CN102040614A - Method for producing cephalothin acid by water phase method - Google Patents
Method for producing cephalothin acid by water phase method Download PDFInfo
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- CN102040614A CN102040614A CN 201010288899 CN201010288899A CN102040614A CN 102040614 A CN102040614 A CN 102040614A CN 201010288899 CN201010288899 CN 201010288899 CN 201010288899 A CN201010288899 A CN 201010288899A CN 102040614 A CN102040614 A CN 102040614A
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Abstract
The invention discloses a method for synthesizing cephalothin acid by using 7-aminocephalosporanic acid (7-ACA) as a raw material, which is characterized in that: the 7-ACA and a 2-thiophene acetylation reagent are subjected to condensation reaction in a water phase solvent, and the production process sequentially comprises the following steps of: performing condensation reaction on the 7-ACA in a water phase; performing centrifugal filtration on a reaction product; refining and decolorizing; and performing crystallization separation, centrifugal filtration and vacuum drying to obtain a cephalothin acid product. The production process is simplified, the requirement on equipment is reduced, the amount of an organic solvent can be saved by over 70 percent, potential safety hazard and environmental pollution due to high consumption of the inflammable, explosive and volatile organic solvent are eliminated, the safety requirement level of the production field is reduced, production cost is greatly reduced, and the method is easy to operate and suitable for mass production and has high technical and economic feasibility.
Description
Technical field
The present invention relates to a kind of preparation method of cephalosporin medical material medicine, relate in particular to a kind of production method of cephalothin acid.
Background technology
Cephalothin acid (Cephalothin), chemical name is: (6R, 7R)-and the 3-[(acetoxyl group) methyl]-7-[2-(2-thienyl) kharophen]-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid, its chemical structure formula I is as follows:
（Ⅰ）
It is synthetic semi-synthetic cephamycin-type microbiotic-cefoxitin (English name: Cefoxitin; chemical name is: (6R; 7S)-and 3-carbamyl yloxymethyl-7-methoxyl group-8-oxo-7-[2-(2-thienyl) kharophen]-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-formic acid) main raw material of (II)
（Ⅱ）
What the production of cephalothin acid was both at home and abroad generally adopted at present is the solvent method production technique, and its technology is as follows:
1), reaction
In reactor, drop into the 500L purified water, and be cooled to about 5 ℃, behind the adding 50Kg7-ACA, drip 11%Na
2CO
3Solution dissolves by it, behind the input acetone 300L, drops into thiophen acetyl chloride/ethyl acetate mixed solution 525L(system this moment and can be warmed up to about 10 ℃, and temperature control is about 5 ℃), when treating that temperature is reduced to 5 ℃ of left and right sides, clock reaction 90min.After reaction finishes, static separatory, the water of telling lower floor changes in the extractor, and the organic phase on upper strata is discarded.Its chemical equation is as follows:
2), extraction
Water in the reaction is washed at twice with 500 L ethyl acetates, static separatory, after the aqueous phase after the washing drops into 500 L ethyl acetates once more, regulate pH value (transferring system PH is 1.4～1.5) with 20%HCL, static separatory: discarded lower floor water, upper organic phase keeps in the jar, with the sodium chloride solution about 500L15% organic phase is washed at twice, static separatory: lower floor's water is discarded, and the organic phase on upper strata is carried out subsequent operations.
3), decolouring
Add anhydrous magnesium sulfate 2Kg, activated carbon 2Kg in the organic phase, stir suction filtration behind 20 min, carry out washing leaching cake, merging filtrate with the 200L ethyl acetate.
4), crystallization
Filtrate put in the crystallizer and temperature control about 10 ℃, drip sherwood oil 875L and carry out crystallization 1h, static growing the grain 60 min, centrifuging (filter cake with sherwood oil 150L washing).
5) drying
Centrifugal wet product product is placed on vacuum drying oven, be dried to about 40 ℃ moisture after less than 1% the about 60-62Kg of cephalothin acid finished product.
