CN102453041A - Environment-friendly impurity-removal manufacturing method - Google Patents
Environment-friendly impurity-removal manufacturing method Download PDFInfo
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- CN102453041A CN102453041A CN2010105249718A CN201010524971A CN102453041A CN 102453041 A CN102453041 A CN 102453041A CN 2010105249718 A CN2010105249718 A CN 2010105249718A CN 201010524971 A CN201010524971 A CN 201010524971A CN 102453041 A CN102453041 A CN 102453041A
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Abstract
The invention relates to an environment-friendly impurity-removal manufacturing method 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 midbody or 7-amino-cephalosporanic acid and active side chain ester and (use (2,2
,-two sulphur are two-the benzene thiazole) and the side chain ester of preparation) the technology of removal by product 2-mercaptobenzothiazole after the condensation reaction.
Background technology
In third generation cephalosporin, some kind is through structure of modification, at the C of cephalo parent nucleus
7Introduced the group of 2-(2-amino-4-thiazolyl) ethanoyl on the-bit amino, this helps to improve the broad spectrum and the efficient anti-enzyme property 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 is gentle, stable, thereby more is applicable to suitability for industrialized production and is much better than chloride method and mixed anhydride method.Generally be with side-chain radical R (containing 2-(2-amino-4-thiazolyl) Acetyl Groups) and (2,2
,-two sulphur are two-the benzene thiazole) and connect to generate and have the highly active stabilization of solid that is easy to preserve-side chain active ester.
The C of this active thioester and cephalosporin midbody or 7-amino-cephalosporanic acid
7When-bit amino carried out condensation reaction, under alkaline condition, the R-S key of active thioester was easy to break off, and R connects C
7The amino of-position, and a large amount of residuing in the reaction system as by product.Because of 2-mercaptobenzothiazole is soluble in methylene dichloride, ETHYLE ACETATE, the acetone equal solvent; Because acetone can't separate with water is miscible; So select methylene dichloride or ETHYLE ACETATE solvent usually for use, make it to separate with the product of aqueous phase as the extraction 2-mercaptobenzothiazole.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 document; As: CN101016365, WO200610368, EP0037380, US20040242557, IN185089, this all is a little relatively methods of classical removal of impurities 2-mercaptobenzothiazole.
Though said these class methods have been used the several years, how without the organic solvent removal of impurity, simplify technology, reduce cost, reaching environmental protection production has been the problem that industry technician and pharmaceutical manufacturer have considered.
Summary of the invention
The method of manufacture that the purpose of this invention is to provide a kind of environmental protection removal of impurities, he is a kind of suitability for industrialized production that is suitable for, technology is simple, avoids the use of the organic solvent removal of impurities, reaches the purpose that environmental protection is produced.
Technical solution of the present invention is that with 100 corresponding cephalo midbody of gram or 7-amino-cephalosporanic acids, 110 to 230 restrain active side chain ester, 1300 to 1700 milliliters of organic solvents earlier; 80～100 milliliters of triethylamines are poured feed liquid in 1600 to 3000 ml waters into 5 to 15 ℃ of reactions 3 to 10 hours afterwards, regulate PH to neutral with hydrochloric acid, have xanchromatic impurity 2-mercaptobenzothiazole to separate out; Stirred 1 hour, and filtered, with 600 ml waters washing impurity; The filtrating of containing product is behind activated carbon decolorizing, and using hydrochloric acid to transfer PH is 2.5 to 2.9, separates out solid; Growing the grain 1 hour filters, washing; Drying promptly gets product, and the above corresponding cephalo midbody is (7-amino-3-(three 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) perhaps ((Z)-2-(thiazolamine-4-yl)-2-methoxycarbonyl methoxyimino thioacetic acid-2-[4-morpholinodithio thioesters); The above organic solvent is acetonitrile, ethanol, THF, acetone, methyl alcohol.
