CN101550149A - Green synthetic method for cefotaxime acid - Google Patents
Green synthetic method for cefotaxime acid Download PDFInfo
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- CN101550149A CN101550149A CNA200910098168XA CN200910098168A CN101550149A CN 101550149 A CN101550149 A CN 101550149A CN A200910098168X A CNA200910098168X A CN A200910098168XA CN 200910098168 A CN200910098168 A CN 200910098168A CN 101550149 A CN101550149 A CN 101550149A
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Abstract
The invention discloses a green synthetic method for cefotaxime acid showed in formula (I), which comprises the following steps: adding 2-methyl tetrahydrofuran, water, 7-Aminocephalosporanic acid showed in formula (II), AE-active ester showed in formula (III) and organic base into a reaction vessel; reacting at the temperature of 0-40 degrees for 1-2 hours; adjusting system pH value to 1-3 by diluted hydrochloric acid after the reaction; precipitating solid, filtering to obtain filter cake and filtrate; and drying the filter cake to obtain cefotaxime acid. the organic base is organic amine or pyridine compound; the ratio of the 7-Aminocephalosporanic acid, the AE-active ester and the organic base is 1.0:1.0-1.8:0.01-1.5. The invention prepares cefotaxime acid in 2-methyl tetrahydrofuran which is a green solvent, avoids the using of poisonous harmful solvent such as dichloromethane; has the advantages of mild condition, good product quality, high yield and low production cost; achieves higher industrial value and potential social economic benefit.
Description
(1) technical field
The present invention relates to a kind of green synthesis method of cefotaxime acid, particularly prepare the environmentally friendly technology of cefotaxime acid, belong to field of medicine and chemical technology with poisonous and harmful solvents such as green solvent 2-methyltetrahydrofuran (2-MeTHF) instead of methylene chloride.
(2) background technology
Cefotaxime sodium is the third generation cephalosporin analog antibiotic of widespread use clinically, and cefotaxime acid is the main raw material of cefotaxime sodium, and is along with the fierceness day by day of market competition, strict more to the specification of quality of cefotaxime sodium.In order to improve the yield of cefotaxime sodium, improve product look level, the new synthetic process of exploitation cefotaxime acid is imperative undoubtedly.
Synthesizing of cefotaxime acid mainly adopted active ester method at present, as: phosphorous active ester method, triazone active ester method, oxadiazole active ester method and AE active ester method.
1, phosphorous active ester method
EP620228 has reported by ainothiazoly loximate and thiophosphatephosphorothioate reaction and has obtained the sulfur-bearing active ester, again with 7-amino-cephalosporanic acid (7-ACA) condensation prepared cefotaxime acid.This technology is with N, and dinethylformamide is a reaction solvent, operate loaded down with trivial details relatively, yield is on the low side and produce and to contain the phosphine waste residue in a large number, easy contaminate environment.
2, triazone active ester method
US6610845 has reported with the triazone active ester and has prepared cefotaxime acid.This technology is reaction solvent with tetrahydrofuran (THF) and water (1: 1), and yield is medium, but aftertreatment trouble, and the reaction feed liquid is not only used the ethyl acetate extraction phase-splitting, and the used acid of crystallization is sulfuric acid, and is bigger to equipment corrosion.
3,, oxadiazole active ester method
US6388070 reports that Yong oxadiazole active ester prepares cefotaxime acid.This technique unit operation is many, aftertreatment bothers: need extracting and demixing and activated carbon decolorizing, the production cycle is long.
4, AE active ester method
WO9620198 reported with two (2-[4-morpholinodithio) disulfide (DM) and ainothiazoly loximate react AE-active ester (MEAM), obtain cefotaxime acid with the 7-ACA condensation again, and obtain by product 2-mercaptobenzothiazole (M).This is the method for present suitability for industrialized production cefotaxime acid, and many enterprises handle the by product 2-mercaptobenzothiazole as waste residue, cause contaminate environment, and cost is higher.
