CN104072516A - Method for synthesizing cefuroxime acid - Google Patents
Method for synthesizing cefuroxime acid Download PDFInfo
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- CN104072516A CN104072516A CN201410284897.5A CN201410284897A CN104072516A CN 104072516 A CN104072516 A CN 104072516A CN 201410284897 A CN201410284897 A CN 201410284897A CN 104072516 A CN104072516 A CN 104072516A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
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- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method for synthesizing cefuroxime acid, which comprises the following steps: A) dropwisely adding isocyanate chlorosulfonate into a mixed solution of ethyl acetate and 3-decarbamoyl-cefuroxime acid at 0-15 temperature; B) while controlling the temperature at 15-25 DEG C, continuing adding activated carbon into the reaction solution, stirring to react, and filtering; and C) taking the filtrate, cooling, adding water, continuously adding sodium bicarbonate, skimming, discarding the ethyl acetate layer, dropwisely adding 30% HCl to regulate the pH value, cooling to 0-10 below, growing the grain, carrying out vacuum filtration, and washing the filter cake with water.
Description
Technical field
The present invention relates to medicine preparation field, be specifically related to the preparation method of cefuroxime acid.
Background technology
Cefuroxime acid (Cefuroxim, structural formula 1), (6R, 7R)-7-[2-furyl (methoxyimino) kharophen]-3-carbamyl oxygen methyl-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formic acid.
Structural formula 1 (cefuroxime acid):
Cephalofruxin is a cephalosporin analog antibiotic by the research and development of Ge Lansu company of Britain, belong to two generation cynnematin, there is broad-spectrum antibacterial action, not only gram-positive cocci is had to stronger anti-microbial activity, and some gram negative bacterium is also had to good anti-microbial activity, especially in the treatment of Gram-positive and gram negative bacterium polyinfection, preferentially select especially this medicine.It produces the pharmaceutically-active lytic enzyme of destruction to bacterium and has high stability, few generation untoward reaction in clinical application.
In the method for the synthetic cefuroxime acid of current most producer, substantially all adopt THF or DMC as solvent; utilize 3-to go formamido group cefuroxime acid (DDC) and CSI in polynary or monobasic system; there is nucleophilic addition and generate chlorosulfonylation cefuroxime acid; add purified water, hydrolysis generates cefuroxime acid again.For example:
Chinese patent CN102134252A has adopted 3-to go formamido group cefuroxime acid (DDC) quantitatively to join in tetrahydrofuran solvent; be cooled to-80 DEG C～-30 DEG C; drip chlorosulfonic acid isocyanate and carry out nucleophilic addition generation chlorosulfonylation cefuroxime acid; add again purified water hydrolysis to make cefuroxime acid reaction solution; add after sodium bicarbonate salify; extract and remove organic phase with methylene dichloride, ethyl acetate and tetrahydrofuran (THF) tri compound extraction agent; water adds hcl acidifying, then adds tri compound extraction agent to extract cefuroxime acid.
Chinese patent CN102093390A has adopted 3-to go formamido group cefuroxime acid (DDC) quantitatively to join in tetrahydrofuran solvent; be cooled to-20 DEG C～0 DEG C; drip chlorosulfonic acid isocyanate and carry out nucleophilic addition generation chlorosulfonylation cefuroxime acid; add again purified water hydrolysis to make cefuroxime acid reaction solution; add after sodium bicarbonate salify, with ethyl acetate washing, retain water; then add hcl acidifying, crystallization obtains cefuroxime acid.
Chinese patent CN101289456A has reported among the such solvent system of methylcarbonate; utilize 3-to go formamido group cefuroxime acid (DDC) and chlorosulfonic acid isocyanate to carry out nucleophilic addition and generate chlorosulfonylation cefuroxime acid; add purified water hydrolysis and obtain cefuroxime acid; then add methylene dichloride; low temperature crystallization obtains cefuroxime acid; gained yield is lower is only 88.23%, and product purity low be only 98.11%.
In the synthetic field of medicine material, due to the singularity of medicine, responsive especially to the purity of product.On the one hand, the stability of impurity effect medicine, may cause that medicine is rotten; On the other hand, impurity may bring unpredictable untoward reaction, on patient's treatment impact greatly.Particularly directly deliver into the injection of blood of human body, extremely the impurity of trace all may cause great injury to human body.In the existing regulation of China, only have purity to reach more than 99.0% pharmaceutical raw material, it is qualified to be only.Making great efforts to improve material purity, the amount of impurity is reduced to minimum, is the insistent objectives of the struggle of those skilled in the art.