Elder generation of the present invention is with 100 grams (7-amino-3-(three azepine piperazine rings) thiomethyl-4-Cephalosporanic acid), and 110 restrain (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole ester), 1300 milliliters of acetonitriles, 5～7 ℃; Drip 100 milliliters of triethylamines, add, 5～7 ℃ of reactions 8 hours, reaction finished; Feed liquid is poured in 1600 ml waters, transferred PH=7.2 to separate out flaxen solid 2-mercaptobenzothiazole, stirred 1 hour, filter; With the washing of 600 ml waters, filtrating hydrochloric acid with 2N behind activated carbon decolorizing is transferred PH to 2.5, separates out solid, growing the grain 1 hour; Filter, washing can obtain white (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) methyl sulphur) }-8-oxygen-5-sulphur-1-azepine a word used for translation (4,2,0) oct-2-ene-2-formic acid.
Above-described elder generation is with 100 gram 7-amino-cephalosporanic acids, 110 grams (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole ester), 1200 milliliters of acetone, 5～7 ℃; Drip 100 milliliters of triethylamines, add, 5～7 ℃ of reactions 10 hours, reaction finished; Feed liquid is poured in 3000 ml waters, transferred PH=5.0 to separate out jonquilleous solid 2-mercaptobenzothiazole, stirred 1 hour, filter; With the washing of 600 ml waters, filtrating hydrochloric acid with 2N behind activated carbon decolorizing is transferred PH to 2.5, separates out solid, growing the grain 1 hour; Filter, washing can obtain white (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.
100 grams (7-amino-3-vinyl-Cephalosporanic acid) that in reaction flask, add of the present invention, 230 grams (2-(Z)-(thiazolamine-4-yl)-2-acetoxyl group acetimidic acid 2-[4-morpholinodithio thioesters), 1600 milliliters of THFs; 5～10 ℃ drip 80 milliliters of triethylamines, add, and 10～15 ℃ were reacted 10 hours; Feed liquid is poured in 2000 ml waters, transferred PH=7.5, stirred 1 hour; Separate out luteotestaceous solid 2-mercaptobenzothiazole, filter, with 600 ml water cleaning products; Reaction solution adds carbon decoloring, filters, and adds 50% yellow soda ash water liquid in the filtrating 30 ℃ of hydrolysis 35 minutes; Using 6N hydrochloric acid to transfer PH 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-described 100 grams (7-amino-3-vinyl-Cephalosporanic acid) that in reaction flask, add, 220 grams ((Z)-and 2-(thiazolamine-4-yl)-2-methoxycarbonyl methoxyimino thioacetic acid-2-[4-morpholinodithio thioesters), 1700 milliliter of 95% ethanol; Be cooled to 10～15 ℃, slowly drip 90 milliliters of triethylamines, dissolve clear after; 30 ℃ of reactions 3 hours, reaction finished, and feed liquid is poured in 1800 ml waters; Transfer PH=7.2, stirred 1 hour, separate out xanchromatic solid 2-mercaptobenzothiazole; Filter, with 600 ml water cleaning products, reaction solution adds carbon decoloring; Filter, with 6N hydrochloric acid crystallization, terminal point PH is 2.9; Growing the grain, filtration, 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.
A kind of new 2-mercaptobenzothiazole method of removing provided by the invention is: after cephalosporin midbody or 7-amino-cephalosporanic acid and side chain active ester are carried out condensation reaction and finished; Need not use methylene dichloride or ethyl acetate extraction removal of impurities, need only adopt the simple water (feed liquid is poured in the water or directly add water to go in the feed liquid) that adds, transfer the method for PH can reach same impurity-eliminating effect; The 2-mercaptobenzothiazole amount of separating out reaches 99.7-100%; Can obtain highly purified yellow solid 2-mercaptobenzothiazole through filtering, this 2-mercaptobenzothiazole particle is thick, loose; Being prone in air air-dryly voluntarily, is 172-177 ℃ through surveying its fusing point.Can be used for as industrial raw material.
The employed water yield is: the weight ratio of midbody or 7-amino-cephalosporanic acid and water is: 1:5-1:200, preferred 1:8-30.
The scope of PH is: 3-10, and preferred: PH=7.5-7.0.
Advantage of the present invention:
1, reduces raw materials cost.Need not remove 2-mercaptobenzothiazole by other organic solvents of extra use, a water can reach the removal of impurities purpose.
2, work simplification, reduce production costs.Need not extracting and demixing, greatly simplified technology.
