CN104830940A - An enzymatic synthesis process of Amoxicillin - Google Patents
An enzymatic synthesis process of Amoxicillin Download PDFInfo
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- CN104830940A CN104830940A CN201510127738.9A CN201510127738A CN104830940A CN 104830940 A CN104830940 A CN 104830940A CN 201510127738 A CN201510127738 A CN 201510127738A CN 104830940 A CN104830940 A CN 104830940A
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- amoxycilline trihydrate
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Abstract
The invention relates to a synthesis method of medicines, and particularly relates to screening of an immobilized Amoxicillin synthase and an enzymatic synthesis process of Amoxicillin. The process includes immobilizing by adoption of an amino epoxy type carrier to obtain an immobilized Amoxicillin enzyme LK218, adding the immobilized Amoxicillin enzyme LK218, 6-aminopenicilanic acid and a D-p-hydroxyphenylglycine derivative into water, stirring, mixing to obtain a mixture, adjusting the pH value of the mixture by utilization of a hydrochloric acid solution and a sodium hydroxide solution, controlling the temperature and reaction time of the mixture, and finishing the reaction until the residual concentration of the 6-APA is 0-2 mg/mL. Aiming at problems, namely difficult screening and evaluation of immobilized enzymes, tedious production steps, poor reference points, long reaction time, low conversion ratios, and the like, the immobilized Amoxicillin enzyme and the novel synthesis process of the Amoxicillin are provided.
Description
Technical field
The present invention relates to a kind of synthetic method of medicine, specifically the screening of a kind of immobilization amoxycilline Trihydrate bp synthetic enzyme and a kind of processing method of enzymatic clarification amoxycilline Trihydrate bp.
Background technology
Amoxycilline Trihydrate bp, real name amoxycillin, be a kind of the most frequently used wide spectrum β-lactam antibitics, tool bacteriolysis, cures mainly the bacterial infection caused by susceptible microorganisms.Amoxycilline Trihydrate bp easy administration, security is high, good effect, and untoward reaction is few, cheap, enjoys the favor of doctor and patient.In Tri-Biocin, amoxycilline Trihydrate bp sales volume is come out top, and accounts for greatly 50% of world's Penicillin antibiotics total sales volume.
Since the mid-90 in 20th century, enzymatic clarification amoxycilline Trihydrate bp has been adopted to become research emphasis.Enzyme process is compared chemical method and have obvious advantage in environmental protection and cost.The technique that enzyme process prepares amoxycilline Trihydrate bp is short relative to flow process, and technique is simple, and bringing into and producing of impurity is less, without solvent and poisonous reagent in building-up process.
In the process of Production by Enzymes amoxycilline Trihydrate bp, the selection of immobilization amoxycilline Trihydrate bp synthetic enzyme is the key of enzyme method technique.Immobilization amoxycilline Trihydrate bp synthetic enzyme plays a part key to the yield of product, the content of impurity, the clarity etc. of product.In addition, the stability of immobilized enzyme determines its work-ing life and production cost.
Summary of the invention
For in the technique of existing enzymatic clarification amoxycilline Trihydrate bp, the screening of immobilized enzyme and evaluation difficulty, production craft step is loaded down with trivial details, reference mark is poor, long reaction time, the problems such as low conversion rate, the invention provides a kind of immobilization amoxycilline Trihydrate bp enzyme, and the novel process of synthesis amoxycilline Trihydrate bp.
Content of the present invention is passed through by following scheme:
A technique for enzymatic clarification amoxycilline Trihydrate bp, concrete steps are as follows:
(1) amino-epoxy type carrier immobilized being fixed amoxycilline Trihydrate bp enzyme LK218 is adopted;
With glutaraldehyde as cross linker; by the acylase that pseudomonas (Pseudomonas sp.) is originated; adopt covalent immobilization; being fixed amoxycilline Trihydrate bp enzyme LK218; immobilization amoxycilline Trihydrate bp enzyme LK218 is adopted to catalyze and synthesize amoxycilline Trihydrate bp; reaction times is short, and product yield is high, and purity is high.
