4-Cephalosporanic acids), 110 grams of (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole esters), 1300 milliliters of acetonitriles, 5-7 DEG C, drip 100 milliliters of triethylamines, add, 5-7 DEG C of reaction 8 hours, react complete, splash into 1600 ml waters, adjust pH=7.2, separate out flaxen solid 2-mercaptobenzothiazole, stir 1 hour, filter, with 600 ml water washings, filtrate hydrochloric acid with 2N after activated carbon decolorizing is adjusted pH to 2.5, separate out solid, growing the grain 1 hour, filter, washing, can obtain white product.Yield is 96%, and product purity reaches 99%, 2-mercaptobenzothiazole residual 0.01%.
Embodiment 4
Preparation (6R, 7R)-7-{ (Z)-2-(2-amino-4-thiazolyl)-2-(methoxy imino) kharophen }-3-{ ((2,5-dihydro-6-hydroxy-2-methyl-5-oxygen-1,2,4-triazine-3-yl) sulphur) methyl }-8-oxygen-5-sulphur-1-azepine a word used for translation (4,2,0) oct-2-ene-2-formic acid
In reaction flask, add 100 grams of (7-amino-3-(tri-azepine piperazine rings) thiomethyl-4-Cephalosporanic acids), 110 grams of (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole esters), 1400 milliliters of acetone, 5-7 DEG C, drip 100 milliliters of triethylamines, add, 5-7 DEG C of reaction 8 hours, react complete, feed liquid is poured in 1600 ml waters, adjust pH=7.2, separate out flaxen solid 2-mercaptobenzothiazole, stir 1 hour, filter, with 600 ml water washings, filtrate hydrochloric acid with 2N after activated carbon decolorizing is adjusted pH to 2.5, separate out solid, growing the grain 1 hour, filter, washing, can obtain white product.Yield is 95%, and product purity reaches 99%, 2-mercaptobenzothiazole residual 0.01%.
Embodiment 5
Preparation (6R, 7R)-7-((2-amino-4-thiazolyl)-(methoxyimino) kharophen)-3-((acetoxyl group) methyl)-8-oxo-5-thia-1-azabicyclo (4,2,0) oct-2-ene-2-formic acid
In reaction flask, add 100 grams of 7-amino-cephalosporanic acids, 110 grams of (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole esters), 1200 milliliters of acetone, 5-7 DEG C, drip 100 milliliters of triethylamines, add, 5-7 DEG C of reaction 10 hours, react complete, feed liquid is poured in 3000 ml waters, adjust pH=7.0, separate out jonquilleous solid 2-mercaptobenzothiazole, stir 1 hour, filter, with 600 ml water washings, filtrate hydrochloric acid with 2N after activated carbon decolorizing is adjusted pH to 2.5, separate out solid, growing the grain 1 hour, filter, washing, can obtain white product.Yield reaches 95%, and product purity reaches 99.5%, 2-mercaptobenzothiazole residual 0.01%.
Embodiment 6
Preparation (6R, 7R)-7-((2-amino-4-thiazolyl)-(methoxyimino) kharophen)-3-((acetoxyl group) methyl)-8-oxo-5-thia-1-azabicyclo (4,2,0) oct-2-ene-2-formic acid
In reaction flask, add 100 grams of 7-amino-cephalosporanic acids, 110 grams of (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole esters), 1200 milliliters of acetone, 5-7 DEG C, drip 100 milliliters of triethylamines, add, 5-7 DEG C of reaction 10 hours, react complete, feed liquid is poured in 3000 ml waters, adjust pH=5.0, separate out jonquilleous solid 2-mercaptobenzothiazole, stir 1 hour, filter, with 600 ml water washings, filtrate hydrochloric acid with 2N after activated carbon decolorizing is adjusted pH to 2.5, separate out solid, growing the grain 1 hour, filter, washing, can obtain white product.Yield is 80%, 2-mercaptobenzothiazole residual 0.2%.