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 cost, will carry out solvent and reclaim, but this recovery can not be adopted simple distillation method; Otherwise behind the solvent evaporate to dryness; The 2-mercaptobenzothiazole that is mixed with other impurity becomes hard bulk, firmly is bonded at the bottom of the retort and can't takes out, and the recovery of solvent can't be implemented.Be the efficient recovery solvent, must carry out comparatively loaded down with trivial details pre-treatment, distill recovery again after 2-mercaptobenzothiazole is removed, increased production process, be unfavorable for the reduction of production cost.And the recovery mother liquor is a mixed solvent, promptly increases recovery difficult, also reduces solvent recovering yield.
3, quality product increases, and is embodied in: reduced the residual quantity of organic solvent kind, the residual difficult thoroughly removal of ethyl acetate solvent, the difficult standard that meets 10 editions Chinese Pharmacopoeias of residual quantity; The removing effect of 2-mercaptobenzothiazole of the present invention is superior to extraction process, and reason is that methylene dichloride and ETHYLE ACETATE are more or less water-soluble, separate not thorough, in addition in suitability for industrialized production because the limitation of equipment, layered effect be difficult to as as the lab scale thoroughly.Through the HPLC analysis verification, the 2-mercaptobenzothiazole residual quantity in the 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 product that obviously is superior to extraction process production through the product stability test with the stability of the product of the present invention's production.
4, yield improves.Use extraction process, more or less product is dissolved in the extraction liquid and runs off.The product yield of producing with the present invention can improve several percentage points.
5, reduce pollution.The present invention has reduced the use of the bigger methylene dichloride of toxicity, to the protection environment with ensure the healthy significant of workman, be suitable for the demand for development of current society.
This technology 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) methyl sulphur) }-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 (7-amino-3-(three azepine piperazine rings) thiomethyl-4-Cephalosporanic acid), 110 gram (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole ester), 1300 milliliters of acetonitriles, 5-7 ℃, drip 100 milliliters of triethylamines, add; 5-7 ℃ of reaction 8 hours, reaction finished, and feed liquid is poured in 1600 ml waters, transferred PH=7.2; Separate out flaxen solid 2-mercaptobenzothiazole, stirred 1 hour, filter, wash with 600 ml waters; Filtrating hydrochloric acid with 2N behind activated carbon decolorizing is transferred PH to 2.5, separates 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) methyl sulphur) }-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 (7-amino-3-(three azepine piperazine rings) thiomethyl-4-Cephalosporanic acid), 110 gram (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole ester), 1300 milliliters of acetonitriles, 5-7 ℃, drip 100 milliliters of triethylamines, add; 5-7 ℃ of reaction 8 hours, reaction finished, and feed liquid is poured in 1600 ml waters, transferred PH=8.0; Separate out flaxen solid 2-mercaptobenzothiazole, stirred 1 hour, filter, wash with 600 ml waters; Filtrating hydrochloric acid with 2N behind activated carbon decolorizing is transferred PH to 2.5, separates 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) methyl sulphur) }-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 (7-amino-3-(three azepine piperazine rings) thiomethyl-4-Cephalosporanic acid), 110 gram (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole ester), 1300 milliliters of acetonitriles, 5-7 ℃, drip 100 milliliters of triethylamines, add; 5-7 ℃ of reaction 8 hours, reaction finished, and splashes into 1600 ml waters, transferred PH=7.2; Separate out flaxen solid 2-mercaptobenzothiazole, stirred 1 hour, filter, wash with 600 ml waters; Filtrating hydrochloric acid with 2N behind activated carbon decolorizing is transferred PH to 2.5, separates 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) methyl sulphur) }-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 (7-amino-3-(three azepine