Due to the requirement of scale operation, the usage quantity of the use to reagent in synthesis technique, particularly solvent or extraction solvent etc. is very large.And in different solvents, toxicity is not of uniform size.Grope in the stage of research in laboratory study, synthetic amount is little, uses the amount of reagent also little, and the impact that human body is caused is not obvious.But in large-scale production, the usage quantity of solvent or extraction solvent etc. is very large, and the necessary Long Term Contact reagent of skilled worker, now, the infringement difference that the toxicity size of reagent causes human body is huge.The toxicity of making great efforts to reduce each technique, makes operational path harmless, green, is also those skilled in the art's the common objective of the struggle.
Moreover, in scale operation, in order to reduce costs and protection of the environment, also very important to the recycling step of reaction solution.The composition of reaction solution or extraction solvent is simpler, and follow-up separation, recycling step are simpler, and cost is also lower, is more conducive to produce.
But, in the synthetic route that patent technique as above is reported, or use the reaction solvent that toxic is larger, serious to human health damage, for example tetrahydrofuran (THF); Use ternary mixed system, such as tetrahydrofuran (THF), methylene dichloride and ethyl acetate etc., cause post-processed with high costs, thereby increased the cost of producing cefuroxime acid.
For this reason suddenly treat that we research and develop environment or more friendly reaction system and the simple production technique of people are synthesized to cefuroxime acid.
Summary of the invention
For above technique shortcoming, we have proposed a kind of novel, method that technique is simplified, the synthetic cefuroxime acid of low cost, in the process of synthetic cefuroxime acid, we have adopted ethyl acetate (EA) to replace THF, DMC, react by such reaction system, and do not use a large amount of extraction agents, obtained equally high yield and high-quality cefuroxime acid.
Concrete scheme route is as follows:
Remarks: tetrahydrofuran (THF) (THF), ethyl acetate (EA), methylcarbonate (DMC), 3-removes formamido group cefuroxime acid (DDC), chlorosulfonic acid isocyanate (CSI), cefuroxime acid (CXM).
More specifically, synthesis technique of the present invention is: at T1 temperature, go in formamido group cefuroxime acid mixed solution to ethyl acetate, 3-, drip chlorosulfonic acid isocyanate.At T2 temperature, add gac, stirring reaction, filtration.Filtrate cooling, drips purified water, then drips NaHCO
3solution.Separatory, discards ethyl acetate layer, drips 30%HCl, regulates pH, cools at T3 temperature growing the grain.Suction filtration, filter cake washes twice with water, drains, and vacuum-drying, obtains white solid product.
Preferably, in above-mentioned synthesis technique, T1 temperature is 0～15 DEG C; Further, when T1 is 5～10 DEG C, reaction effect the best.
Preferably, in above-mentioned synthesis technique, when T2 temperature is 15～20 DEG C, reaction effect the best.
Preferably, in above-mentioned synthesis technique, T3 temperature is 0～10 DEG C; Further, when T3 is 0～5 DEG C, reaction effect the best.
Preferably, in above-mentioned synthesis technique, regulating pH is 1～4; Further, pH is 2 o'clock, reaction effect the best.
Preferably, in above-mentioned synthesis technique, reaction churning time is 25～35 minutes; Further, when churning time is 30 minutes, reaction effect the best.
Preferably, in above-mentioned synthesis technique, the quality feed ratio of ethyl acetate and DDC is 7～11: 1; Further, its feed ratio is 9: 1 o'clock, reaction effect the best.
Production technique of the present invention, has following outstanding advantages:
1, adopt ethyl acetate as the synthetic cefuroxime acid of action solvent, environmental protection.Ethyl acetate is compared with the reagent such as tetrahydrofuran (THF), and toxicity is less, and price is lower, and solvent recuperation cost is lower; Compared with the reagent such as methylcarbonate, the cefuroxime acid purity of acquisition is higher, and yield is higher.
2, do not use extraction agent, greatly improved yield, shortened the operation duration, removed the complex steps of subsequent recovery extraction agent from.
3, reaction conditions gentleness, without being significantly cooled to below 0 DEG C, reduces production costs greatly.
4, reaction required time is short, is conducive to produce.
5, reaction product purity is high, and color and luster is qualified, detects through high performance liquid chromatography, and reaction product purity is more than 99.0%; Reaction yield is high, more than 90%, is conducive to produce.