Those skilled in the art once attempted above-mentioned technology is improved; a kind of preparation method of cephalothin acid is disclosed as Chinese patent application 200910074960.1; it is to add 7-ACA in haloalkane; drip silylating reagent and carry out the silanization protection; add thiophen acetyl chloride afterwards, acyl chloride reaction changes product over to water after finishing, and adds ethyl acetate in aqueous phase liquid; stir dripping hydrochloric acid down, growing the grain after-filtration, drying obtain product.Although the carboxyl that it adopts silylating reagent first silanization protection 7-ACA in haloalkane makes it be dissolved in fully in the haloalkane then, reduced the link of saltouing, decolour in the existing technology.
But there is following defective in such technology:
1) production cost height.Because reaction, separation, crystallizing system all carry out in organic solvent, needed organic solvent (comprising haloalkane, silylating reagent, acetone, ethyl acetate, sherwood oil etc.) wide in variety, consumption are very big, it consumes more than 20t/t, and the market price of organic solvent is all than higher, thereby increased production cost greatly.
2) technological operation requires height, and labour intensity is big.Because a large amount of addings of organic solvent have increased batching, discharging time, metering and operational requirement height, thus increased labor intensity of operating personnel greatly.
3) potential safety hazard is many, and environmental pollution is big.Because in the production process, big portion system is inflammable and explosive, volatile organic solvent, the production scene smell is big, safety requirements rank height, environmental pollution are big.
Summary of the invention:
The objective of the invention is to provides a kind of water method to produce the technology of cephalothin acid at the deficiency of prior art, and it can be avoided in a large number with an organic solvent, has simple to operately, and environmental pollution is little, and production cost is low, the advantage that technical and economic feasibility is good.
Technical scheme of the present invention is:
A kind of production method of cephalothin acid is a raw material with 7-amino-cephalo-alkanoic acid, it is characterized in that: the condensation reaction of described 7-amino-cephalo-alkanoic acid and 2-thiophene acetyl reagent is carried out in aqueous phase solvent.
As to further improvement of the present invention, described cephalothin acid production process comprises water condensation reaction, reaction product filtration, decolouring, Crystallization Separation, vacuum drying step successively, carries out according to the following steps:
Step 1: earlier solid 7-amino-cephalo-alkanoic acid is dissolved in the aqueous phase solvent under neutrality or alkaline condition, carry out condensation reaction with 2-thiophene acetyl reagent then, behind the reaction certain hour, add reaction terminating agent and make reaction terminating, make the reaction product post precipitation by reacting short heavy agent, filter, adopt organic solvent that filter residue is washed, the gained solid precipitation is the wet product of Glaxo);
Step 2: the wet product of Glaxo) are dissolved in the water, adding discoloring agent decolours, filtering separation is removed insoluble particle, the solvent that in filtrate, adds doses, with the pH acid regulator pH value of filtrate is transferred to 2.5-2.6, stir growing the grain 30-60min after, system is cooled off, crystal centrifugal, that separation obtains is the wet product of cephalothin acid, will promptly get the cefoxitin acid product after the wet product vacuum-drying of cephalothin acid.
As to further improvement of the present invention, 2-thiophene acetyl reagent is any in 2-thiophene acetic acid, 2-thiophene acetyl bromide, 2-thiophen acetyl chloride, the 2-thiophene acetic acid methyl esters.
As to further improvement of the present invention: the pH alkaline conditioner in the described step 1 is any in yellow soda ash, sodium-chlor or the sodium bicarbonate.
As to further improvement of the present invention: described reaction terminating agent is any in EDTA (disodium), sodium bisulfite, Sulfothiorine, the Sodium Pyrosulfite.
As to further improvement of the present invention: the water in the described step 1 is high purity deionized water.
As to further improvement of the present invention: the short heavy agent of described reaction is any or the mixture more than two kinds wherein in Sodium Bromide, sodium sulfate, the sodium-chlor.
As to further improvement of the present invention: the solvent in the described step 2 be in sherwood oil, acetone, the ethyl acetate any, two or more mixture wherein.