When adopting the AE active ester method to prepare cefotaxime acid, solvent commonly used has methylene dichloride, tetrahydrofuran (THF), acetone etc.The rate of recovery of methylene dichloride is lower, and cumulative effect is arranged in underground water, and has certain toxicity, and is stronger to the pungency of skin and mucous membrane, infringement nervus centralis and respiratory system; Tetrahydrofuran (THF) and acetone are all easy and water is miscible, are difficult to recovery set usefulness, cause cost higher.Therefore, develop the environmentally friendly technology for preparing cefotaxime acid with poisonous and harmful solvents such as green solvent instead of methylene chloride, the environmental pollution of avoiding solvent to cause from the source reduces production costs, and reduces the three wastes, has important society and economic implications.
(3) summary of the invention
The present invention is intended to overcome the shortcoming of prior art, and the environmental friendliness synthesis technique of a preparation cefotaxime acid in green solvent 2-methyltetrahydrofuran is provided, and concrete scheme is as follows:
A kind of green synthesis method suc as formula the cefotaxime acid shown in (I), described method comprises the steps: in reaction vessel to add 2-methyltetrahydrofuran, water, suc as formula the 7-amino-cephalosporanic acid (7-ACA) shown in (II), suc as formula AE-active ester (MEAM), the organic bases shown in (III), insulation reaction is 1～12 hour under 0～40 ℃ temperature, after reaction finishes, with dilute hydrochloric acid regulation system pH value is 1～3, there is solid to separate out, filter, get filter cake and filtrate, described filtration cakes torrefaction gets cefotaxime acid; Described organic bases is organic amine or pyridine compounds and their; The amount of substance ratio of described 7-ACA, AE-active ester, organic bases is 1.0: 1.0～1.8: 0.01～1.5; The consumption of described 2-methyltetrahydrofuran is 1～10 times of 7-ACA quality; The consumption of described water is feed intake 0.01～1 times of quality of 7-ACA.
Synthetic route is as follows:
Described 2-methyltetrahydrofuran (2-MeTHF) is a kind of non-protonic solvent, can be miscible with most of solvents such as ester, alcohol, ketone, hydrocarbon, hydrochloric ethers, and 80.2 ℃ of boiling points can form azeotrope (71 ℃ of azeotropic points) with water.Compare with the methylene dichloride equal solvent, 2-MeTHF has following advantage: 1) 2-MeTHF and water section are miscible, easy and product separation and recovery; 2) 2-MeTHF toxicity is less, can be rated as green solvent, and is used as the solvent of organometallic reaction and two phase reaction more and more; 3) be difficult for forming emulsification, help layering.
Described organic bases is organic amine or pyridine compounds and their, be preferably following one or more mixture: triethylamine, Tri-n-Propylamine, tri-isopropyl amine, quadrol, tri-n-butylamine, tri-isobutylamine, triethylene diamine, pyridine, 2-picoline, 3-picoline, 4-picoline, 2,6-lutidine, N, dinethylformamide (DMF), N, N-N,N-DIMETHYLACETAMIDE (DMA), N, accelerine, N, N-Diethyl Aniline, N, N dimethylamine base-4-pyridine, N-methylpyrrole, N-Methylimidazole, N-methylmorpholine; More preferably following one or more mixture: N, dinethylformamide, triethylamine, tri-n-butylamine or pyridine.
Described 7-ACA: AE-active ester: the amount of substance ratio that feeds intake of organic bases is 1.0: 1.0～1.8: 0.01～1.5, be preferably 1.0: 1.0～1.5: 0.05～and 1.5.
The consumption of described 2-methyltetrahydrofuran is feed intake 1～10 times of quality of 7-ACA, is preferably feed intake 2～6 times of quality of 7-ACA.
The consumption of described water is feed intake 0.01～1.0 times of quality of 7-ACA, is preferably feed intake 0.2～0.6 times of quality of 7-ACA.
Described cefotaxime acid synthesis reaction temperature is preferably 10～25 ℃.The described reaction times is preferably 2～8 hours.