Specific embodiment
Embodiment 1:
In 1000ml there-necked flask, add successively: ethyl acetate (500ml), DDC (50g, 117.82mmol), rear temperature control T1=5-10 DEG C, 10min drips off 15mLCSI.Temperature control T2=15-20 DEG C, adds gac 2.5g, after stirring reaction 30min, filters.Filtrate is cooled to 5 DEG C of left and right, and then 5min drips 70mL purified water, then drips NaHCO3 solution (53gNaHCO
3+ 284mL water), 30min drips off.Separatory, discards ethyl acetate layer, drips 30%HCl, regulates pH value, cools to T3=0-5 DEG C of growing the grain 1h.Suction filtration, filter cake washes twice with water, and each 50mL, drains, and in 50 DEG C of vacuum-drying 3h, obtains reaction product as shown in Table 1:
Table one, the impact of different PH on reaction product
Conclusion: can be had by table one: when pH value is during at 1-4, reaction product purity is more than 99.0%, and molar yield is more than 86%, and reaction effect is good, is optimal selection; In the time of pH value≤1.0, reaction product purity is low, and product is defective; And when pH value > 4, reaction yield is low.
Embodiment 2:
In 1000ml there-necked flask, add successively: ethyl acetate (500ml), DDC (50g, 117.82mmol), rear temperature control T1=0-5 DEG C, 10min drips off 15mLCSI.Temperature control T2=15-20 DEG C, adds gac 2.5g, after stirring reaction 30min, filters.Filtrate is cooled to 5 DEG C of left and right, and then 5min drips 70mL purified water, then drips NaHCO
3solution (53gNaHCO
3+ 284mL water), 30min drips off.Separatory, discards ethyl acetate layer, drips 30%HCl, regulates pH=2.0, cools to T3=0-5 DEG C of growing the grain 1h.Suction filtration, filter cake washes twice with water, and each 50mL, drains, and in 50 DEG C of vacuum-drying 3h, obtains white solid product 50.8g, moisture 0.18%, HPLC purity 99.25%, molar yield 91.30%.
Embodiment 3:
In 1000ml there-necked flask, add successively: ethyl acetate (500ml), DDC (50g, 117.82mmol), rear temperature control T1=10-15 DEG C, 10min drips off 15mLCSI.Temperature control T2=15-20 DEG C, adds gac 2.5g, after stirring reaction 30min, filters.Filtrate is cooled to 5 DEG C of left and right, and then 5min drips 70mL purified water, then drips NaHCO
3solution (53gNaHCO
3+ 284mL water), 30min drips off.Separatory, discards ethyl acetate layer, drips 30%HCl, regulates pH=2.0, cools to T3=0-5 DEG C of growing the grain 1h.Suction filtration, filter cake washes twice with water, and each 50mL, drains, and in 50 DEG C of vacuum-drying 3h, obtains white solid product 49.5g, moisture 0.16%, HPLC purity 99.00%, molar yield 88.96%.
Embodiment 4:
In 1000ml there-necked flask, add successively: ethyl acetate (500ml), DDC (50g, 117.82mmol), rear temperature control T1=5-10 DEG C, 10min drips off 15mLCSI.Temperature control T2, adds gac 2.5g, after stirring reaction 30min, filters.Filtrate is cooled to 5 DEG C of left and right, and then 5min drips 70mL purified water, then drips NaHCO
3solution (53gNaHCO
3+ 284mL water), 30min drips off.Separatory, discards ethyl acetate layer, drips 30%HCl, regulates pH=2.0, cools to T3=0-5 DEG C of growing the grain 1h.Suction filtration, filter cake washes twice with water, and each 50mL, drains, and in 50 DEG C of vacuum-drying 3h, obtains reaction product as shown in Table 2:
Table two, the impact of different T2 value on reaction product
Conclusion: can be found out by table two, when temperature of reaction T2 is during at 15-20 DEG C, reaction product purity is high, productive rate is high, is optimal selection; When T2 temperature is lower than 15 DEG C or during higher than 20 DEG C, reaction product purity will be lower than 90.0%, and product is defective.