As to further improvement of the present invention: the pH acid regulator is any in sulfuric acid, hydrochloric acid or the phosphoric acid in the described step 2.
As to further improvement of the present invention: the vacuum-drying of the wet product of described cephalothin acid be under 40-44 ℃ temperature vacuum-drying to moisture content≤0.5%.
Reaction principle of the present invention is:
Condensation reaction:
Crystallization Separation:
(2-thiophene acetic acid) (X=Br, 2-thiophene acetyl bromide)
(X=Cl, 2-thiophen acetyl chloride)
(X=OCH
3, 2-thiophene acetic acid methyl esters)
Beneficial effect of the present invention is:
The characteristics that the condensation reaction that the present invention utilizes 7-amino-cephalo-alkanoic acid and 2-thiophene acetyl reagent can be carried out at aqueous phase solvent in certain pH value scope; make the wet product of Glaxo) at aqueous phase earlier; again the wet product of Glaxo) being finished it at aqueous phase makes with extra care; decolouring; its Crystallization Separation process also can be carried out at aqueous phase; only add a small amount of organic solvent in the whole process of production; compared to traditional solvent method production technique; the present invention has simplified production process; reduced requirement to equipment; significantly reduce the add-on of organic solvent, can save the organic solvent amount more than 70%, reduced raw-material consumption; reduced labour intensity; technological operation is simple, has reduced batching; discharging time, metering and operational requirement are relatively low; thereby reduced the operators'skills requirement; be convenient to production control, yield height, steady quality; significantly reduce production cost, be suitable for fairly largeization production.Eliminated inflammable and explosive because of a large amount of uses, that volatile organic solvent brought potential safety hazard and environmental pollution, production scene safety requirements rank is reduced, technical and economic feasibility is good.
Embodiment:
Embodiment 1:
A kind of water method is produced the production technique of cephalothin acid.Its process flow sheet carries out as shown in Figure 1 successively according to the following steps:
1) reaction
Under the room temperature, in reactor, add successively: deionized water 300L, 7-ACA50Kg, organic solvent acetic acid second fat 45L; Then within a certain period of time, room temperature condition adds the about 40.0Kg of alkaline conditioner yellow soda ash down, is stirred to 7-ACA and thoroughly dissolves.System temperature is cooled to about 10 ℃, in 150 min, add about 20 L of 2-thiophene acetyl reagent 2-thiophene acetyl bromide, after adding material, clock reaction reaction in 30 minutes end back adds reaction terminating agent Sodium Pyrosulfite 5.0Kg, be warming up to add under the certain temperature and urge the heavy about 60.0Kg of agent sodium-chlor, leave standstill 30min precipitation Glaxo); Carry out suction filtration at ambient temperature, and be promptly to get the wet product of Glaxo) after the solvent of 80 L washs at twice with total amount.Its chemical reaction engineering formula is as follows:
2) refining, decolouring
Under the room temperature, the wet Glaxo) behind the suction filtration is dissolved in the 600 L purified water deionized waters, adds discoloring agent medical activated carbon 5.0Kg, stir 30min, suction filtration, and, collect filtrate with 120L purified water and 75L solvent ethyl acetate washing filter and filter residue.
3) crystallization, drying
Collect the filtrate made from extra care after decolouring, at ambient temperature, with acid regulator phosphoric acid system pH is transferred to about 2.4-2.6, this process chemistry reaction engineering formula is as follows:
Stir growing the grain 45min, cooling suction filtration, and with the wet product of purified water washing of total amount 250L, taking-up wet product and under+42 ± 2 ℃ of vacuum dry 20-22 hour until H
2O≤0.5% promptly obtains the about 64.0-68.0Kg of cefoxitin acid product.