Embodiment 7
Preparation (6R, 7R)-7-((2-amino-4-thiazolyl)-(methoxyimino) kharophen)-3-((acetoxyl group) methyl)-8-oxo-5-thia-1-azabicyclo (4,2,0) oct-2-ene-2-formic acid
In reaction flask, add 100 grams of 7-amino-cephalosporanic acids, 110 grams of (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole esters), 1300 milliliters of acetone, 5-7 DEG C, drip 100 milliliters of triethylamines, add, 5-7 DEG C of reaction 10 hours, react complete, feed liquid is poured in 1500 ml waters, adjust pH=7.0, separate out jonquilleous solid 2-mercaptobenzothiazole, stir 1 hour, filter, with 600 ml water washings, filtrate hydrochloric acid with 2N after activated carbon decolorizing is adjusted pH to 2.5, separate out solid, growing the grain 1 hour, filter, washing, can obtain white product.Yield reaches 97%, and product purity is 92%, 2-mercaptobenzothiazole residual 1.0%.
Embodiment 8
Preparation (6R, 7R)-7-((2-amino-4-thiazolyl)-(methoxyimino) kharophen)-3-((acetoxyl group) methyl)-8-oxo-5-thia-1-azabicyclo (4,2,0) oct-2-ene-2-formic acid
In reaction flask, add 100 grams of 7-amino-cephalosporanic acids, 110 grams of (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole esters), 1300 milliliters of acetonitriles, 5-7 DEG C, drip 100 milliliters of triethylamines, add, 5-7 DEG C of reaction 10 hours, react complete, feed liquid is poured in 3000 ml waters, adjust pH=7.0, separate out jonquilleous solid 2-mercaptobenzothiazole, stir 1 hour, filter, with 600 ml water washings, filtrate hydrochloric acid with 2N after activated carbon decolorizing is adjusted pH to 2.5, separate out solid, growing the grain 1 hour, filter, washing, can obtain white product.Yield reaches 96%, and product purity reaches 99.5%, 2-mercaptobenzothiazole residual 0.01%.
Embodiment 9
Preparation (6R, 7R)-7-{ ((2-amino-4-thiazolyl)-(oximido) ethanoyl) amino }-3-vinyl-8-oxo-5-thia-1-azabicyclo (4,2,0) oct-2-ene-2-carboxylic acid
In reaction flask, add 100 grams (7-amino-3-vinyl-Cephalosporanic acids), 230 grams (2-(Z)-(thiazolamine-4-yl)-2-acetoxyl group acetimidic acid 2-[4-morpholinodithio thioesters), 1600 milliliters of tetrahydrofuran (THF)s, 5-10 DEG C drips 80 milliliters of triethylamines, add, 10-15 DEG C is reacted 10 hours, and feed liquid is poured in 2000 ml waters, adjusts pH=7.5, stir 1 hour, separate out luteotestaceous solid 2-mercaptobenzothiazole, filter, with 600 ml water cleaning products.Reaction solution adds carbon decoloring, filters, and adds 50% sodium carbonate water liquid 30 DEG C of hydrolysis 35 minutes in filtrate, adjusting pH with 6N hydrochloric acid is 2.5, obtains flaxen product, and yield is 80%, content reaches 98%, and 2-mercaptobenzothiazole is residual 0.02%, and other indexs meet 10 editions Chinese Pharmacopoeia standards.
Embodiment 10
Preparation (6R, 7R)-7-{ ((2-amino-4-thiazolyl)-(oximido) ethanoyl) amino }-3-vinyl-8-oxo-5-thia-1-azabicyclo (4,2,0) oct-2-ene-2-carboxylic acid
In reaction flask, add 100 grams (7-amino-3-vinyl-Cephalosporanic acids), 230 grams (2-(Z)-(thiazolamine-4-yl)-2-acetoxyl group acetimidic acid 2-[4-morpholinodithio thioesters), 1600 milliliters of tetrahydrofuran (THF)s, 5-10 DEG C drips 80 milliliters of triethylamines, add, 10-15 DEG C is reacted 10 hours, and feed liquid is poured in 15 premium on currency, adjusts pH=7.5, stir 1 hour, separate out luteotestaceous solid 2-mercaptobenzothiazole, filter, with 600 ml water cleaning products.Reaction solution adds carbon decoloring, filters, and adds 50% sodium carbonate water liquid 30 DEG C of hydrolysis 35 minutes in filtrate, adjusting pH with 6N hydrochloric acid is 2.5, obtains light yellow product, and yield is 80%, content reaches 98%, and 2-mercaptobenzothiazole is residual 0.02%, and other indexs meet 10 editions Chinese Pharmacopoeia standards.