Embodiment 5:
In 1000ml there-necked flask, add successively: ethyl acetate (500ml), DDC (50g, 117.82mmol), rear temperature control T1=5-10 DEG C, 10min drips off 15mLCSI.Temperature control T2=15-20 DEG C, adds gac 2.5g, after stirring reaction 30min, filters.Filtrate is cooled to 5 DEG C of left and right, and then 5min drips 70mL purified water, then drips NaHCO
3solution (53gNaHCO
3+ 284mL water), 30min drips off.Separatory, discards ethyl acetate layer, drips 30%HCl, regulates pH=2.0, cools to T3 growing the grain 1h.Suction filtration, filter cake washes twice with water, and each 50mL, drains, and in 50 DEG C of vacuum-drying 3h, obtains reaction product as shown in Table 3:
Table three, the impact of different T3 value on reaction product
Conclusion: can be found out by table three, when temperature of reaction T3 is during at 0-10 DEG C, reaction product purity is high, productive rate is high, is optimal selection; When T3 temperature is during higher than 10 DEG C, reaction molar yield is on the low side, is unfavorable for producing.
Embodiment 6:
In 1000ml there-necked flask, add successively: ethyl acetate (500ml), DDC (50g, 117.82mmol), rear temperature control T1=5-10 DEG C, 10min drips off 15mLCSI.Temperature control T2=15-20 DEG C, adds gac 2.5g, after stirring reaction, filters.Filtrate is cooled to 5 DEG C of left and right, and then 5min drips 70mL purified water, then drips NaHCO
3solution (53gNaHCO
3+ 284mL water), 30min drips off.Separatory, discards ethyl acetate layer, drips 30%HCl, regulates pH=2.0, cools to T3=0-5 DEG C of growing the grain 1h.Suction filtration, filter cake washes twice with water, and each 50mL, drains, and in 50 DEG C of vacuum-drying 3h, obtains reaction product as shown in Table 4:
Table four, the impact of different stirring reaction time on reaction product
Conclusion: can be found out by table four, in the time that the stirring reaction time is greater than 35min or is less than 20min, the purity of product all, below 90%, can not get qualified product.
Embodiment 7:
In 1000ml there-necked flask, add successively ethyl acetate and the DDC of certain weight ratio to count like DDC50g117.82mmol), rear temperature control T1=5-10 DEG C, 10min drips off 15mLCSI.Temperature control T2=15-20 DEG C, adds gac 2.5g, after stirring reaction 30min, filters.Filtrate is cooled to 5 DEG C of left and right, and then 5min drips 70mL purified water, then drips NaHCO
3solution (53gNaHCO
3+ 284mL water), 30min drips off.Separatory, discards ethyl acetate layer, drips 30%HCl, regulates pH=2.0, cools to T3=0-5 DEG C of growing the grain 1h.Suction filtration, filter cake washes twice with water, and each 50mL, drains, and in 50 DEG C of vacuum-drying 3h, obtains reaction product as shown in Table 5:
The impact of the weight ratio of table five, different ethyl acetate and DDC on reaction product
| Component | Ethyl acetate: DDC | Product characters | Product moisture | Product HPLC purity | Product weight | Molar yield |
| ? | (weight ratio) | ? | ? | (should be greater than 90%) | ? | ? |
| 1 | 5.4∶1 | White solid | 0.18％ | 80.22％ | 46g | 82.67％ |
| 2 | 6.3∶1 | White solid | 0.16％ | 83.12％ | 45.7g | 82.14％ |
| 3 | 7∶1 | White solid | 0.18％ | 84.89％ | 46g | 82.67％ |
| 4 | 9∶l | White solid | 0.15％ | 99.20％ | 51g | 91.66％ |
| 5 | 11∶1 | White solid | 0.15％ | 85.10％ | 50.9g | 91.48％ |
| 6 | 12∶1 | White solid | 0.15％ | 84.32％ | 43.5g | 78.18％ |
Conclusion: can be found out by table five, ethyl acetate can impact reacting with the usage quantity of DDC.When the weight ratio of ethyl acetate and DDC is 7-11: when 1 (ethyl acetate density is calculated by 0.902g/ml), reaction product purity is high, molar yield is high, and reaction effect is good; In the time that its ratio value is not within the scope of this, product purity and molar yield all decline, and product is defective.
Embodiment 8:
In 1000ml there-necked flask, add successively: ethyl acetate (500ml), DDC (50g, 117.82mmol), rear temperature control T1=5-10 DEG C, 10min drips off 15mLCSI.Temperature control T2=15-20 DEG C, adds gac 2.5g, after stirring reaction 30min, filters.Filtrate is cooled to 5 DEG C of left and right, and then 5min drips 70mL purified water, then drips NaHCO
3solution (53gNaHCO
3+ 284mL water), 30min drips off.Separatory, discards ethyl acetate layer, drips 30%HCl, regulates pH=2.0, cools to T3=5-10 DEG C of growing the grain 1h.Suction filtration, filter cake washes twice with water, and each 50mL, drains, and in 50 DEG C of vacuum-drying 3h, obtains white solid product 50g, moisture 0.14%, HPLC purity 99.28%, molar yield 89.86%.