Embodiment 2:
A kind of water method is produced the production technique of cephalothin acid, carries out according to the following steps successively:
Under the room temperature, in reactor, add successively: deionized water 650L, 7-ACA100Kg, sherwood oil 100L; Then within a certain period of time, room temperature condition adds the about 85.0Kg of sodium bicarbonate down, is stirred to 7-ACA and thoroughly dissolves.System temperature is cooled to about 15 ℃, in 120 min, add about 45 L of 2-thiophen acetyl chloride, add material after, clock reaction reaction in 30 minutes finishes the back and adds sodium bisulfite 10.0Kg, be warming up to 20 ℃ and add the about 125.0Kg of Sodium Bromide down, leave standstill 30min precipitation Glaxo); Suction filtration under 10 ℃ of temperature, and be promptly to get the wet product of Glaxo) after the sherwood oil of 165 L washs at twice with total amount.
Embodiment 3:
The wet product of Glaxo) of embodiment 2 gained are dissolved in the 600 L purified water at ambient temperature, add medical activated carbon 5.0Kg, stir 30min, suction filtration, and, collect filtrate with 120L purified water and 75L ethyl acetate washing filter and filter residue.
Collect the filtrate after the refining decolouring, at ambient temperature, system pH transferred to about 2.4-2.6, stir growing the grain 1h with hydrochloric acid, cooling suction filtration, and with the wet product of purified water washing of total amount 250L, taking-up wet product and at+42 ± 2 ℃ of following vacuum-drying 20-22 hours until H
2O≤0.5% promptly obtains the about 64.0-68.0Kg of cefoxitin acid product.
Embodiment 4:
The wet product of Glaxo) of embodiment 2 gained are dissolved in the 1250 L purified water at ambient temperature, add medical activated carbon 10.5Kg, stir 30min, suction filtration, and, collect filtrate with 250L purified water and 160L washing with acetone strainer and filter cake.
Collect the filtrate made from extra care after decolouring, at ambient temperature, with dilute sulphuric acid system pH is transferred to about 2.4-2.6, stir growing the grain 35min, carry out centrifugation after being cooled to about about 10 ℃, and with the wet product of the purified water of total amount 550L washing, take out the product of wetting and at+42 ± 2 ℃ of following vacuum-drying 20-22 hours until H
2O≤0.5% promptly obtains the about 130.0-135.0Kg of cefoxitin acid product.
Claims (10)
1. the production method of a cephalothin acid is a raw material with 7-amino-cephalo-alkanoic acid, it is characterized in that: the condensation reaction of described 7-amino-cephalo-alkanoic acid and 2-thiophene acetyl reagent is carried out in aqueous phase solvent.
2. the production method of cephalothin acid according to claim 1, it is characterized in that: described cephalothin acid production process comprises water condensation reaction, reaction product filtration, decolouring, Crystallization Separation, vacuum drying step successively, carries out according to the following steps:
Step 1: earlier solid 7-amino-cephalo-alkanoic acid is dissolved in the aqueous phase solvent under neutrality or alkaline condition, carry out condensation reaction with 2-thiophene acetyl reagent then, behind the reaction certain hour, add reaction terminating agent and make reaction terminating, make the reaction product post precipitation by reacting short heavy agent, filter, adopt organic solvent that filter residue is washed, the gained solid precipitation is the wet product of Glaxo);
Step 2: the wet product of Glaxo) are dissolved in the water, adding discoloring agent decolours, filtering separation is removed insoluble particle, the solvent that in filtrate, adds doses, with the pH acid regulator pH value of filtrate is transferred to 2.4-2.6, stir growing the grain 30-60min after, system is cooled off, crystal centrifugal, that separation obtains is the wet product of cephalothin acid, will promptly get the cefoxitin acid product after the wet product vacuum-drying of cephalothin acid.
3. the production method of cephalothin acid according to claim 2, it is characterized in that: 2-thiophene acetyl reagent is any in 2-thiophene acetic acid, 2-thiophene acetyl bromide, 2-thiophen acetyl chloride, the 2-thiophene acetic acid methyl esters.
4. the production method of cephalothin acid according to claim 2, it is characterized in that: the pH alkaline conditioner in the described step 1 is any in yellow soda ash, sodium-chlor or the sodium bicarbonate.