piperazine rings) thiomethyl-4-Cephalosporanic acid), 110 gram (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole ester), 1400 milliliters of acetone, 5-7 ℃, drip 100 milliliters of triethylamines, add; 5-7 ℃ of reaction 8 hours, reaction finished, and feed liquid is poured in 1600 ml waters, transferred PH=7.2; Separate out flaxen solid 2-mercaptobenzothiazole, stirred 1 hour, filter, wash with 600 ml waters; Filtrating hydrochloric acid with 2N behind activated carbon decolorizing is transferred PH to 2.5, separates 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 gram 7-amino-cephalosporanic acids, 110 gram (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole ester), 1200 milliliters of acetone, 5-7 ℃, drip 100 milliliters of triethylamines, add; 5-7 ℃ of reaction 10 hours, reaction finished, and feed liquid is poured in 3000 ml waters, transferred PH=7.0; Separate out jonquilleous solid 2-mercaptobenzothiazole, stirred 1 hour, filter, wash with 600 ml waters; Filtrating hydrochloric acid with 2N behind activated carbon decolorizing is transferred PH to 2.5, separates 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 gram 7-amino-cephalosporanic acids, 110 gram (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole ester), 1200 milliliters of acetone, 5-7 ℃, drip 100 milliliters of triethylamines, add; 5-7 ℃ of reaction 10 hours, reaction finished, and feed liquid is poured in 3000 ml waters, transferred PH=5.0; Separate out jonquilleous solid 2-mercaptobenzothiazole, stirred 1 hour, filter, wash with 600 ml waters; Filtrating hydrochloric acid with 2N behind activated carbon decolorizing is transferred PH to 2.5, separates 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 gram 7-amino-cephalosporanic acids, 110 gram (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole ester), 1300 milliliters of acetone, 5-7 ℃, drip 100 milliliters of triethylamines, add; 5-7 ℃ of reaction 10 hours, reaction finished, and feed liquid is poured in 1500 ml waters, transferred PH=7.0; Separate out jonquilleous solid 2-mercaptobenzothiazole, stirred 1 hour, filter, wash with 600 ml waters; Filtrating hydrochloric acid with 2N behind activated carbon decolorizing is transferred PH to 2.5, separates 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 gram 7-amino-cephalosporanic acids, 110 gram (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole ester), 1300 milliliters of acetonitriles, 5-7 ℃, drip 100 milliliters of triethylamines, add; 5-7 ℃ of reaction 10 hours, reaction finished, and feed liquid is poured in 3000 ml waters, transferred PH=7.0; Separate out jonquilleous solid 2-mercaptobenzothiazole, stirred 1 hour, filter, wash with 600 ml waters; Filtrating hydrochloric acid with 2N behind activated carbon decolorizing is transferred PH to 2.5, separates 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 acid), 230 gram (2-(Z)-(thiazolamine-4-yl)-2-acetoxyl group acetimidic acid 2-[4-morpholinodithio thioesters), 1600 milliliters of THFs, 5-10 ℃ drips 80 milliliters of triethylamines, adds; 10-15 ℃ was reacted 10 hours, and feed liquid is poured in 2000 ml waters, transferred PH=7.5; Stirred 1 hour; Separate out luteotestaceous solid 2-mercaptobenzothiazole, filter, with 600 ml water cleaning products.Reaction solution adds carbon decoloring, filters, and adds 50% yellow soda ash water liquid in the filtrating 30 ℃ of hydrolysis 35 minutes; Using 6N hydrochloric acid to transfer PH 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 acid), 230 gram (2-(Z)-(thiazolamine-4-yl)-2-acetoxyl group acetimidic acid 2-[4-morpholinodithio thioesters), 1600 milliliters of THFs, 5-10 ℃ drips 80 milliliters of triethylamines, adds; 10-15 ℃ was reacted 10 hours, and feed liquid is poured in 15 premium on currency, transferred PH=7.5; Stirred 1 hour; Separate out luteotestaceous solid 2-mercaptobenzothiazole, filter, with 600 ml water cleaning products.Reaction solution adds carbon decoloring, filters, and adds 50% yellow soda ash water liquid in the filtrating 30 ℃ of hydrolysis 35 minutes; Using 6N hydrochloric acid to transfer PH 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 acid), 230 gram (2-(Z)-(thiazolamine-4-yl)-2-acetoxyl group acetimidic acid 2-[4-morpholinodithio thioesters), 1000 ml methanol, 5-10 ℃ drips 80 milliliters of triethylamines, adds; 10-15 ℃ was reacted 12 hours, and feed liquid is poured in 2000 ml waters, transferred