After described reaction finishes, with dilute hydrochloric acid regulation system pH value is 1～3, there is solid to separate out, filter, get filter cake and filtrate, described filtration cakes torrefaction gets cefotaxime acid, and the azeotropic liquid of 2-methyltetrahydrofuran and water is reclaimed in described filtrate air distillation, residual solution is cooled to room temperature and separates out solid, and filtration drying gets the by product 2-mercaptobenzothiazole.
Described dilute hydrochloric acid concentration is 0.5～6mol/L, is 1～3 with dilute hydrochloric acid regulation system pH value, is preferably 2～3.
Comparatively concrete, the preparation cefotaxime acid is recommended to carry out according to following steps in green solvent 2-methyltetrahydrofuran: under 10～25 ℃, add 2-methyltetrahydrofuran, water, 7-ACA, AE-active ester, organic bases successively, insulation reaction 2～8 hours, reaction is 2～3 with 0.5～6mol/L dilute hydrochloric acid regulation system pH value after finishing, there is solid to separate out, filter, get filter cake and filtrate, described filtration cakes torrefaction gets cefotaxime acid; Described filtrate is carried out the azeotropic liquid that 2-methyltetrahydrofuran and water are reclaimed in air distillation, and residual solution is cooled to room temperature and separates out solid, and filtration drying gets the by product 2-mercaptobenzothiazole; Described organic bases is following one or more mixture: N, dinethylformamide, triethylamine, tri-n-butylamine or pyridine; The amount of substance ratio of described 7-ACA, AE-active ester, organic bases is 1.0: 1.0～1.5: 0.05～1.5; The consumption of described 2-methyltetrahydrofuran is 2～6 times of 7-ACA quality; The consumption of described water is feed intake 0.2～0.6 times of quality of 7-ACA.
The technical process of synthetic method of the present invention as shown in Figure 1.
The present invention compared with prior art, its beneficial effect is:
A) in green solvent 2-methyltetrahydrofuran, prepare cefotaxime acid, avoid the use of poisonous and harmful solvents such as methylene dichloride from the source.
B) rate of recovery of 2-methyltetrahydrofuran reaches 98%, and the 2-MeTHF after the recovery can realize repeatedly recovery set usefulness through simple process, both reduces cost, and reduces the three wastes again.
C) rate of recovery of 2-mercaptobenzothiazole reduces three wastes discharge amount greatly more than 95%.
In sum, the present invention is with 2-methyltetrahydrofuran advantage such as to be that method that solvent prepares cefotaxime acid has easy and simple to handle, mild condition, good product quality, yield height, production cost are low, efficiently solve problems such as complex operation that traditional technology exists, environmental pollution, thereby have bigger implementary value and potential economic results in society.
(4) description of drawings
Fig. 1 is the technical process of synthetic method of the present invention.
(5) embodiment
With specific embodiment technical scheme of the present invention is described below, but protection scope of the present invention is not limited thereto.
Embodiment 1
The amount of substance that feeds intake is than being 7-ACA: AE-active ester: organic bases=1: 1.0: 0.4; Described organic bases is a triethylamine, and the consumption of 2-methyltetrahydrofuran is feed intake 4 times of quality of 7-ACA, and the consumption of water is feed intake 0.6 times of quality of 7-ACA.
23 ± 2 ℃ of temperature controls (t), add 7-ACA (250.0g, 0.918mol) and AE-active ester (321.7g, 0.918mol) in the mixed solvent that 2-MeTHF (1000g), water (150g) are formed, add simultaneously triethylamine (37.1g, 0.367mol), stirring reaction 2 hours (T).With 6mol/L dilute hydrochloric acid conditioned reaction liquid pH to 2.5 ± 0.3, separate out white solid, to filter, drying gets the 407.7g cefotaxime acid, and yield is 97.5%, HPLC purity 98.9%.Filtrate is through the azeotropic liquid 1096g (containing 2-MeTHF 980g) of normal pressure distillation recovery 2-methyltetrahydrofuran and water, and raffinate is cooled to room temperature can separate out the by product 2-mercaptobenzothiazole, and filtration drying gets 145.9g, the rate of recovery 95.0%.