Embodiment 9:
In 1000ml there-necked flask, add successively: ethyl acetate (500m1), DDC (50g, 117.82mmol), rear temperature control T1=5-10 DEG C, 10min drips off 15mLCSI.Temperature control T2=15-20 DEG C, adds gac 2.5g, after stirring reaction 30min, filters.Filtrate is cooled to 5 DEG C of left and right, and then 5min drips 70mL purified water, then drips NaHCO
3solution (53gNaHCO
3+ 284mL water), 30min drips off.Separatory, discards ethyl acetate layer, drips 30%HCl, regulates pH=2.0, cools to T3=0-5 DEG C of growing the grain 2h.Suction filtration, filter cake washes twice with water, and each 50mL, drains, and in 50 DEG C of vacuum-drying 3h, obtains white solid product 51g, moisture 0.14%, HPLC purity 99.18%, molar yield 91.66%.
Claims (8)
1. a preparation method for synthetic cefuroxime acid, comprises the following steps:
A) at 0～15 DEG C of temperature, go in formamido group cefuroxime acid mixed solution to ethyl acetate, 3-, drip chlorosulfonic acid isocyanate;
B) control temperature within the scope of 15～25 DEG C, continue in reaction solution, to add gac, stirring reaction, filtration;
C) get filtrate, cooling, adds after water, continues to add sodium bicarbonate, and separatory, discards ethyl acetate layer, drips 30%HCl, regulates pH, cools at 0～10 DEG C of temperature growing the grain, suction filtration, washing filter cake.
2. a preparation method for synthetic cefuroxime acid, comprises the following steps:
A) at 5～10 DEG C of temperature, go in formamido group cefuroxime acid mixed solution to ethyl acetate, 3-, drip chlorosulfonic acid isocyanate;
B) control temperature within the scope of 15～20 DEG C, continue in reaction solution, to add gac, stirring reaction, filtration;
C) get filtrate, cooling, adds after water, continues to add sodium bicarbonate, and separatory, discards ethyl acetate layer, drips 30%HCl, regulates pH, cools at 0～5 DEG C of temperature growing the grain, suction filtration, washing filter cake.
3. preparation method according to claim 2, is characterized in that steps A) in, it is 9: 1 that ethyl acetate and 3-remove the quality feed ratio of formamido group cefuroxime acid.
4. preparation method according to claim 3, is characterized in that steps A) in, it is 7～11: 1 that ethyl acetate and 3-remove the quality feed ratio of formamido group cefuroxime acid.
5. preparation method according to claim 2, is characterized in that step C) in, regulating pH is 1～4.
6. preparation method according to claim 5, is characterized in that step C) in, regulating pH is 2.
7. preparation method according to claim 2, is characterized in that step B) in, churning time is 25～35 minutes.
8. preparation method according to claim 7, is characterized in that step B) in, churning time is 30 minutes.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106432267A (en) * | 2016-08-28 | 2017-02-22 | 珠海保税区丽珠合成制药有限公司 | Method for preparing cefuroxime acid |
| CN106478668A (en) * | 2016-08-31 | 2017-03-08 | 河北科技大学 | A kind of preparation technology of cefuroxime acid crystal |
| CN109988183A (en) * | 2019-04-17 | 2019-07-09 | 广东立国制药有限公司 | A kind of environment-friendly preparation method of the intermediate of cefuroxime acid |
| CN112745337A (en) * | 2021-01-22 | 2021-05-04 | 华北制药河北华民药业有限责任公司 | Preparation method of cefuroxime acid |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106432267A (en) * | 2016-08-28 | 2017-02-22 | 珠海保税区丽珠合成制药有限公司 | Method for preparing cefuroxime acid |
| CN106478668A (en) * | 2016-08-31 | 2017-03-08 | 河北科技大学 | A kind of preparation technology of cefuroxime acid crystal |
| CN109988183A (en) * | 2019-04-17 | 2019-07-09 | 广东立国制药有限公司 | A kind of environment-friendly preparation method of the intermediate of cefuroxime acid |
| CN112745337A (en) * | 2021-01-22 | 2021-05-04 | 华北制药河北华民药业有限责任公司 | Preparation method of cefuroxime acid |
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Application publication date: 20141001 |