(2) the immobilization amoxycilline Trihydrate bp enzyme LK218 of step (1) gained, 6-amino-penicillanic acid, D-pHPG derivative are added in water and are uniformly mixed, obtain mixed solution;
6-APA is that the English of 6-amino-penicillanic acid is write a Chinese character in simplified form;
The mol ratio of described 6-APA and D-pHPG derivative is 1/1.02 ~ 1.05, and the concentration of immobilization amoxycilline Trihydrate bp enzyme LK218 in reaction system is 5 ~ 20u/mL;
(3) with the hydrochloric acid soln of 3mol/L and the sodium hydroxide solution regulating step 2 of 1mol/L) the mixed solution pH value of gained is 6.2-6.4, control mixeding liquid temperature is 10-20 DEG C, reaction 40-80min, HPLC is adopted to carry out tracing detection, until 6-APA residual concentration is 0-2mg/mL, terminate reaction;
The preferred reaction time is 50-70min, reacts too short, low conversion rate, and reaction not exclusively; But the reaction times is long, amoxycilline Trihydrate bp starts hydrolysis.This reaction times is investigated out according to LK218 enzyme.
(4) step 3 is got) mixed solution of gained, by screen cloth, isolate reaction solution and immobilized enzyme;
Described screen cloth is 80-120 order, preferred 90-110 order; Sieve number is excessive, and immobilized enzyme is just easy to be revealed from screen cloth, and order number is too small, and amoxycilline Trihydrate bp crude product is just more difficult from screen cloth blowing;
(5) hydrochloric acid soln of reaction solution 6mol/L is clearly molten, then uses the ammonia soln crystallization of 6mol/L, growing the grain, washing, dry, obtains product amoxycilline Trihydrate bp.
Amino-epoxy type carrier described in step (1) is one or both combinations in polystyrene macroporous adsorbent resin, acrylic acid series macroporous adsorbent resin.
D-pHPG derivative described in step (2) is selected from one or more combinations in D-para hydroxybenzene glycine methyl ester, D-pHPG ethyl ester, D-para hydroxybenzene glycine methyl ester hydrochloride, D-pHPG carbethoxy hydrochloride.
6-APA residual concentration described in step (3) is 0-1mg/mL.
Screen cloth described in step (4) is 80-120 order.
Described in step (5) is 0.9-1.1 by acid-soluble clear pH value, and alkali crystallization pH is 5.0-5.2.
The amoxycilline Trihydrate bp purity more than 99.8% of described product, clarity is less than 0.5, reaction molar yield more than 92%.
Immobilized enzyme drops in aqueous phase by the present invention, only needs mother liquor and washed with de-ionized water to use after every secondary response again.6-APA and D-pHPG derivative is disposable in proportion adds.In reaction process, pH value is more stable.After having reacted, by screen cloth blowing.Be integrated into process, technique is simple, and easy to operate, the reaction times is short, energy consumption is low, pollution is few.Products obtained therefrom quality is good, and yield is high.Therefore, the present invention is a kind of high efficiency green production process.
About innovative point of the present invention, can be set forth by following aspect:
(1) immobilized enzyme can reclaim and reuse, and reduces cost.Immobilized enzyme performance is more stable in addition.After reaction, be easier to be separated.In addition, be also convenient to transport, store and automated operation.
(2) LK218 enzyme is the kind of new research and development, and prior art does not also use this product.In addition, with commercially available analogous products first than, in catalytic reaction process, the reaction times is shorter, and reacted amoxicillin products better quality, yield is higher.
(3) 1) reaction times is short, compares commercially available like product, and average reaction time shortens half; 2) product purity is high, can reach more than 99.8%; 3) yield is high, and molar yield compares current commercially available prod, can improve 1%; 4) clarity is better, be less than 0.5, and commercially available prod clarity is less than 1.
Accompanying drawing explanation
When Fig. 1 is reference substance enzyme catalysis 6-APA transformation efficiency with batch variation relation;
Fig. 2 be reference substance enzyme time of turning white of representing fade performance with batch variation relation;
When Fig. 3 is LK218 enzyme catalysis 6-APA transformation efficiency with batch variation relation;
Fig. 4 be LK218 enzyme attenuation with batch variation relation.