The amount of substance that feeds intake is than being 7-ACA: AE-active ester: organic bases=1: 1.3: 0.05; Organic bases is a pyridine.Concrete add-on is 250.0g (0.918mol) 7-ACA, 418.1gMEAM (1.193mol), 3.6g (0.046mol) pyridine, and the consumption of 2-methyltetrahydrofuran is 1750g, and the consumption of water is 37.5g; Described concentration of hydrochloric acid is 2mol/L, and the initial pH of crystallization is 2.85; T=20 ± 2 ℃, T=2 hour.
Other operations are with embodiment 1.Obtain cefotaxime acid 409.3g, yield is 97.9%, HPLC purity 98.7%.Reclaim the azeotropic liquid 1770g (containing 2-MeTHF 1743g) of 2-methyltetrahydrofuran and water, by product 2-mercaptobenzothiazole 146.2g.
Embodiment 3
The amount of substance that feeds intake is than being 7-ACA: AE-active ester: organic bases=1: 1.8: 0.5; Organic bases is the N-methylpyrrole.Concrete add-on is 250.0g (0.918mol) 7-ACA, 579.1g (1.652mol) MEAM, 37.7g (0.459mol) N-methylpyrrole, and the consumption of 2-methyltetrahydrofuran is 750g, and the consumption of water is 250g; Described concentration of hydrochloric acid is 1mol/L, and the initial pH of crystallization is 1.5; T=18 ± 2 ℃, T=2.5 hour.
Other operations are with embodiment 1.Obtain cefotaxime acid 411.0g, yield is 98.3%, HPLC purity 98.5%.Reclaim the azeotropic liquid 818g (containing 2-MeTHF 736g) of 2-methyltetrahydrofuran and water, by product 2-mercaptobenzothiazole 145.1g.
Embodiment 4
The amount of substance that feeds intake is than being 7-ACA: AE-active ester: organic bases=1: 1.5: 1; Organic bases is a tri-n-butylamine.Concrete add-on is 250.0g (0.918mol) 7-ACA, 482.6g (1.377mol) MEAM, 170.1g (0.918mol) tri-n-butylamine, and the consumption of 2-methyltetrahydrofuran is 2500g, and the consumption of water is 125g; Described concentration of hydrochloric acid is 3mol/L, and the initial pH of crystallization is 2.4 ± 0.2; T=10 ± 2 ℃, T=6 hour.
Other operations are with embodiment 1.Obtain cefotaxime acid 405.6g, yield is 97.0%, HPLC purity 98.6%.Reclaim the azeotropic liquid 2597g (containing 2-MeTHF 2483g) of 2-methyltetrahydrofuran and water, by product 2-mercaptobenzothiazole 146.5g.
Embodiment 5
The amount of substance that feeds intake is than being 7-ACA: AE-active ester: organic bases=1: 1: 1.2; Organic bases is a triethylene diamine.Concrete add-on is 250.0g (0.918mol) 7-ACA, 321.7g (0.918mol) MEAM, 124.2g (1.102mol) triethylene diamine, and the consumption of 2-methyltetrahydrofuran is 1000g, and the consumption of water is 75g; Described concentration of hydrochloric acid is 6mol/L, and the initial pH of crystallization is 2.5; T=18 ± 2 ℃, T=5 hour.
Other are with embodiment 1.Obtain cefotaxime acid 411.8g, yield is 98.5%, HPLC purity 98.8%.Reclaim the azeotropic liquid 1032g (containing 2-MeTHF982g) of 2-methyltetrahydrofuran and water, by product 2-mercaptobenzothiazole 147.2g.
Embodiment 6
The amount of substance that feeds intake is than being 7-ACA: AE-active ester: organic bases=1: 1.5: 0.1; Organic bases is a quadrol.Concrete add-on is 250.0g (0.918mol) 7-ACA, 482.6g (1.377mol) MEAM, 5.5g (0.092mol) quadrol, and the consumption of water is 25g, and the consumption of 2-methyltetrahydrofuran is 1375g; Described concentration of hydrochloric acid is 4mol/L, and the initial pH of crystallization is 2.90; T=38 ± 2 ℃, T=1 hour.