Embodiment 11
Preparation (6R, 7R)-7-{ ((2-amino-4-thiazolyl)-(oximido) ethanoyl) amino }-3-vinyl-8-oxo-5-thia-1-azabicyclo (4,2,0) oct-2-ene-2-carboxylic acid
In reaction flask, add 100 grams (7-amino-3-vinyl-Cephalosporanic acids), 230 grams (2-(Z)-(thiazolamine-4-yl)-2-acetoxyl group acetimidic acid 2-[4-morpholinodithio thioesters), 1000 ml methanol, 5-10 DEG C drips 80 milliliters of triethylamines, add, 10-15 DEG C is reacted 12 hours, and feed liquid is poured in 2000 ml waters, adjusts pH=7.5, stir 1 hour, separate out luteotestaceous solid 2-mercaptobenzothiazole, filter, with 600 ml water cleaning products.Reaction solution adds carbon decoloring, filters, and adds 50% sodium carbonate water liquid 30 DEG C of hydrolysis 35 minutes in filtrate, and adjusting pH with 6N hydrochloric acid is 2.5, obtains light yellow product, and yield is 82%, and content is 93%, 2-mercaptobenzothiazole residual 0.6%.
Embodiment 12
Preparation (6R, 7R)-7-{ ((2-amino-4-thiazolyl)-(oximido) ethanoyl) amino }-3-vinyl-8-oxo-5-thia-1-azabicyclo (4,2,0) oct-2-ene-2-carboxylic acid
In reaction flask, add 100 grams (7-amino-3-vinyl-Cephalosporanic acids), 230 grams (2-(Z)-(thiazolamine-4-yl)-2-acetoxyl group acetimidic acid 2-[4-morpholinodithio thioesters), 1600 milliliters of tetrahydrofuran (THF)s, 5-10 DEG C drips 80 milliliters of triethylamines, add, 10-15 DEG C is reacted 10 hours, and feed liquid is poured in 500 ml waters, adjusts pH=7.5, stir 1 hour, separate out luteotestaceous solid 2-mercaptobenzothiazole, filter, with 600 ml water cleaning products.Reaction solution adds carbon decoloring, filters, and adds 50% sodium carbonate water liquid 30 DEG C of hydrolysis 35 minutes in filtrate, and adjusting pH with 6N hydrochloric acid is 2.5, obtains light yellow product, and yield is 78%, and content is 86%, 2-mercaptobenzothiazole residual 1.5%.
Embodiment 13
Preparation (6R, 7R)-7-{(2Z) and-(thiazolamine-4-yl) ((2-methoxyl group-2-oxo oxyethyl group) imino-) acetamido }-3-vinyl-8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-ene-2-carboxylic acid }
In reaction flask, add 100 grams (7-amino-3-vinyl-Cephalosporanic acids), 220 grams of MICA esters ((Z)-2-(thiazolamine-4-yl)-2-methoxycarbonyl methoxyimino thioacetic acid-2-[4-morpholinodithio thioesters), 1700 milliliter of 95% ethanol, be cooled to 10-15 DEG C, slowly drip 90 milliliters of triethylamines, molten clear after, 30 DEG C of reactions 3 hours, react complete, feed liquid is poured in 1800 ml waters, adjust pH=7.2, stir 1 hour, separate out yellow solid 2-mercaptobenzothiazole, filter, with 600 ml water washings, filtrate is after carbon decoloring, with 6N hydrochloric acid crystallization, terminal pH is 2.9, growing the grain, filter, washing, dry, obtain white product.Molar yield reaches 100%, purity 99.5%, 2-mercaptobenzothiazole residual 0.01%.
Embodiment 14
Preparation (6R, 7R)-7-{(2Z) and-(thiazolamine-4-yl) ((2-methoxyl group-2-oxo oxyethyl group) imino-) acetamido }-3-vinyl-8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-ene-2-carboxylic acid }
In reaction flask, add 100 grams (7-amino-3-vinyl-Cephalosporanic acids), 220 grams ((Z)-2-(thiazolamine-4-yl)-2-methoxycarbonyl methoxyimino thioacetic acid-2-[4-morpholinodithio thioesters), 1700 milliliter of 95% ethanol, be cooled to 10-15 DEG C, slowly drip 90 milliliters of triethylamines, molten clear after, 30 DEG C of reactions 3 hours, react complete, feed liquid is poured in 1800 ml waters, adjust pH=8.0, stir 1 hour, separate out yellow solid 2-mercaptobenzothiazole, filter, with 600 ml water washings, filtrate is after carbon decoloring, with 6N hydrochloric acid crystallization, terminal pH is 2.9, growing the grain, filter, washing, dry, obtain white product.Molar yield reaches 100%, purity 96%, 2-mercaptobenzothiazole residual 0.5%.