5. the production method of cephalothin acid according to claim 2, it is characterized in that: described reaction terminating agent is any in EDTA (disodium), sodium bisulfite, Sulfothiorine, the Sodium Pyrosulfite.
6. the production method of cephalothin acid according to claim 2, it is characterized in that: the water in the described step 1 is high purity deionized water.
7. the production method of cephalothin acid according to claim 2 is characterized in that: the short heavy agent of described reaction is any or the mixture more than two kinds wherein in Sodium Bromide, sodium sulfate, the sodium-chlor.
8. the production method of cephalothin acid according to claim 2 is characterized in that: the solvent in the described step 2 be in sherwood oil, acetone, the ethyl acetate any, two or more mixture wherein.
9. the production method of cephalothin acid according to claim 2, it is characterized in that: the pH acid regulator is any in sulfuric acid, hydrochloric acid or the phosphoric acid in the described step 2.
10. the production method of cephalothin acid according to claim 2 is characterized in that: the vacuum-drying of the wet product of described cephalothin acid be under 40-44 ℃ temperature vacuum-drying to moisture content≤0.5%.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 201010288899 CN102040614A (en) | 2010-09-21 | 2010-09-21 | Method for producing cephalothin acid by water phase method |
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|---|---|---|---|
| CN 201010288899 CN102040614A (en) | 2010-09-21 | 2010-09-21 | Method for producing cephalothin acid by water phase method |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103242346A (en) * | 2013-05-21 | 2013-08-14 | 重庆替安科技有限公司 | Cefalonium preparation method |
| CN103772415A (en) * | 2013-12-31 | 2014-05-07 | 福建省福抗药业股份有限公司 | Method for preparing cephalonium from 7-aminocephalosporanic acid at one step |
| CN104447800A (en) * | 2014-11-21 | 2015-03-25 | 辽宁天华化工有限责任公司 | Synthesis technology of cefoxitin acid |
| CN104610280A (en) * | 2015-02-12 | 2015-05-13 | 浙江东邦药业有限公司 | Preparation method of cephalotin acid |
| CN106083895A (en) * | 2016-06-16 | 2016-11-09 | 河北莫兰斯环境科技股份有限公司 | A kind of method purifying recovery cefotaxime acid from Cefotaxime Sodium |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3218318A (en) * | 1962-08-31 | 1965-11-16 | Lilly Co Eli | 7-heterocyclic-substituted-acylamido cephalosporins |
| CN101613358A (en) * | 2009-07-23 | 2009-12-30 | 河北九派制药有限公司 | The preparation method of cephalothin acid |
-
2010
- 2010-09-21 CN CN 201010288899 patent/CN102040614A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3218318A (en) * | 1962-08-31 | 1965-11-16 | Lilly Co Eli | 7-heterocyclic-substituted-acylamido cephalosporins |
| CN101613358A (en) * | 2009-07-23 | 2009-12-30 | 河北九派制药有限公司 | The preparation method of cephalothin acid |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103242346A (en) * | 2013-05-21 | 2013-08-14 | 重庆替安科技有限公司 | Cefalonium preparation method |
| CN103772415A (en) * | 2013-12-31 | 2014-05-07 | 福建省福抗药业股份有限公司 | Method for preparing cephalonium from 7-aminocephalosporanic acid at one step |
| CN104447800A (en) * | 2014-11-21 | 2015-03-25 | 辽宁天华化工有限责任公司 | Synthesis technology of cefoxitin acid |
| CN104610280A (en) * | 2015-02-12 | 2015-05-13 | 浙江东邦药业有限公司 | Preparation method of cephalotin acid |
| CN106083895A (en) * | 2016-06-16 | 2016-11-09 | 河北莫兰斯环境科技股份有限公司 | A kind of method purifying recovery cefotaxime acid from Cefotaxime Sodium |
| CN106083895B (en) * | 2016-06-16 | 2019-01-29 | 河北莫兰斯环境科技股份有限公司 | A method of the purification and recovery cefotaxime acid from Cefotaxime Sodium |
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Application publication date: 20110504 |