Other operations are with embodiment 1.Obtain cefotaxime acid 406.0g, yield is 97.1%, HPLC purity 98.6%.Reclaim the azeotropic liquid 1385g (containing 2-MeTHF 1365g) of 2-methyltetrahydrofuran and water, by product 2-mercaptobenzothiazole 146.0g.
The amount of substance that feeds intake is than being 7-ACA: AE-active ester: organic bases=1: 1: 0.5; Organic bases is a triethylamine.Concrete add-on is 250.0g (0.918mol) 7-ACA, 321.7g (0.918mol) MEAM, 46.4g (0.459mol) triethylamine, and the consumption of 2-methyltetrahydrofuran is 250g, and the consumption of water is 250g; Described concentration of hydrochloric acid is 2.5mol/L, and the initial pH of crystallization is 1.25; T=13 ± 2 ℃, T=4 hour.
Other operations are with embodiment 1.Obtain cefotaxime acid 404.7g, yield is 96.8%, HPLC purity 98.5%.Reclaim the azeotropic liquid 367g (containing 2-MeTHF 245g) of 2-methyltetrahydrofuran and water, by product 2-mercaptobenzothiazole 147.3g.
Embodiment 8
The amount of substance that feeds intake is than being 7-ACA: AE-active ester: organic bases=1: 1.25: 1.4; Organic bases is the mixing (mol ratio is 6: 1) of Tri-n-Propylamine and DMF.Concrete add-on is 250.0g (0.918mol) 7-ACA, 402.3g (1.148mol) MEAM, 157.9g (1.102mol) Tri-n-Propylamine and 13.43g (0.184mol) DMF, and the consumption of 2-methyltetrahydrofuran is 500g, and the consumption of water is 75g; Described concentration of hydrochloric acid is 5mol/L, and the initial pH of crystallization is 3; T=15 ± 2 ℃, T=5.5 hour.
Other operations are with embodiment 1.Obtain cefotaxime acid 407.7g, yield is 97.5%, HPLC purity 98.8%.Reclaim the azeotropic liquid 513g (containing 2-MeTHF 492g) of 2-methyltetrahydrofuran and water, by product 2-mercaptobenzothiazole 146.4g.
Embodiment 9
The amount of substance that feeds intake is than being 7-ACA: AE-active ester: organic bases=1: 1.05: 0.01; Organic bases is the 3-picoline.Concrete add-on is 250.0g (0.918mol) 7-ACA, 337.8g (0.964mol) MEAM, 0.8g (0.009mol) 3-picoline, and the consumption of 2-methyltetrahydrofuran is 1500g, and the consumption of water is 2.5g; Described concentration of hydrochloric acid is 3mol/L, and the initial pH of crystallization is 2.5; T=13 ± 2 ℃, T=3.5 hour.
Other operations are with embodiment 1.Obtain cefotaxime acid 401.8g, yield is 96.1%, HPLC purity 98.9%.Reclaim the azeotropic liquid 1492g (containing 2-MeTHF 1490g) of 2-methyltetrahydrofuran and water, by product 2-mercaptobenzothiazole 145.2g.
Embodiment 10
The amount of substance that feeds intake is than being 7-ACA: AE-active ester: organic bases=1: 1.25: 0.6; Organic bases is the mixing (mol ratio is 10: 1) of triethylene diamine and DMA, concrete add-on is 250.0g (0.918mol) 7-ACA, 402.3g (1.148mol) MEAM, 56.5g (0.501mol) triethylene diamine and 4.36g (0.050mol) DMA, the consumption of 2-methyltetrahydrofuran is 1250g, the consumption of water is 112.5g; Described concentration of hydrochloric acid is 4.5mol/L, and the initial pH of crystallization is 2 ± 0.3; T=0 ± 2 ℃, T=12 hour.