Embodiment 15
Preparation (6R, 7R)-7-{(2Z) and-(thiazolamine-4-yl) ((2-methoxyl group-2-oxo oxyethyl group) imino-) acetamido }-3-vinyl-8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-ene-2-carboxylic acid }
In reaction flask, add 100 grams (7-amino-3-vinyl-Cephalosporanic acids), 220 grams ((Z)-2-(thiazolamine-4-yl)-2-methoxycarbonyl methoxyimino thioacetic acid-2-[4-morpholinodithio thioesters), 1700 milliliter of 95% ethanol, be cooled to 10-15 DEG C, slowly drip 90 milliliters of triethylamines, molten clear after, 30 DEG C of reactions 3 hours, react complete, feed liquid is poured in 20 premium on currency, adjust pH=7.2, stir 1 hour, separate out yellow solid 2-mercaptobenzothiazole, filter, with 600 ml water washings, filtrate is after carbon decoloring, with 6N hydrochloric acid crystallization, terminal pH is 2.9, growing the grain, filter, washing, dry, obtain white product.Molar yield reaches 100%, purity 99.5%, 2-mercaptobenzothiazole residual 0.01%.
Claims (5)
1. except 2-mercaptobenzothiazole method, it is characterized in that first by 100 grams of corresponding cephalosporin intermediates or 7-amino-cephalosporanic acid, 110 to 230 grams of active side chain esters, 1300 to 1700 milliliters of organic solvents, 80～100 milliliters of triethylamines were 5 to 30 DEG C of reactions 3 to 10 hours, afterwards feed liquid is poured in 1600 to 3000 ml waters, extremely neutral with salt acid for adjusting pH, there is yellow solid impurity 2-mercaptobenzothiazole to separate out, stir 1 hour, filter, with 600 ml water washing impurity, the filtrate of containing product is after activated carbon decolorizing, adjusting pH with hydrochloric acid is 2.5 to 2.9, separate out solid, growing the grain 1 hour, filter, washing, dry, obtain product, the above corresponding cephalosporin intermediate is (7-amino-3-(tri-azepine piperazine rings) thiomethyl-4-Cephalosporanic acid) and (7-amino-3-vinyl-Cephalosporanic acid), the above active side chain ester is (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole ester), (2-(Z)-(thiazolamine-4-yl)-2-acetoxyl group acetimidic acid 2-[4-morpholinodithio thioesters) or ((Z)-2-(thiazolamine-4-yl)-2-methoxycarbonyl methoxyimino thioacetic acid-2-[4-morpholinodithio thioesters), the above organic solvent is acetonitrile, ethanol, tetrahydrofuran (THF), acetone, methyl alcohol.
2. according to claim 1 except 2-mercaptobenzothiazole method, it is characterized in that first by 100 grams of (7-amino-3-(tri-azepine piperazine rings) thiomethyl-4-Cephalosporanic acids), 110 grams of (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole esters), 1300 milliliters of acetonitriles, 5～7 DEG C, drip 100 milliliters of triethylamines, add, 5～7 DEG C of reactions 8 hours, react complete, feed liquid is poured in 1600 ml waters, adjust pH=7.2, separate out the 2-mercaptobenzothiazole of faint yellow solid, stir 1 hour, filter, with 600 ml water washings, filtrate hydrochloric acid with 2N after activated carbon decolorizing is adjusted pH to 2.5, separate out solid, growing the grain 1 hour, filter, washing, can obtain (the 6R of white, 7R)-7-{ (Z)-2-(2-amino-4-thiazolyl)-2-(methoxy imino) kharophen }-3-{ ((2, 5-dihydro-6-hydroxy-2-methyl-5-oxygen-1, 2, 4-triazine-3-yl) sulphur) methyl }-8-oxygen-5-sulphur-1-azepine a word used for translation (4, 2, 0) oct-2-ene-2-formic acid.