PH=7.5; Stirred 1 hour; Separate out luteotestaceous solid 2-mercaptobenzothiazole, filter, with 600 ml water cleaning products.Reaction solution adds carbon decoloring, filters, and adds 50% yellow soda ash water liquid in the filtrating 30 ℃ of hydrolysis 35 minutes, and using 6N hydrochloric acid to transfer PH 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 acid), 230 gram (2-(Z)-(thiazolamine-4-yl)-2-acetoxyl group acetimidic acid 2-[4-morpholinodithio thioesters), 1600 milliliters of THFs, 5-10 ℃ drips 80 milliliters of triethylamines, adds; 10-15 ℃ was reacted 10 hours, and feed liquid is poured in 500 ml waters, transferred PH=7.5; Stirred 1 hour; Separate out luteotestaceous solid 2-mercaptobenzothiazole, filter, with 600 ml water cleaning products.Reaction solution adds carbon decoloring, filters, and adds 50% yellow soda ash water liquid in the filtrating 30 ℃ of hydrolysis 35 minutes, and using 6N hydrochloric acid to transfer PH 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)-(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 acid), 220 gram 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 ℃, slowly drip 90 milliliters of triethylamines, dissolve clearly after; 30 ℃ of reactions 3 hours, reaction finished, and feed liquid is poured in 1800 ml waters, transferred PH=7.2; Stirred 1 hour, and separated out xanchromatic solid 2-mercaptobenzothiazole, filter; With the washing of 600 ml waters, filtrating is behind carbon decoloring, with 6N hydrochloric acid crystallization; Terminal point PH is 2.9, and growing the grain, filtration, washing, drying obtain white product.Molar yield reaches 100%, purity 99.5%, 2-mercaptobenzothiazole residual 0.01%.
Embodiment 14
Preparation (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 }
In reaction flask, add 100 grams (7-amino-3-vinyl-Cephalosporanic acid), 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 ℃, slowly drip 90 milliliters of triethylamines, dissolve clearly after; 30 ℃ of reactions 3 hours, reaction finished, and feed liquid is poured in 1800 ml waters, transferred PH=8.0; Stirred 1 hour, and separated out xanchromatic solid 2-mercaptobenzothiazole, filter; With the washing of 600 ml waters, filtrating is behind carbon decoloring, with 6N hydrochloric acid crystallization; Terminal point PH is 2.9, and growing the grain, filtration, washing, drying obtain white product.Molar yield reaches 100%, purity 96%, 2-mercaptobenzothiazole residual 0.5%.
Embodiment 15
Preparation (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 }
In reaction flask, add 100 grams (7-amino-3-vinyl-Cephalosporanic acid), 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 ℃, slowly drip 90 milliliters of triethylamines, dissolve clearly after; 30 ℃ of reactions 3 hours, reaction finished, and feed liquid is poured in 20 premium on currency, transferred PH=7.2; Stirred 1 hour, and separated out xanchromatic solid 2-mercaptobenzothiazole, filter; With the washing of 600 ml waters, filtrating is behind carbon decoloring, with 6N hydrochloric acid crystallization; Terminal point PH is 2.9, and growing the grain, filtration, washing, drying obtain white product.Molar yield reaches 100%, purity 99.5%, 2-mercaptobenzothiazole residual 0.01%.
Claims (5)
1. an environmental protection removal of impurities method of manufacture is characterized in that restraining corresponding cephalo midbody or 7-amino-cephalosporanic acids with 100 earlier, the active side chain ester of 110 to 230 grams, 1300 to 1700 milliliters of organic solvents; 80～100 milliliters of triethylamines are poured feed liquid in 1600 to 3000 ml waters into 5 to 15 ℃ of reactions 3 to 10 hours afterwards, regulate PH to neutral with hydrochloric acid, have xanchromatic solid impurity 2-mercaptobenzothiazole to separate out; Stirred 1 hour, and filtered, with 600 ml waters washing impurity; The filtrating of containing product is behind activated carbon decolorizing, and using hydrochloric acid to transfer PH is 2.5 to 2.9, separates out solid; Growing the grain 1 hour filters, washing; Drying promptly gets product, and the above corresponding cephalo midbody is (7-amino-3-(three 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) perhaps ((Z)-2-(thiazolamine-4-yl)-2-methoxycarbonyl methoxyimino thioacetic acid-2-[4-morpholinodithio thioesters); The above organic solvent is acetonitrile, ethanol, THF, acetone, methyl alcohol.