Other operations are with embodiment 1.Obtain cefotaxime acid 411.4g, yield is 98.4%, HPLC purity 99%.Reclaim the azeotropic liquid 1293g (containing 2-MeTHF 1229g) of 2-methyltetrahydrofuran and water, by product 2-mercaptobenzothiazole 145.9g.
Embodiment 11
The amount of substance that feeds intake is than being 7-ACA: AE-active ester: organic bases=1: 1.4: 1.5; Organic bases is a quadrol, and concrete add-on is 250.0g (0.918mol) 7-ACA, 450.4g (1.285mol) MEAM, 82.3g (1.377mol) quadrol, and the consumption of 2-methyltetrahydrofuran is 500g, and the consumption of water is 2.5g; Described concentration of hydrochloric acid is 0.5mol/L, and the initial pH of crystallization is 2.5; T=25 ± 2 ℃, T=2.5 hour.
Other are with embodiment 1.Obtain cefotaxime acid 406.8g, yield is 97.3%, HPLC purity 98.8%.Reclaim the azeotropic liquid 497g (containing 2-MeTHF95g) of 2-methyltetrahydrofuran and water, by product 2-mercaptobenzothiazole 146.1g.
Embodiment 12
The amount of substance that feeds intake is than being 7-ACA: AE-active ester: organic bases=1: 1.1: 0.75; Organic bases is a tri-n-butylamine, and concrete add-on is 250.0g (0.918mol) 7-ACA, 353.9g (1.010mol) MEAM, 127.7g (0.689mol) tri-n-butylamine, and the consumption of 2-methyltetrahydrofuran is 1000g, and the consumption of water is 150g; Described concentration of hydrochloric acid is 4mol/L, and the initial pH of crystallization is 1; T=13 ± 2 ℃, T=3.5 hour.
Other operations are with embodiment 1.Obtain cefotaxime acid 403.5g, yield is 96.5%, HPLC purity 99.1%.Reclaim the azeotropic liquid 1130g (containing 2-MeTHF 1080g) of 2-methyltetrahydrofuran and water, by product 2-mercaptobenzothiazole 145.2g.
Embodiment 13
The amount of substance that feeds intake is than being 7-ACA: AE-active ester: organic bases=1: 1.5: 0.45; Organic bases is a triethylamine, and concrete add-on is 250.0g (0.918mol) 7-ACA, 482.6g (1.377mol) MEAM, 41.7g (0.413mol) triethylamine, and 2-MeTHF is from embodiment 4 solvent that reclaims, and consumption is 2000g, and the consumption of water is 100g; Described concentration of hydrochloric acid is 6mol/L, and the initial pH of crystallization is 2.75; T=25 ± 2 ℃, T=2 hour.
Other operations are with embodiment 1.Obtain cefotaxime acid 405.6g, yield is 97%, HPLC purity 98.9%.Reclaim the azeotropic liquid 1995g (containing 2-MeTHF 1958g) of 2-methyltetrahydrofuran and water again, by product 2-mercaptobenzothiazole 147.0g.
Embodiment 14
The amount of substance that feeds intake is than being 7-ACA: AE-active ester: organic bases=1: 1: 0.6; Organic bases is DMA, and concrete add-on is 250.0g (0.918mol) 7-ACA, 321.7g (0.918mol) MEAM, 48.1g (0.551mol) DMA, and 2-MeTHF is from embodiment 6 solvent that reclaims, and consumption is 500g, and the consumption of water is 10g; Described concentration of hydrochloric acid is 2mol/L, and the initial pH of crystallization is 2.5; T=5 ± 2 ℃, T=7 hour.
Other operations are with embodiment 1.Obtain cefotaxime acid 403.9g, yield is 96.6%, HPLC purity 99.0%.Reclaim the azeotropic liquid 503g (containing 2-MeTHF 488g) of 2-methyltetrahydrofuran and water again, by product 2-mercaptobenzothiazole 145.9g.