3. according to claim 1 except 2-mercaptobenzothiazole method, it is characterized in that first by 100 grams of 7-amino-cephalosporanic acids, 110 grams of (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole esters), 1200 milliliters of acetone, 5～7 DEG C, drip 100 milliliters of triethylamines, add, 5～7 DEG C of reactions 10 hours, react complete, feed liquid is poured in 3000 ml waters, adjust pH=5.0, separate out jonquilleous solid 2-mercaptobenzothiazole, stir 1 hour, filter, with 600 ml water washings, filtrate hydrochloric acid with 2N after activated carbon decolorizing is adjusted pH to 2.5, separate out solid, growing the grain 1 hour, filter, washing, can obtain (the 6R of white, 7R)-7-((2-amino-4-thiazolyl)-(methoxyimino) kharophen)-3-((acetoxyl group) methyl)-8-oxo-5-thia-1-azabicyclo (4, 2, 0) oct-2-ene-2-formic acid.
4. according to claim 1 except 2-mercaptobenzothiazole method, it is characterized in that adding 100 grams (7-amino-3-vinyl-Cephalosporanic acids) in reaction flask, 230 grams (2-(Z)-(thiazolamine-4-yl)-2-acetoxyl group acetimidic acid 2-[4-morpholinodithio thioesters), 1600 milliliters of tetrahydrofuran (THF)s, 5～10 DEG C drip 80 milliliters of triethylamines, add, 10～15 DEG C are reacted 10 hours, feed liquid is poured in 2000 ml waters, adjust pH=7.5, stir 1 hour, separate out luteotestaceous solid 2-mercaptobenzothiazole, filter, with 600 ml water washings, reaction solution adds carbon decoloring, filter, in filtrate, add 50% sodium carbonate water liquid 30 DEG C of hydrolysis 35 minutes, adjusting pH with 6N hydrochloric acid is 2.5, obtain faint yellow (6R, 7R)-7-{ ((2-amino-4-thiazolyl)-(oximido) ethanoyl) amino }-3-vinyl-8-oxo-5-thia-1-azabicyclo (4, 2, 0) oct-2-ene-2-carboxylic acid.
5. according to claim 1 except 2-mercaptobenzothiazole method, it is characterized in that adding 100 grams (7-amino-3-vinyl-Cephalosporanic acids) in reaction flask, 220 grams ((Z)-2-(thiazolamine-4-yl)-2-methoxycarbonyl methoxyimino thioacetic acid-2-[4-morpholinodithio thioesters), 1700 milliliter of 95% ethanol, be cooled to 10～15 DEG C, slowly drip 90 milliliters of triethylamines, molten clear after, 30 DEG C of reactions 3 hours, react complete, feed liquid is poured in 1800 ml waters, adjust pH=7.2, stir 1 hour, separate out yellow solid 2-mercaptobenzothiazole, filter, with 600 ml water washings, reaction solution adds carbon decoloring, filter, with 6N hydrochloric acid crystallization, terminal pH is 2.9, growing the grain, filter, washing, obtain white { (6R, 7R)-7-{(2Z)-(thiazolamine-4-yl) ((2-methoxyl group-2-oxo oxyethyl group) imino-) acetamido }-3-vinyl-8-oxo-5-thia-1-azabicyclo (4.2.0) oct-2-ene-2-carboxylic acid }.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010524971.8A CN102453041B (en) | 2010-10-29 | 2010-10-29 | Environment-friendly impurity-removal manufacturing method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010524971.8A CN102453041B (en) | 2010-10-29 | 2010-10-29 | Environment-friendly impurity-removal manufacturing method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102453041A CN102453041A (en) | 2012-05-16 |
| CN102453041B true CN102453041B (en) | 2014-11-05 |
Family
ID=46036766
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010524971.8A Active CN102453041B (en) | 2010-10-29 | 2010-10-29 | Environment-friendly impurity-removal manufacturing method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102453041B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103980293B (en) * | 2014-05-21 | 2016-08-17 | 广州白云山医药集团股份有限公司白云山化学制药厂 | 3-vinyl-7-(thiazole methoxyimino) preparation method of Cephalosporanic acid |
| CN114249750A (en) * | 2021-12-29 | 2022-03-29 | 河南立诺制药有限公司 | Preparation method of ceftiofur hydrochloride |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5574154A (en) * | 1994-09-29 | 1996-11-12 | Alnejma Bulk Pharmaceutical Co. A.B.P.C. | Process for the preparation of cephalosporanic compounds |