Embodiment
The present invention illustrates the present invention by comparative example and embodiment, but does not limit the present invention in any form.
Embodiment one
In the reactor, the immobilization amoxycilline Trihydrate bp synthetic enzyme LK218 of 1300u is added in the deionized water of 130mL, opens and stir.Add the D-para hydroxybenzene glycine methyl ester of 6-APA and 0.0612mol of 0.06mol.Add sodium hydroxide, adjust pH value in reaction to 6.3.Maintenance temperature of reaction is 19-20 DEG C.Reaction 55min.Reaction solution is separated with immobilization amoxycilline Trihydrate bp synthetic enzyme.Products therefrom hydrochloric acid adjusts pH to 0.9-1.1 to dissolve, and filters, with the crystallization of sodium hydroxide adjust pH, and terminal pH5.0-5.2.After 0-5 DEG C of growing the grain 1h, washing, dry, obtain amoxycilline Trihydrate bp finished product.
Embodiment two
In the reactor, the immobilization amoxycilline Trihydrate bp synthetic enzyme LK218 of 1300u is added in the deionized water of 130mL, opens and stir.Add the D-para hydroxybenzene glycine methyl ester hydrochloride of 6-APA and 0.0618mol of 0.06mol.Add sodium hydroxide, adjust pH value in reaction to 6.3.Maintenance temperature of reaction is 14-15 DEG C.Reaction 65min.Reaction solution is separated with immobilization amoxycilline Trihydrate bp synthetic enzyme.Products therefrom hydrochloric acid adjusts pH to 0.9-1.1 to dissolve, and filters, with the crystallization of sodium hydroxide adjust pH, and terminal pH5.0-5.2.After 0-5 DEG C of growing the grain 1h, washing, dry, obtain amoxycilline Trihydrate bp finished product.
Embodiment three
In the reactor, the immobilization amoxycilline Trihydrate bp synthetic enzyme LK218 of 1300u is added in the deionized water of 130mL, opens and stir.Add the D-para hydroxybenzene glycine methyl ester of 6-APA and 0.0612mol of 0.06mol.Add sodium hydroxide, adjust pH value in reaction to 6.3.Maintenance temperature of reaction is 10-11 DEG C.Reaction 70min.Reaction solution is separated with immobilization amoxycilline Trihydrate bp synthetic enzyme.Products therefrom hydrochloric acid adjusts pH to 0.9-1.1 to dissolve, and filters, with the crystallization of sodium hydroxide adjust pH, and terminal pH5.0-5.2.After 0-5 DEG C of growing the grain 1h, washing, dry, obtain amoxycilline Trihydrate bp finished product.
Embodiment four
In the reactor, the immobilization amoxycilline Trihydrate bp synthetic enzyme LK218 of 1300u is added in the deionized water of 130mL, opens and stir.Add the D-para hydroxybenzene glycine methyl ester of 6-APA and 0.063mol of 0.06mol.Add sodium hydroxide, adjust pH value in reaction to 6.3.Maintenance temperature of reaction is 19-20 DEG C.Reaction 50min.Reaction solution is separated with immobilization amoxycilline Trihydrate bp synthetic enzyme.Products therefrom hydrochloric acid adjusts pH to 0.9-1.1 to dissolve, and filters, with the crystallization of sodium hydroxide adjust pH, and terminal pH5.0-5.2.After 0-5 DEG C of growing the grain 1h, washing, dry, obtain amoxycilline Trihydrate bp finished product.
Embodiment five
In the reactor, the immobilization amoxycilline Trihydrate bp synthetic enzyme LK218 of 1040u is added in the deionized water of 130mL, opens and stir.Add the D-para hydroxybenzene glycine methyl ester of 6-APA and 0.0624mol of 0.06mol.Add sodium hydroxide, adjust pH value in reaction to 6.3.Maintenance temperature of reaction is 16-17 DEG C.Reaction 70min.Reaction solution is separated with immobilization amoxycilline Trihydrate bp synthetic enzyme.Products therefrom hydrochloric acid adjusts pH to 0.9-1.1 to dissolve, and filters, with the crystallization of sodium hydroxide adjust pH, and terminal pH5.0-5.2.After 0-5 DEG C of growing the grain 1h, washing, dry, obtain amoxycilline Trihydrate bp finished product.