Embodiment 15
The amount of substance that feeds intake is than being 7-ACA: AE-active ester: organic bases=1: 1.15: 1.25; Organic bases is a Tri-n-Propylamine, and concrete add-on is 250.0g (0.918mol) 7-ACA, 370.0g (1.056mol) MEAM, 164.5g (1.148mol) Tri-n-Propylamine, and 2-MeTHF reclaims from embodiment 2, and consumption is 1250g, and the consumption of water is 25g; Described concentration of hydrochloric acid is 3mol/L, and the initial pH of crystallization is 2.25; T=13 ± 2 ℃, T=5 hour.
Other operations are with embodiment 1.Obtain cefotaxime acid 406.0g, yield is 97.1%, HPLC purity 98.9%.Reclaim the azeotropic liquid 1235g (containing 2-MeTHF 1220g) of 2-methyltetrahydrofuran and water again, by product 2-mercaptobenzothiazole 145.6g.
Claims (10)
1, a kind of green synthesis method suc as formula the cefotaxime acid shown in (I), it is characterized in that described method is: in reaction vessel, add 2-methyltetrahydrofuran, water, suc as formula the 7-amino-cephalosporanic acid shown in (II), suc as formula AE-active ester, the organic bases shown in (III), under 0～40 ℃ temperature, reacted 1～12 hour, after reaction finishes, with dilute hydrochloric acid regulation system pH value is 1～3, has solid to separate out, and filters, get filter cake and filtrate, described filtration cakes torrefaction gets cefotaxime acid; Described organic bases is organic amine or pyridine compounds and their; The amount of substance ratio of described 7-amino-cephalosporanic acid, AE-active ester, organic bases is 1.0: 1.0～1.8: 0.01～1.5; The consumption of described 2-methyltetrahydrofuran is 1～10 times of 7-amino-cephalosporanic acid quality; The consumption of described water is 0.01～1 times of 7-amino-cephalosporanic acid quality;
2, the green synthesis method of cefotaxime acid as claimed in claim 1, it is characterized in that described organic bases is following one or more mixing: triethylamine, Tri-n-Propylamine, tri-isopropyl amine, quadrol, tri-n-butylamine, tri-isobutylamine, triethylene diamine, pyridine, the 2-picoline, the 3-picoline, the 4-picoline, 2, the 6-lutidine, N, dinethylformamide, N, the N-N,N-DIMETHYLACETAMIDE, N, accelerine, N, the N-Diethyl Aniline, N, N dimethylamine base-4-pyridine, the N-methylpyrrole, N-Methylimidazole or N-methylmorpholine.
3, the green synthesis method of cefotaxime acid as claimed in claim 1 is characterized in that described organic bases is following one or more mixing: N, dinethylformamide, triethylamine, tri-n-butylamine or pyridine.
4. synthetic method as claimed in claim 1 is characterized in that the amount of substance ratio of described 7-amino-cephalosporanic acid, AE-active ester, organic bases is 1.0: 1.0～1.5: 0.05～1.5.
5, the green synthesis method of cefotaxime acid as claimed in claim 1, the consumption that it is characterized in that described 2-methyltetrahydrofuran are 2～6 times of 7-amino-cephalosporanic acid quality.
6, the green synthesis method of cefotaxime acid as claimed in claim 1, the consumption that it is characterized in that described water are 0.2～0.6 times of 7-amino-cephalosporanic acid quality.
7, the green synthesis method of cefotaxime acid as claimed in claim 1 is characterized in that described temperature of reaction is 10～25 ℃, and the reaction times is 2～8 hours.
8, the green synthesis method of cefotaxime acid as claimed in claim 1 is characterized in that described dilute hydrochloric acid concentration is 0.5～6mol/L.
9, the green synthesis method of cefotaxime acid as claimed in claim 1, after it is characterized in that described reaction finishes, the azeotropic liquid of 2-methyltetrahydrofuran and water is reclaimed in described filtrate air distillation, and residual solution is cooled to room temperature and separates out solid, and filtration drying gets the by product 2-mercaptobenzothiazole.