2. the method for manufacture of a kind of environmental protection removal of impurities according to claim 1 is characterized in that restraining (7-amino-3-(three azepine piperazine rings) thiomethyl-4-Cephalosporanic acid) with 100 earlier 110 grams (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole ester), 1300 milliliters of acetonitriles; 5～7 ℃, drip 100 milliliters of triethylamines, add, 5～7 ℃ of reactions 8 hours; Reaction finishes, and feed liquid is poured in 1600 ml waters, transfers PH=7.2, separates out the 2-mercaptobenzothiazole of faint yellow solid; Stirred 1 hour, and filtered, with the washing of 600 ml waters, filtrating hydrochloric acid with 2N behind activated carbon decolorizing is transferred PH to 2.5; Separate out solid, growing the grain 1 hour filters, washing; Can obtain white (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) methyl sulphur) }-8-oxygen-5-sulphur-1-azepine a word used for translation (4,2,0) oct-2-ene-2-formic acid.
3. the method for manufacture of a kind of environmental protection removal of impurities according to claim 1 is characterized in that earlier with 100 gram 7-amino-cephalosporanic acids, 110 grams (2-methoxyimino-2-(2-amino-4-thiazolyl)-(Z)-thioacetic acid benzothiazole ester), 1200 milliliters of acetone; 5～7 ℃, drip 100 milliliters of triethylamines, add, 5～7 ℃ of reactions 10 hours; Reaction finishes, and feed liquid is poured in 3000 ml waters, transfers PH=5.0, separates out jonquilleous solid 2-mercaptobenzothiazole; Stirred 1 hour, and filtered, wash with 600 ml waters; Filtrating hydrochloric acid with 2N behind activated carbon decolorizing is transferred PH to 2.5, separates out solid, growing the grain 1 hour; Filter, washing can obtain white (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.
4. the method for manufacture of a kind of environmental protection removal of impurities according to claim 1 is characterized in that in reaction flask, adding 100 grams (7-amino-3-vinyl-Cephalosporanic acid), 230 grams (2-(Z)-(thiazolamine-4-yl)-2-acetoxyl group acetimidic acid 2-[4-morpholinodithio thioesters); 1600 milliliters of THFs, 5～10 ℃ drip 80 milliliters of triethylamines, add; 10～15 ℃ were reacted 10 hours, and feed liquid is poured in 2000 ml waters, transferred PH=7.5; Stirred 1 hour, and separated out luteotestaceous solid 2-mercaptobenzothiazole, filter; With the washing of 600 ml waters, reaction solution adds carbon decoloring, filters; Add 50% yellow soda ash water liquid in the filtrating 30 ℃ of hydrolysis 35 minutes, using 6N hydrochloric acid to transfer PH is 2.5, obtains 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. the method for manufacture of a kind of environmental protection removal of impurities according to claim 1 is characterized in that in reaction flask, adding 100 grams (7-amino-3-vinyl-Cephalosporanic acid), 220 grams ((Z)-and 2-(thiazolamine-4-yl)-2-methoxycarbonyl methoxyimino thioacetic acid-2-[4-morpholinodithio thioesters), 1700 milliliter of 95% ethanol; Be cooled to 10～15 ℃, slowly drip 90 milliliters of triethylamines, dissolve clear after; 30 ℃ of reactions 3 hours, reaction finished, and feed liquid is poured in 1800 ml waters; Transfer PH=7.2, stirred 1 hour, separate out xanchromatic solid 2-mercaptobenzothiazole; Filter, with the washing of 600 ml waters, reaction solution adds carbon decoloring; Filter, with 6N hydrochloric acid crystallization, terminal point PH is 2.9; Growing the grain, filtration, 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.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103980293A (en) * | 2014-05-21 | 2014-08-13 | 广州白云山制药股份有限公司广州白云山化学制药厂 | Method for preparing 3-ethenyl-7-(thiazolemethoxyimino)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 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103980293A (en) * | 2014-05-21 | 2014-08-13 | 广州白云山制药股份有限公司广州白云山化学制药厂 | Method for preparing 3-ethenyl-7-(thiazolemethoxyimino)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 |
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