Embodiment six
In the reactor, the immobilization amoxycilline Trihydrate bp synthetic enzyme LK218 of 260u is added in the deionized water of 130mL, opens and stir.Add the D-para hydroxybenzene glycine methyl ester of 6-APA and 0.063mol of 0.06mol.Add sodium hydroxide, adjust pH value in reaction to 6.3.Maintenance temperature of reaction is 19-20 DEG C.Reaction 70min.Reaction solution is separated with immobilization amoxycilline Trihydrate bp synthetic enzyme.Products therefrom hydrochloric acid adjusts pH to 0.9-1.1 to dissolve, and filters, with the crystallization of sodium hydroxide adjust pH, and terminal pH5.0-5.2.After 0-5 DEG C of growing the grain 1h, washing, dry, obtain amoxycilline Trihydrate bp finished product.
Experimental example
The catalytic performance of 1, immobilized enzyme LK218 is investigated
The contrast of immobilized enzyme LK218 and reference substance (the Fu Laige immobilization amoxycilline Trihydrate bp synthetic enzyme that existing market consumption is maximum) catalytic performance:
(1) reference substance immobilized enzyme:
Reference substance immobilized enzyme has carried out the multiple batches of performance catalyzing and synthesizing amoxycilline Trihydrate bp, 6-APA transformation efficiency with batch variation relation as shown in Figure 1.The time of turning white that reference substance enzyme represents fade performance with batch change as shown in Figure 2.As can be seen from Figure 1, reference substance enzyme 6-APA transformation efficiency with batch change totally steady, average conversion is 97.06%.As can be seen from Figure 2, the time attenuation slope that turns white is 0.0446.
(2) immobilization amoxycilline Trihydrate bp synthetic enzyme LK218:
When immobilized enzyme LK218 catalyzes and synthesizes amoxycilline Trihydrate bp, 6-APA transformation efficiency with batch variation relation as shown in Figure 3.The time of turning white that immobilized enzyme LK218 represents fade performance with batch change as shown in Figure 4.As shown in Figure 3, during immobilized enzyme LK218 catalysis, 6-APA transformation efficiency is more stable, and average conversion is 97.59%.As shown in Figure 4, the time attenuation slope that turns white is 0.0261.
Find out from above-mentioned contrast, during immobilized enzyme LK218 catalyzed reaction, 6-APA transformation efficiency is higher than reference substance, and reaction batch is many, and attenuation slope is little, more stable.
2, performance test is carried out to the amoxicillin products of embodiment one ~ six gained
Purity, single assorted, total assorted main HPLC detect; The main detection side of clarity (position) method is the method for Chinese Pharmacopoeia.
Detected result is as shown in the table:
From above result: present invention process is simple, and easy to operate, the reaction times is short, energy consumption is low, pollution is few.Products obtained therefrom quality is good, and yield is high.Therefore, the present invention is a kind of high efficiency green production process.
Claims (6)
1. a technique for enzymatic clarification amoxycilline Trihydrate bp, is characterized in that, concrete steps are as follows:
(1) amino-epoxy type carrier immobilized being fixed amoxycilline Trihydrate bp enzyme LK218 is adopted;
(2) the immobilization amoxycilline Trihydrate bp enzyme LK218 of step (1) gained, 6-amino-penicillanic acid, D-pHPG derivative are added in water and are uniformly mixed, obtain mixed solution;
The mol ratio of described 6-APA and D-pHPG derivative is 1/1.02 ~ 1.05, and the concentration of immobilization amoxycilline Trihydrate bp enzyme LK218 in reaction system is 5 ~ 20u/mL;
(3) with the hydrochloric acid soln of 3mol/L and the sodium hydroxide solution regulating step 2 of 1mol/L) the mixed solution pH value of gained is 6.2-6.4, control mixeding liquid temperature is 10-20 DEG C, reaction 40-80min, until 6-APA residual concentration is 0-2mg/mL, terminates reaction;
(4) step 3 is got) mixed solution of gained, by screen cloth, isolate reaction solution and immobilized enzyme;
(5) hydrochloric acid soln of reaction solution 6mol/L is clearly molten, then uses the ammonia soln crystallization of 6mol/L, growing the grain, washing, dry, obtains product amoxycilline Trihydrate bp.