10, the green synthesis method of cefotaxime acid as claimed in claim 1, it is characterized in that described method is: under 10～25 ℃, add 2-methyltetrahydrofuran, water, 7-amino-cephalosporanic acid, AE-active ester, organic bases successively, insulation reaction 2～8 hours, reaction is 2～3 with 0.5～6mol/L dilute hydrochloric acid regulation system pH value after finishing, there is solid to separate out, filter, get filter cake and filtrate, described filtration cakes torrefaction gets cefotaxime acid; Described filtrate is carried out the azeotropic liquid that 2-methyltetrahydrofuran and water are reclaimed in air distillation, and residual solution is cooled to room temperature and separates out solid, and filtration drying gets the by product 2-mercaptobenzothiazole; Described organic bases is following one or more mixture: N, dinethylformamide, triethylamine, tri-n-butylamine or pyridine; The amount of substance ratio of described 7-amino-cephalosporanic acid, AE-active ester, organic bases is 1.0: 1.0～1.5: 0.05～1.5; The consumption of described 2-methyltetrahydrofuran is 2～6 times of 7-amino-cephalosporanic acid quality; The consumption of described water is feed intake 0.2～0.6 times of quality of 7-amino-cephalosporanic acid.
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| CNA200910098168XA Pending CN101550149A (en) | 2009-05-04 | 2009-05-04 | Green synthetic method for cefotaxime acid |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011042776A1 (en) * | 2009-10-09 | 2011-04-14 | Nectar Lifesciences Ltd. | Process for preparation of cefotaxime acid and pharmaceutically acceptable salt thereof |
| CN102453041A (en) * | 2010-10-29 | 2012-05-16 | 广州白云山制药股份有限公司 | Environment-friendly impurity-removal manufacturing method |
| CN102702230A (en) * | 2012-05-30 | 2012-10-03 | 华北制药河北华民药业有限责任公司 | Method for preparing cefotaxime acid |
| CN104840423A (en) * | 2015-04-27 | 2015-08-19 | 四川制药制剂有限公司 | Preparation process of cefotaxime sodium for injection |
| CN105503904A (en) * | 2015-12-30 | 2016-04-20 | 河南康达制药有限公司 | Preparation method for cefotaxime acid |
| CN109608476A (en) * | 2018-12-28 | 2019-04-12 | 广州白云山医药集团股份有限公司白云山化学制药厂 | A kind of the production method for treating waste liquid and production method of cephalosporin analog antibiotic |
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2009
- 2009-05-04 CN CNA200910098168XA patent/CN101550149A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011042776A1 (en) * | 2009-10-09 | 2011-04-14 | Nectar Lifesciences Ltd. | Process for preparation of cefotaxime acid and pharmaceutically acceptable salt thereof |
| CN102453041A (en) * | 2010-10-29 | 2012-05-16 | 广州白云山制药股份有限公司 | Environment-friendly impurity-removal manufacturing method |
| CN102453041B (en) * | 2010-10-29 | 2014-11-05 | 广州白云山制药股份有限公司 | Environment-friendly impurity-removal manufacturing method |
| CN102702230A (en) * | 2012-05-30 | 2012-10-03 | 华北制药河北华民药业有限责任公司 | Method for preparing cefotaxime acid |
| CN102702230B (en) * | 2012-05-30 | 2014-09-10 | 华北制药河北华民药业有限责任公司 | Method for preparing cefotaxime acid |
| CN104840423A (en) * | 2015-04-27 | 2015-08-19 | 四川制药制剂有限公司 | Preparation process of cefotaxime sodium for injection |
| CN105503904A (en) * | 2015-12-30 | 2016-04-20 | 河南康达制药有限公司 | Preparation method for cefotaxime acid |
| CN109608476A (en) * | 2018-12-28 | 2019-04-12 | 广州白云山医药集团股份有限公司白云山化学制药厂 | A kind of the production method for treating waste liquid and production method of cephalosporin analog antibiotic |
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