| WO2004037833A1 (en) * | 2002-10-24 | 2004-05-06 | Orchid Chemicals & Pharmaceuticals Ltd | Process for the preparation of cephalosporin antibiotics |
| CN101550149A (en) * | 2009-05-04 | 2009-10-07 | 浙江工业大学 | Green synthetic method for cefotaxime acid |
-
2010
- 2010-10-29 CN CN201010524971.8A patent/CN102453041B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5574154A (en) * | 1994-09-29 | 1996-11-12 | Alnejma Bulk Pharmaceutical Co. A.B.P.C. | Process for the preparation of cephalosporanic compounds |
| WO2004037833A1 (en) * | 2002-10-24 | 2004-05-06 | Orchid Chemicals & Pharmaceuticals Ltd | Process for the preparation of cephalosporin antibiotics |
| CN101550149A (en) * | 2009-05-04 | 2009-10-07 | 浙江工业大学 | Green synthetic method for cefotaxime acid |
Non-Patent Citations (3)
| Title |
|---|
| 刘惠玲，等.从头孢噻肟钠生产废渣中回收2-硫醇基苯并噻唑.《化工环保》.1999,第19卷(第5期),第304页左栏第1段. * |
| 刘惠玲，等.头孢噻肟钠生产废渣资源化.《环境保护科学》.2002,第28卷(第109期),第30页1.1，第31页1.2. * |
| 辛海红，等.头孢噻肟酸合成母液回收工艺的研究.《黑龙江医药》.2004,第17卷(第2期),第122页第1.3.3节. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102453041A (en) | 2012-05-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102286003B (en) | Manufacture method of ceftazidime compound | |
| CN102134252B (en) | Preparation method of high-purity cefuroxime acid | |
| CN1492867A (en) | Novel thioes derivatives of thiazolyl acetic acid and their use in preparation of cephalosporin compounds | |
| CN101812076B (en) | Cefuroxime sodium and preparation method thereof | |
| CN102153585B (en) | Synthesis method of minodronate midbody and synthesis of minodronate | |
| CN103555807B (en) | Method for preparing 7-ACA (aminocephalosporanic acid) and obtaining alpha-aminoadipic acid by one-step enzymatic reaction | |
| CN101337971B (en) | Method for synthesizing antibiotic cefepime hydrochloride | |
| CN102807533A (en) | Method utilizing cefotaxime acid waste-liquor to prepare 2, 2'-dithio-dibenzo thiazole | |
| CN102453041B (en) | Environment-friendly impurity-removal manufacturing method | |
| CN1628118A (en) | Process for prepn. of cefdinir | |
| CN102816172A (en) | Preparation process of cefamandole nafate | |
| CN101210019A (en) | Methoxy cephalosporin intermediate | |
| CN109608476B (en) | Method for treating production waste liquid of cephalosporin antibiotics and production method | |
| CN1044246C (en) | Bicyclic beta-lactam/paraben complexes | |
| CN104447800A (en) | Synthesis technology of cefoxitin acid | |
| CN101906109B (en) | Method for preparing cefuroxime sodium | |
| CN103319503A (en) | Preparation method of cefdinir | |
| CN1029965C (en) | Process and intermediates for beta-lactams having aminothiazole (iminoxyacetic acid) acetic acid sidechains | |
| CN109776572B (en) | Method for purifying cefepime hydrochloride | |
| CN102351809A (en) | Method for recovering 2-mercaptobenzothiazole from crystallization mother liquor of ceflriarone sodium | |
| CN102336721B (en) | Method for synthesizing AE-active ester by using water-containing 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino acetic acid | |
| CN101550146A (en) | Cefetamet pivoxil hydrochloride compound and preparation method thereof | |
| CN104277053A (en) | High purity cefodizime and preparation method for intermediate cefodizime acid | |
| CN107286183B (en) | Refining method of cefixime | |
| CN102617327B (en) | Dexibuprofen compound and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20160418 Address after: Baiyun District of Guangzhou City, Guangdong province 510515 street and with the same road No. 78 Patentee after: White Cloud Mountain chemical pharmaceutical factory of Guangzhou Baiyunshan Pharmaceutical Group Co., Ltd. Patentee after: Guangzhou Baiyun Mountain Pharmaceutical Group Limited by Share Ltd Address before: Baiyun District of Guangzhou City, Guangdong province 510515 street and with the Cloud Road No. 88 Patentee before: Baiyuanshan Pharmaceutical Co Ltd, Guangzhou |