2. the technique of enzymatic clarification amoxycilline Trihydrate bp as claimed in claim 1, is characterized in that, the amino-epoxy type carrier described in step (1) is one or both combinations in polystyrene macroporous adsorbent resin, acrylic acid series macroporous adsorbent resin.
3. the technique of enzymatic clarification amoxycilline Trihydrate bp as claimed in claim 1, it is characterized in that, the D-pHPG derivative described in step (2) is selected from one or more combinations in D-para hydroxybenzene glycine methyl ester, D-pHPG ethyl ester, D-para hydroxybenzene glycine methyl ester hydrochloride, D-pHPG carbethoxy hydrochloride.
4. the technique of enzymatic clarification amoxycilline Trihydrate bp as claimed in claim 1, it is characterized in that, the 6-APA residual concentration described in step (3) is 0-1mg/mL.
5. the technique of enzymatic clarification amoxycilline Trihydrate bp as claimed in claim 1, it is characterized in that, the screen cloth described in step (4) is 80-120 order.
6. the technique of enzymatic clarification amoxycilline Trihydrate bp as claimed in claim 1, it is characterized in that, described in step (5) is 0.9-1.1 by acid-soluble clear pH value, and alkali crystallization pH is 5.0-5.2.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106244660A (en) * | 2016-08-25 | 2016-12-21 | 艾美科健（中国）生物医药有限公司 | A kind of technique of enzymatic clarification cefdinir |
| CN106434616A (en) * | 2016-12-19 | 2017-02-22 | 山东思科新材料有限公司 | Preparation and application method of immobilized esterifying enzyme for baijiu |
| CN109867687A (en) * | 2017-12-05 | 2019-06-11 | 上海朝瑞化工有限公司 | A kind of highly-water-soluble Amoxicillin and preparation method thereof |
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| CN102660621A (en) * | 2012-05-04 | 2012-09-12 | 联邦制药(内蒙古)有限公司 | Improved method for preparing amoxicillin by enzymic method |
| CN104357528A (en) * | 2014-10-29 | 2015-02-18 | 国药集团威奇达药业有限公司 | Method for comprehensively recovering effective ingredients in amoxicillin mother liquid prepared by enzyme process |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102660621A (en) * | 2012-05-04 | 2012-09-12 | 联邦制药(内蒙古)有限公司 | Improved method for preparing amoxicillin by enzymic method |
| CN104357528A (en) * | 2014-10-29 | 2015-02-18 | 国药集团威奇达药业有限公司 | Method for comprehensively recovering effective ingredients in amoxicillin mother liquid prepared by enzyme process |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106244660A (en) * | 2016-08-25 | 2016-12-21 | 艾美科健（中国）生物医药有限公司 | A kind of technique of enzymatic clarification cefdinir |
| CN106434616A (en) * | 2016-12-19 | 2017-02-22 | 山东思科新材料有限公司 | Preparation and application method of immobilized esterifying enzyme for baijiu |
| CN109867687A (en) * | 2017-12-05 | 2019-06-11 | 上海朝瑞化工有限公司 | A kind of highly-water-soluble Amoxicillin and preparation method thereof |
| CN109867687B (en) * | 2017-12-05 | 2021-08-17 | 上海朝瑞化工有限公司 | High water-soluble amoxicillin and preparation method thereof |
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Address after: 272073 Shandong city of Jining province high tech Zone Shixian Road No. 1688 Applicant after: Amy Kejian (Chinese) Biological Medicine Co Ltd Address before: 272073 Shandong city of Jining province Shixian Road No. 1688 Applicant before: SHANDONG LUKANG RECORD PHARMACEUTICALS CO., LTD. |
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Application publication date: 20150812 |